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prion
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prion
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[
"Gerstmann-Sträussler-Scheinker Syndrome (GSS)",
"Genetic Creutzfeldt-Jakob Disease (Genetic CJD)",
"Fatal Familial Insomnia (FFI)",
"Major prion protein",
"PRNP",
"Genetic Prion Disease"
] |
Genetic Prion Disease
|
Inga Zerr, Matthias Schmitz
|
Summary Genetic prion disease generally manifests with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs). The order of appearance and/or predominance of these features and other associated neurologic and psychiatric findings vary. The three major phenotypes of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker (GSS) syndrome. Although these phenotypes display overlapping clinical and pathologic features, recognition of these phenotypes can be useful when providing affected individuals and their families with information about the expected clinical course. The age at onset typically ranges from 50 to 60 years. The disease course ranges from a few months in gCJD and FFI to a few (up to 4, and in rare cases up to 10) years in GSS syndrome. The diagnosis of genetic prion disease is established in a proband with suggestive findings and a heterozygous Genetic prion disease is inherited in an autosomal dominant manner. Some individuals diagnosed with genetic prion disease may have a parent who is heterozygous for a
|
Genetic Creutzfeldt-Jakob Disease (genetic CJD)
Fatal familial insomnia (FFI)
Gerstmann-Sträussler-Scheinker syndrome (GSS)
May also be referred to as familial CJD
• Genetic Creutzfeldt-Jakob Disease (genetic CJD)
• Fatal familial insomnia (FFI)
• Gerstmann-Sträussler-Scheinker syndrome (GSS)
## Diagnosis
Genetic prion disease should be suspected in individuals with the following clinical, laboratory, and imaging findings and family history.
Genetic prion disease is a progressive neurodegenerative syndrome with rapid evolution of clinical signs (which reflect involvement of various neuroanatomic structures) – typically, dementia in combination with the following developing within a few months or (rarely) a few years:
Extrapyramidal/pyramidal involvement
Ataxia
Myoclonus
In fatal familial insomnia (FFI) early autonomic disturbances and weight loss are frequent.
Cerebrospinal fluid analysis may be abnormal with high levels of 14-3-3 protein and protein tau.
Abnormally conformed prion protein using aggregation assays (RT QuIC) is typically positive in genetic Creutzfeldt-Jakob disease (gCJD), but not always in FFI or Gerstmann-Sträussler-Scheinker syndrome (GSS).
In some individuals with genetic CJD, MRI may display high signal abnormalities in the basal ganglia (caudate nucleus) and cortical areas, mostly in diffusion-weighted imaging (DWI), but also T
In individuals with FFI and GSS, MRI is typically not suggestive.
Family history is consistent with autosomal dominant inheritance (i.e., multiple affected family members in successive generations or a single affected family member). Absence of a known family history does not preclude the diagnosis.
The diagnosis of genetic prion disease is established in a proband with
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
P102L (c.305C>T; p.Pro102Leu)
D178N (c.532G>A; p.Asp178Asn)
V180I (c.538G>A; p.Val180Ile)
E200K (c.598G>A; p.Glu200Lys)
V210I (c.628G>A; p.Val210Ile)
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Genetic Prion 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
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.
• Extrapyramidal/pyramidal involvement
• Ataxia
• Myoclonus
• In some individuals with genetic CJD, MRI may display high signal abnormalities in the basal ganglia (caudate nucleus) and cortical areas, mostly in diffusion-weighted imaging (DWI), but also T
• In individuals with FFI and GSS, MRI is typically not suggestive.
• P102L (c.305C>T; p.Pro102Leu)
• D178N (c.532G>A; p.Asp178Asn)
• V180I (c.538G>A; p.Val180Ile)
• E200K (c.598G>A; p.Glu200Lys)
• V210I (c.628G>A; p.Val210Ile)
## Suggestive Findings
Genetic prion disease should be suspected in individuals with the following clinical, laboratory, and imaging findings and family history.
Genetic prion disease is a progressive neurodegenerative syndrome with rapid evolution of clinical signs (which reflect involvement of various neuroanatomic structures) – typically, dementia in combination with the following developing within a few months or (rarely) a few years:
Extrapyramidal/pyramidal involvement
Ataxia
Myoclonus
In fatal familial insomnia (FFI) early autonomic disturbances and weight loss are frequent.
Cerebrospinal fluid analysis may be abnormal with high levels of 14-3-3 protein and protein tau.
Abnormally conformed prion protein using aggregation assays (RT QuIC) is typically positive in genetic Creutzfeldt-Jakob disease (gCJD), but not always in FFI or Gerstmann-Sträussler-Scheinker syndrome (GSS).
In some individuals with genetic CJD, MRI may display high signal abnormalities in the basal ganglia (caudate nucleus) and cortical areas, mostly in diffusion-weighted imaging (DWI), but also T
In individuals with FFI and GSS, MRI is typically not suggestive.
Family history is consistent with autosomal dominant inheritance (i.e., multiple affected family members in successive generations or a single affected family member). Absence of a known family history does not preclude the diagnosis.
• Extrapyramidal/pyramidal involvement
• Ataxia
• Myoclonus
• In some individuals with genetic CJD, MRI may display high signal abnormalities in the basal ganglia (caudate nucleus) and cortical areas, mostly in diffusion-weighted imaging (DWI), but also T
• In individuals with FFI and GSS, MRI is typically not suggestive.
## Clinical
Genetic prion disease is a progressive neurodegenerative syndrome with rapid evolution of clinical signs (which reflect involvement of various neuroanatomic structures) – typically, dementia in combination with the following developing within a few months or (rarely) a few years:
Extrapyramidal/pyramidal involvement
Ataxia
Myoclonus
In fatal familial insomnia (FFI) early autonomic disturbances and weight loss are frequent.
• Extrapyramidal/pyramidal involvement
• Ataxia
• Myoclonus
## Laboratory
Cerebrospinal fluid analysis may be abnormal with high levels of 14-3-3 protein and protein tau.
Abnormally conformed prion protein using aggregation assays (RT QuIC) is typically positive in genetic Creutzfeldt-Jakob disease (gCJD), but not always in FFI or Gerstmann-Sträussler-Scheinker syndrome (GSS).
## Imaging
In some individuals with genetic CJD, MRI may display high signal abnormalities in the basal ganglia (caudate nucleus) and cortical areas, mostly in diffusion-weighted imaging (DWI), but also T
In individuals with FFI and GSS, MRI is typically not suggestive.
• In some individuals with genetic CJD, MRI may display high signal abnormalities in the basal ganglia (caudate nucleus) and cortical areas, mostly in diffusion-weighted imaging (DWI), but also T
• In individuals with FFI and GSS, MRI is typically not suggestive.
## Family History
Family history is consistent with autosomal dominant inheritance (i.e., multiple affected family members in successive generations or a single affected family member). Absence of a known family history does not preclude the diagnosis.
## Establishing the Diagnosis
The diagnosis of genetic prion disease is established in a proband with
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
P102L (c.305C>T; p.Pro102Leu)
D178N (c.532G>A; p.Asp178Asn)
V180I (c.538G>A; p.Val180Ile)
E200K (c.598G>A; p.Glu200Lys)
V210I (c.628G>A; p.Val210Ile)
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Genetic Prion 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
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.
• P102L (c.305C>T; p.Pro102Leu)
• D178N (c.532G>A; p.Asp178Asn)
• V180I (c.538G>A; p.Val180Ile)
• E200K (c.598G>A; p.Glu200Lys)
• V210I (c.628G>A; p.Val210Ile)
## Option 1
P102L (c.305C>T; p.Pro102Leu)
D178N (c.532G>A; p.Asp178Asn)
V180I (c.538G>A; p.Val180Ile)
E200K (c.598G>A; p.Glu200Lys)
V210I (c.628G>A; p.Val210Ile)
For an introduction to multigene panels click
• P102L (c.305C>T; p.Pro102Leu)
• D178N (c.532G>A; p.Asp178Asn)
• V180I (c.538G>A; p.Val180Ile)
• E200K (c.598G>A; p.Glu200Lys)
• V210I (c.628G>A; p.Val210Ile)
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Genetic Prion 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
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
Genetic prion disease generally manifests with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs). The order of appearance and/or predominance of these features and other associated neurologic and psychiatric findings vary. The three major phenotypes of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker (GSS) syndrome. Although these phenotypes display overlapping clinical and pathologic features, recognition of these phenotypes can be useful when providing affected individuals and their families with information about the expected clinical course. The age at onset typically ranges from ages 50 to 60 years. The disease course ranges from a few months in gCJD and FFI to a few (up to 4, and in rare cases up to 10) years in GSS syndrome.
Select Features of Genetic Prion Disease by Phenotype and
Adapted from
Genetic prion disease caused by pathogenic variants
A prodromal phase with marked autonomic disturbances, hyperhidrosis, weight loss, and sleep disturbances is common. Polysomnography shows complete disruption of the physiologic EEG sleep pattern.
After a nonspecific stage as described for gCJD, affected individuals develop progressive dementia, ataxia, muscle rigidity and involuntary movements. At the end stage of the disease, the clinical manifestations are similar to those of other genetic prion disease phenotypes.
The median age at onset is between 50 and 60 years. The median survival is 16 months. See
The typical clinical manifestations are a rapidly progressive cerebellar syndrome with ataxia at onset followed by cognitive decline and other neurologic signs within a few weeks, or at most a few months.
The typical age at onset, earlier than in the other genetic prion diseases, is early in the sixth decade (51 years) with disease duration typically up to four years.
Typical GSS syndrome with early ataxia, late dementia, and long disease duration (up to 4 years)
GSS syndrome beginning with areflexia and paresthesias, and later ataxia and dementia
Pure dementia GSS syndrome with early onset (age 35 years) with predominant dementia and late ataxia
Creutzfeldt-Jakob disease-like GSS syndrome with dementia and ataxia at onset and rapid disease progression
Although some
Note that the phenotype may be modified by the presence of the polymorphic codon 129 (p.Asp178Asn) on the same allele as the
The penetrance for genetic prion disease in general is assumed to be 100%; however, only a limited number of studies have been performed to address this issue.
The penetrance for the E200K variant (which has been studied more extensively than for other variants) was 60%-70% in Italian and Slovak families [
Epidemiologic studies utilizing reports of prion disease from centers around the world are frequently consistent with respect to the prevalence of genetic prion disease, as 15% of all individuals with newly diagnosed prion disease have genetic prion disease (i.e., are heterozygous for a
The E200K variant has been identified in populations worldwide, including in Slovakia, in Jewish families from Libya, Chile, and Tunisia, and in individuals of non-Jewish origin in other countries. Studies of ancestral origins by microsatellite markers flanking
• Typical GSS syndrome with early ataxia, late dementia, and long disease duration (up to 4 years)
• GSS syndrome beginning with areflexia and paresthesias, and later ataxia and dementia
• Pure dementia GSS syndrome with early onset (age 35 years) with predominant dementia and late ataxia
• Creutzfeldt-Jakob disease-like GSS syndrome with dementia and ataxia at onset and rapid disease progression
## Clinical Description
Genetic prion disease generally manifests with cognitive difficulties, ataxia, and myoclonus (abrupt jerking movements of muscle groups and/or entire limbs). The order of appearance and/or predominance of these features and other associated neurologic and psychiatric findings vary. The three major phenotypes of genetic prion disease are genetic Creutzfeldt-Jakob disease (gCJD), fatal familial insomnia (FFI), and Gerstmann-Sträussler-Scheinker (GSS) syndrome. Although these phenotypes display overlapping clinical and pathologic features, recognition of these phenotypes can be useful when providing affected individuals and their families with information about the expected clinical course. The age at onset typically ranges from ages 50 to 60 years. The disease course ranges from a few months in gCJD and FFI to a few (up to 4, and in rare cases up to 10) years in GSS syndrome.
Select Features of Genetic Prion Disease by Phenotype and
Adapted from
Genetic prion disease caused by pathogenic variants
A prodromal phase with marked autonomic disturbances, hyperhidrosis, weight loss, and sleep disturbances is common. Polysomnography shows complete disruption of the physiologic EEG sleep pattern.
After a nonspecific stage as described for gCJD, affected individuals develop progressive dementia, ataxia, muscle rigidity and involuntary movements. At the end stage of the disease, the clinical manifestations are similar to those of other genetic prion disease phenotypes.
The median age at onset is between 50 and 60 years. The median survival is 16 months. See
The typical clinical manifestations are a rapidly progressive cerebellar syndrome with ataxia at onset followed by cognitive decline and other neurologic signs within a few weeks, or at most a few months.
The typical age at onset, earlier than in the other genetic prion diseases, is early in the sixth decade (51 years) with disease duration typically up to four years.
Typical GSS syndrome with early ataxia, late dementia, and long disease duration (up to 4 years)
GSS syndrome beginning with areflexia and paresthesias, and later ataxia and dementia
Pure dementia GSS syndrome with early onset (age 35 years) with predominant dementia and late ataxia
Creutzfeldt-Jakob disease-like GSS syndrome with dementia and ataxia at onset and rapid disease progression
• Typical GSS syndrome with early ataxia, late dementia, and long disease duration (up to 4 years)
• GSS syndrome beginning with areflexia and paresthesias, and later ataxia and dementia
• Pure dementia GSS syndrome with early onset (age 35 years) with predominant dementia and late ataxia
• Creutzfeldt-Jakob disease-like GSS syndrome with dementia and ataxia at onset and rapid disease progression
## Genetic Creutzfeldt-Jakob Disease (gCJD)
Genetic prion disease caused by pathogenic variants
## Fatal Familial Insomnia (FFI)
A prodromal phase with marked autonomic disturbances, hyperhidrosis, weight loss, and sleep disturbances is common. Polysomnography shows complete disruption of the physiologic EEG sleep pattern.
After a nonspecific stage as described for gCJD, affected individuals develop progressive dementia, ataxia, muscle rigidity and involuntary movements. At the end stage of the disease, the clinical manifestations are similar to those of other genetic prion disease phenotypes.
The median age at onset is between 50 and 60 years. The median survival is 16 months. See
## Gerstmann-Sträussler-Scheinker (GSS) Syndrome
The typical clinical manifestations are a rapidly progressive cerebellar syndrome with ataxia at onset followed by cognitive decline and other neurologic signs within a few weeks, or at most a few months.
The typical age at onset, earlier than in the other genetic prion diseases, is early in the sixth decade (51 years) with disease duration typically up to four years.
Typical GSS syndrome with early ataxia, late dementia, and long disease duration (up to 4 years)
GSS syndrome beginning with areflexia and paresthesias, and later ataxia and dementia
Pure dementia GSS syndrome with early onset (age 35 years) with predominant dementia and late ataxia
Creutzfeldt-Jakob disease-like GSS syndrome with dementia and ataxia at onset and rapid disease progression
• Typical GSS syndrome with early ataxia, late dementia, and long disease duration (up to 4 years)
• GSS syndrome beginning with areflexia and paresthesias, and later ataxia and dementia
• Pure dementia GSS syndrome with early onset (age 35 years) with predominant dementia and late ataxia
• Creutzfeldt-Jakob disease-like GSS syndrome with dementia and ataxia at onset and rapid disease progression
## Genotype-Phenotype Correlations
Although some
Note that the phenotype may be modified by the presence of the polymorphic codon 129 (p.Asp178Asn) on the same allele as the
## Penetrance
The penetrance for genetic prion disease in general is assumed to be 100%; however, only a limited number of studies have been performed to address this issue.
The penetrance for the E200K variant (which has been studied more extensively than for other variants) was 60%-70% in Italian and Slovak families [
## Prevalence
Epidemiologic studies utilizing reports of prion disease from centers around the world are frequently consistent with respect to the prevalence of genetic prion disease, as 15% of all individuals with newly diagnosed prion disease have genetic prion disease (i.e., are heterozygous for a
The E200K variant has been identified in populations worldwide, including in Slovakia, in Jewish families from Libya, Chile, and Tunisia, and in individuals of non-Jewish origin in other countries. Studies of ancestral origins by microsatellite markers flanking
## Genetically Related (Allelic) Disorders
No phenotypes other than those of genetic prion disease that are discussed in this
## Differential Diagnosis
Because of the progressive neurologic decline, the range of neurologic signs, and the heterogeneous presentation of genetic prion disease, the differential diagnosis is broad and needs to include other hereditary neurodegenerative disorders as well as a variety of acquired disorders. Because potential treatment options depend on identification of the underlying cause, autoimmune and paraneoplastic disorders need to be considered (see
Disorders Potentially Associated with Rapid Progression of Interest in the Differential Diagnosis of Genetic Prior Disease
Adapted from
ALS = amyotrophic lateral sclerosis; CNS = central nervous system; FTD = frontotemporal dementia; HIV = human immunodeficiency virus; IBMPFD = inclusion body myopathy associated with Paget disease of bone and/or frontotemporal dementia
Listed genes are associated with early-onset familial Alzheimer disease (EOFAD): Alzheimer disease that occurs in multiple members of a family with a mean onset usually before age 65 years. EOFAD represents fewer than 2% of Alzheimer disease cases. Late-onset familial Alzheimer disease (age >60-65 years), representing 15%-25% of Alzheimer disease cases, is thought to be a complex disorder possibly involving multiple susceptibility genes (see
See
See
The hereditary ataxias are a large group of autosomal dominant, autosomal recessive, and X-linked disorders characterized by slowly progressive incoordination of gait and often associated with poor coordination of hands, speech, and eye movements; see
See
For a detailed review of disorders to consider in an individual with rapidly progressive dementia, see
## Other Prion Diseases
## Management
To establish the extent of disease and needs in an individual diagnosed with genetic prion disease, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Because of very rapid disease progression and short survival time after the diagnosis, evaluations for supportive care must be performed early. They include the following:
Need for gastrostomy tube feeding for nutrition and to reduce risk of aspiration
Evaluation for bladder and bowel incontinence
Need for physical therapy and occupational therapy for mobility and activities of daily living
Psychiatric manifestations
Consultation with a social worker (or other medical professional) to determine need for:
Caregiver support including use of community resources &
Specific 24-hour/day care assistance
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 genetic prion disease in order to facilitate medical and personal decision making
No treatment of the underlying cause of genetic prion disease is available. Only a few controlled trials have been performed. Some data point toward slowing of disease progression with doxycycline (100-200 mg/day) when administered early in the disease course [
Supportive care by a multidisciplinary team of specialists including neurologists, psychiatrists, physical therapists, occupational therapists, speech and language therapists, and social workers is recommended.
Symptomatic treatment may include the following:
For psychiatric manifestations such as depression or psychosis, antidepressant or neuroleptic treatment
Myoclonic jerks respond well to clonazepam.
Muscle rigidity may require dopamine or dopaminergic drugs.
Spasticity may respond to regular antispastic medication.
Physical therapy for exercises and/or stretching to prevent contractures; durable medical devices for positioning and/or mobility
Occupational therapy for home adaptation to improve safety and activities of daily living
Feeding issues addressed by nutritionists, speech pathologists
Communication (including alternative means of communication) by speech pathologists
Because of very rapid disease progression, close periodic monitoring by the multidisciplinary team is needed, typically every 14 days to evaluate need for treatment of symptoms.
See
Search
• Need for gastrostomy tube feeding for nutrition and to reduce risk of aspiration
• Evaluation for bladder and bowel incontinence
• Need for physical therapy and occupational therapy for mobility and activities of daily living
• Psychiatric manifestations
• Consultation with a social worker (or other medical professional) to determine need for:
• Caregiver support including use of community resources &
• Specific 24-hour/day care assistance
• Caregiver support including use of community resources &
• Specific 24-hour/day care assistance
• 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 genetic prion disease in order to facilitate medical and personal decision making
• Caregiver support including use of community resources &
• Specific 24-hour/day care assistance
• For psychiatric manifestations such as depression or psychosis, antidepressant or neuroleptic treatment
• Myoclonic jerks respond well to clonazepam.
• Muscle rigidity may require dopamine or dopaminergic drugs.
• Spasticity may respond to regular antispastic medication.
• Physical therapy for exercises and/or stretching to prevent contractures; durable medical devices for positioning and/or mobility
• Occupational therapy for home adaptation to improve safety and activities of daily living
• Feeding issues addressed by nutritionists, speech pathologists
• Communication (including alternative means of communication) by speech pathologists
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with genetic prion disease, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Because of very rapid disease progression and short survival time after the diagnosis, evaluations for supportive care must be performed early. They include the following:
Need for gastrostomy tube feeding for nutrition and to reduce risk of aspiration
Evaluation for bladder and bowel incontinence
Need for physical therapy and occupational therapy for mobility and activities of daily living
Psychiatric manifestations
Consultation with a social worker (or other medical professional) to determine need for:
Caregiver support including use of community resources &
Specific 24-hour/day care assistance
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 genetic prion disease in order to facilitate medical and personal decision making
• Need for gastrostomy tube feeding for nutrition and to reduce risk of aspiration
• Evaluation for bladder and bowel incontinence
• Need for physical therapy and occupational therapy for mobility and activities of daily living
• Psychiatric manifestations
• Consultation with a social worker (or other medical professional) to determine need for:
• Caregiver support including use of community resources &
• Specific 24-hour/day care assistance
• Caregiver support including use of community resources &
• Specific 24-hour/day care assistance
• 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 genetic prion disease in order to facilitate medical and personal decision making
• Caregiver support including use of community resources &
• Specific 24-hour/day care assistance
## Treatment of Manifestations
No treatment of the underlying cause of genetic prion disease is available. Only a few controlled trials have been performed. Some data point toward slowing of disease progression with doxycycline (100-200 mg/day) when administered early in the disease course [
Supportive care by a multidisciplinary team of specialists including neurologists, psychiatrists, physical therapists, occupational therapists, speech and language therapists, and social workers is recommended.
Symptomatic treatment may include the following:
For psychiatric manifestations such as depression or psychosis, antidepressant or neuroleptic treatment
Myoclonic jerks respond well to clonazepam.
Muscle rigidity may require dopamine or dopaminergic drugs.
Spasticity may respond to regular antispastic medication.
Physical therapy for exercises and/or stretching to prevent contractures; durable medical devices for positioning and/or mobility
Occupational therapy for home adaptation to improve safety and activities of daily living
Feeding issues addressed by nutritionists, speech pathologists
Communication (including alternative means of communication) by speech pathologists
• For psychiatric manifestations such as depression or psychosis, antidepressant or neuroleptic treatment
• Myoclonic jerks respond well to clonazepam.
• Muscle rigidity may require dopamine or dopaminergic drugs.
• Spasticity may respond to regular antispastic medication.
• Physical therapy for exercises and/or stretching to prevent contractures; durable medical devices for positioning and/or mobility
• Occupational therapy for home adaptation to improve safety and activities of daily living
• Feeding issues addressed by nutritionists, speech pathologists
• Communication (including alternative means of communication) by speech pathologists
## Surveillance
Because of very rapid disease progression, close periodic monitoring by the multidisciplinary team is needed, typically every 14 days to evaluate need for treatment of symptoms.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Genetic prion disease is inherited in an autosomal dominant manner.
Some individuals diagnosed with genetic prion disease have a parent who is heterozygous for a
Some individuals with genetic prion disease have the disorder as the result of a
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, 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. Though theoretically possible, no instances of a proband inheriting a
The family history of some individuals diagnosed with genetic prion disease may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband [
If a parent of the proband is affected and/or is known to have a pathogenic
The likelihood that a heterozygous sib will develop manifestations of genetic prion disease varies depending on the specific
A sib who inherits a familial
If the proband has a known
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 genetic prion disease, 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 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. For more information, see the National Society of Genetic Counselors
• Some individuals diagnosed with genetic prion disease have a parent who is heterozygous for a
• Some individuals with genetic prion disease have the disorder as the result of a
• 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, 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. Though theoretically possible, no instances of a proband inheriting a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a
• The family history of some individuals diagnosed with genetic prion disease may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a
• If a parent of the proband is affected and/or is known to have a pathogenic
• The likelihood that a heterozygous sib will develop manifestations of genetic prion disease varies depending on the specific
• A sib who inherits a familial
• The likelihood that a heterozygous sib will develop manifestations of genetic prion disease varies depending on the specific
• A sib who inherits a familial
• If the proband has a known
• If the parents have not been tested for the
• The likelihood that a heterozygous sib will develop manifestations of genetic prion disease varies depending on the specific
• A sib who inherits a familial
• 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 at risk.
## Mode of Inheritance
Genetic prion disease is inherited in an autosomal dominant manner.
## Risk to Family Members
Some individuals diagnosed with genetic prion disease have a parent who is heterozygous for a
Some individuals with genetic prion disease have the disorder as the result of a
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, 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. Though theoretically possible, no instances of a proband inheriting a
The family history of some individuals diagnosed with genetic prion disease may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband [
If a parent of the proband is affected and/or is known to have a pathogenic
The likelihood that a heterozygous sib will develop manifestations of genetic prion disease varies depending on the specific
A sib who inherits a familial
If the proband has a known
If the parents have not been tested for the
• Some individuals diagnosed with genetic prion disease have a parent who is heterozygous for a
• Some individuals with genetic prion disease have the disorder as the result of a
• 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, 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. Though theoretically possible, no instances of a proband inheriting a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a
• The family history of some individuals diagnosed with genetic prion disease may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. Though theoretically possible, no instances of a proband inheriting a
• If a parent of the proband is affected and/or is known to have a pathogenic
• The likelihood that a heterozygous sib will develop manifestations of genetic prion disease varies depending on the specific
• A sib who inherits a familial
• The likelihood that a heterozygous sib will develop manifestations of genetic prion disease varies depending on the specific
• A sib who inherits a familial
• If the proband has a known
• If the parents have not been tested for the
• The likelihood that a heterozygous sib will develop manifestations of genetic prion disease varies depending on the specific
• A sib who inherits a familial
## 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 genetic prion disease, 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 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 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. For more information, see the National Society of Genetic Counselors
## Resources
341 West 38th Street
Suite 501
New York City NY 10018
•
•
•
• 341 West 38th Street
• Suite 501
• New York City NY 10018
•
•
•
## Molecular Genetics
Genetic Prion Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Genetic Prion Disease (
The designation of the polymorphic variant at nucleotide 385 will vary depending on the reference sequence used. The
Insertional pathogenic variants are associated with the genetic Creutzfeldt-Jakob disease phenotype and the Gerstmann-Sträussler-Scheinker syndrome phenotype. Insertion variants of one or more octapeptide repeat segments (sometimes designated as a duplication) predict a prion protein extended by additional amino acids. The insertion variants involve one or more additional octapeptide repeat segments between codons 51 and 90, a highly unstable region that is enriched for encoding proline, glycine, and glutamine residues. Each repeat segment adds 24 nucleotides (i.e., 8 amino acids). Typically, these variants are described as an octapeptide repeat rather than a 24-bp nucleotide repeat because the nucleotide sequence encoding the octapeptide varies.
Normal
Notable
Variants listed in the table have been provided by the authors.
FFI = fatal familial insomnia; gCJD = genetic Creutzfeldt-Jakob disease; gPrD = genetic prion disease; GSS = Gerstmann-Sträussler-Scheinker
One of the five most common variants that account for 85% of gPrD [
Note that p.[Asp178Asn;Met129Val] is the HGVS standard nomenclature for two variants on one allele (i.e., on one chromosome), commonly referred to as a haplotype. p.Met129Val indicates that the Met residue at codon 129 in this reference sequence changes to a Val.
The phenotype in persons w/the p.Asp178Asn pathogenic variant typically depends on which variant – Val129 or Met129 – is on the same allele (see
## Molecular Pathogenesis
The designation of the polymorphic variant at nucleotide 385 will vary depending on the reference sequence used. The
Insertional pathogenic variants are associated with the genetic Creutzfeldt-Jakob disease phenotype and the Gerstmann-Sträussler-Scheinker syndrome phenotype. Insertion variants of one or more octapeptide repeat segments (sometimes designated as a duplication) predict a prion protein extended by additional amino acids. The insertion variants involve one or more additional octapeptide repeat segments between codons 51 and 90, a highly unstable region that is enriched for encoding proline, glycine, and glutamine residues. Each repeat segment adds 24 nucleotides (i.e., 8 amino acids). Typically, these variants are described as an octapeptide repeat rather than a 24-bp nucleotide repeat because the nucleotide sequence encoding the octapeptide varies.
Normal
Notable
Variants listed in the table have been provided by the authors.
FFI = fatal familial insomnia; gCJD = genetic Creutzfeldt-Jakob disease; gPrD = genetic prion disease; GSS = Gerstmann-Sträussler-Scheinker
One of the five most common variants that account for 85% of gPrD [
Note that p.[Asp178Asn;Met129Val] is the HGVS standard nomenclature for two variants on one allele (i.e., on one chromosome), commonly referred to as a haplotype. p.Met129Val indicates that the Met residue at codon 129 in this reference sequence changes to a Val.
The phenotype in persons w/the p.Asp178Asn pathogenic variant typically depends on which variant – Val129 or Met129 – is on the same allele (see
## Chapter Notes
This research was funded by the Robert Koch-Institute through funds of the Federal Ministry of Health (grant no 1369-341),
James A Mastrianni, MD, PhD; University of Chicago (2003-2020)Matthias Schmitz, MD (2021-present)Inga Zerr, MD (2021-present)
7 January 2021 (bp) Comprehensive update posted live
2 January 2014 (me) Comprehensive update posted live
18 December 2008 (me) Comprehensive update posted live
16 May 2005 (me) Comprehensive update posted live
27 March 2003 (me) Review posted live
12 April 2002 (jm) Original submission
• 7 January 2021 (bp) Comprehensive update posted live
• 2 January 2014 (me) Comprehensive update posted live
• 18 December 2008 (me) Comprehensive update posted live
• 16 May 2005 (me) Comprehensive update posted live
• 27 March 2003 (me) Review posted live
• 12 April 2002 (jm) Original submission
## Author Notes
## Acknowledgments
This research was funded by the Robert Koch-Institute through funds of the Federal Ministry of Health (grant no 1369-341),
## Author History
James A Mastrianni, MD, PhD; University of Chicago (2003-2020)Matthias Schmitz, MD (2021-present)Inga Zerr, MD (2021-present)
## Revision History
7 January 2021 (bp) Comprehensive update posted live
2 January 2014 (me) Comprehensive update posted live
18 December 2008 (me) Comprehensive update posted live
16 May 2005 (me) Comprehensive update posted live
27 March 2003 (me) Review posted live
12 April 2002 (jm) Original submission
• 7 January 2021 (bp) Comprehensive update posted live
• 2 January 2014 (me) Comprehensive update posted live
• 18 December 2008 (me) Comprehensive update posted live
• 16 May 2005 (me) Comprehensive update posted live
• 27 March 2003 (me) Review posted live
• 12 April 2002 (jm) Original submission
## References
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Published Guidelines / Consensus Statements
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Literature Cited
|
[] |
27/3/2003
|
7/1/2021
|
7/9/2010
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
prolidase-def
|
prolidase-def
|
[
"Xaa-Pro dipeptidase",
"PEPD",
"Prolidase Deficiency"
] |
Prolidase Deficiency
|
Francis Rossignol, Heng Wang, Carlos Ferreira
|
Summary Prolidase deficiency is characterized by skin lesions (typically severe, chronic, recalcitrant, and painful skin ulcers of the lower extremities and telangiectasias of the face and hands), recurrent infections (particularly of the skin and respiratory tract), dysmorphic facial features, variable intellectual disability, and organomegaly (typically splenomegaly but occasionally associated with hepatomegaly) with elevated liver enzymes. Skeletal anomalies, chronic pulmonary disease, anemia, thrombocytopenia, hypergammaglobulinemia, and hypocomplementemia are observed in a minority of affected individuals. An association between prolidase deficiency and autoimmune conditions – particularly systemic lupus erythematosus (SLE) – has been described. The clinical diagnosis of prolidase deficiency can be established in a proband with characteristic clinical findings and imidodipeptiduria or reduced prolidase enzyme activity. The molecular diagnosis can be established in a proband with suggestive findings and biallelic pathogenic variants in Prolidase 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
|
## Diagnosis
No consensus clinical diagnostic criteria for prolidase deficiency have been published.
Prolidase deficiency
Skin lesions, typically lower-extremity ulcers (
Recurrent infections, particularly of the skin and respiratory tract
Chronic lung disease with digital clubbing and a cystic fibrosis-like phenotype
Dysmorphic facial features including widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairline (
Developmental delay of variable degree
Splenomegaly
Immunologic abnormalities, including systemic lupus erythematosus-like phenotype and hypergammaglobulinemia
Massive imidodipeptiduria * (10-30 mmol/day) on urine amino acid analysis, in conjunction with suggestive clinical findings or a positive family history, is highly suggestive of the disorder. The concentration of imidodipeptides is much lower in serum than in urine.
Imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease.
The absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency.
Click
Gly-Pro has been reported in the plasma by some investigators, but not others. Detection of Gly-Pro or other imidodipeptides in plasma require a sensitive method, and in the case of tandem mass spectrometry methods, specific ion monitoring [
* Note: A number of published reports mistakenly refer to imidodipeptiduria as "iminodipeptiduria." Iminodipeptides are dipeptides in which proline or hydroxyproline is the N-terminal amino acid (i.e., Pro/Hyp-X, for example, prolylglycine), whereas imidodipeptides are dipeptides in which proline or hydroxyproline is the C-terminal amino acid (i.e., X-Pro/Hyp, for example, glycylproline).
Anemia, usually mild (hemoglobin >10 g/dL), but occasionally more severe
Thrombocytopenia, usually mild (>100,000 platelets per μL), although it can be more severe
Elevated liver enzymes, with elevation of aspartate aminotransferase in the hundreds
Hypergammaglobulinemia, mainly elevation of IgG and IgA, although occasionally also elevation of IgM
IgG levels >2,000 mg/dL
IgA levels >500 mg/dL and as high as 850 mg/dL
IgM concentrations as high as 568 mg/dL
Note: Reference ranges for immunoglobulins are age dependent, but upper limits of normal at any age are: IgG = ~1600 mg/dL, IgA = 350 mg/dL, and IgM = 280 mg/dL.
Hypocomplementemia, with levels of C3 ranging from 30 to 74 mg/dL (normal: 75-175 mg/dL) and C4 as low as 9 mg/dL (normal: 20-40 mg/dL)
The clinical diagnosis of prolidase deficiency
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 laboratory findings suggest the diagnosis of prolidase deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first for Amish individuals from Geauga County, Ohio, and Druze and Arab Muslim individuals from northern Israel (see
For an introduction to multigene panels click
When the diagnosis of prolidase deficiency has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Prolidase 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
Sequence analysis should also be able to detect the founder
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.
Click
• Skin lesions, typically lower-extremity ulcers (
• Recurrent infections, particularly of the skin and respiratory tract
• Chronic lung disease with digital clubbing and a cystic fibrosis-like phenotype
• Dysmorphic facial features including widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairline (
• Developmental delay of variable degree
• Splenomegaly
• Immunologic abnormalities, including systemic lupus erythematosus-like phenotype and hypergammaglobulinemia
• Massive imidodipeptiduria * (10-30 mmol/day) on urine amino acid analysis, in conjunction with suggestive clinical findings or a positive family history, is highly suggestive of the disorder. The concentration of imidodipeptides is much lower in serum than in urine.
• Imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease.
• The absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency.
• Click
• Imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease.
• The absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency.
• Gly-Pro has been reported in the plasma by some investigators, but not others. Detection of Gly-Pro or other imidodipeptides in plasma require a sensitive method, and in the case of tandem mass spectrometry methods, specific ion monitoring [
• Imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease.
• The absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency.
• Anemia, usually mild (hemoglobin >10 g/dL), but occasionally more severe
• Thrombocytopenia, usually mild (>100,000 platelets per μL), although it can be more severe
• Elevated liver enzymes, with elevation of aspartate aminotransferase in the hundreds
• Hypergammaglobulinemia, mainly elevation of IgG and IgA, although occasionally also elevation of IgM
• IgG levels >2,000 mg/dL
• IgA levels >500 mg/dL and as high as 850 mg/dL
• IgM concentrations as high as 568 mg/dL
• Note: Reference ranges for immunoglobulins are age dependent, but upper limits of normal at any age are: IgG = ~1600 mg/dL, IgA = 350 mg/dL, and IgM = 280 mg/dL.
• IgG levels >2,000 mg/dL
• IgA levels >500 mg/dL and as high as 850 mg/dL
• IgM concentrations as high as 568 mg/dL
• Hypocomplementemia, with levels of C3 ranging from 30 to 74 mg/dL (normal: 75-175 mg/dL) and C4 as low as 9 mg/dL (normal: 20-40 mg/dL)
• IgG levels >2,000 mg/dL
• IgA levels >500 mg/dL and as high as 850 mg/dL
• IgM concentrations as high as 568 mg/dL
• Note: Targeted analysis for pathogenic variants can be performed first for Amish individuals from Geauga County, Ohio, and Druze and Arab Muslim individuals from northern Israel (see
• For an introduction to multigene panels click
## Suggestive Findings
Prolidase deficiency
Skin lesions, typically lower-extremity ulcers (
Recurrent infections, particularly of the skin and respiratory tract
Chronic lung disease with digital clubbing and a cystic fibrosis-like phenotype
Dysmorphic facial features including widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairline (
Developmental delay of variable degree
Splenomegaly
Immunologic abnormalities, including systemic lupus erythematosus-like phenotype and hypergammaglobulinemia
Massive imidodipeptiduria * (10-30 mmol/day) on urine amino acid analysis, in conjunction with suggestive clinical findings or a positive family history, is highly suggestive of the disorder. The concentration of imidodipeptides is much lower in serum than in urine.
Imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease.
The absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency.
Click
Gly-Pro has been reported in the plasma by some investigators, but not others. Detection of Gly-Pro or other imidodipeptides in plasma require a sensitive method, and in the case of tandem mass spectrometry methods, specific ion monitoring [
* Note: A number of published reports mistakenly refer to imidodipeptiduria as "iminodipeptiduria." Iminodipeptides are dipeptides in which proline or hydroxyproline is the N-terminal amino acid (i.e., Pro/Hyp-X, for example, prolylglycine), whereas imidodipeptides are dipeptides in which proline or hydroxyproline is the C-terminal amino acid (i.e., X-Pro/Hyp, for example, glycylproline).
Anemia, usually mild (hemoglobin >10 g/dL), but occasionally more severe
Thrombocytopenia, usually mild (>100,000 platelets per μL), although it can be more severe
Elevated liver enzymes, with elevation of aspartate aminotransferase in the hundreds
Hypergammaglobulinemia, mainly elevation of IgG and IgA, although occasionally also elevation of IgM
IgG levels >2,000 mg/dL
IgA levels >500 mg/dL and as high as 850 mg/dL
IgM concentrations as high as 568 mg/dL
Note: Reference ranges for immunoglobulins are age dependent, but upper limits of normal at any age are: IgG = ~1600 mg/dL, IgA = 350 mg/dL, and IgM = 280 mg/dL.
Hypocomplementemia, with levels of C3 ranging from 30 to 74 mg/dL (normal: 75-175 mg/dL) and C4 as low as 9 mg/dL (normal: 20-40 mg/dL)
• Skin lesions, typically lower-extremity ulcers (
• Recurrent infections, particularly of the skin and respiratory tract
• Chronic lung disease with digital clubbing and a cystic fibrosis-like phenotype
• Dysmorphic facial features including widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairline (
• Developmental delay of variable degree
• Splenomegaly
• Immunologic abnormalities, including systemic lupus erythematosus-like phenotype and hypergammaglobulinemia
• Massive imidodipeptiduria * (10-30 mmol/day) on urine amino acid analysis, in conjunction with suggestive clinical findings or a positive family history, is highly suggestive of the disorder. The concentration of imidodipeptides is much lower in serum than in urine.
• Imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease.
• The absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency.
• Click
• Imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease.
• The absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency.
• Gly-Pro has been reported in the plasma by some investigators, but not others. Detection of Gly-Pro or other imidodipeptides in plasma require a sensitive method, and in the case of tandem mass spectrometry methods, specific ion monitoring [
• Imidodipeptiduria has been detected as early as in the newborn period, even in the absence of signs or symptoms of the disease.
• The absence of detectable imidodipeptiduria in properly processed samples is sufficient evidence to rule out a diagnosis of prolidase deficiency.
• Anemia, usually mild (hemoglobin >10 g/dL), but occasionally more severe
• Thrombocytopenia, usually mild (>100,000 platelets per μL), although it can be more severe
• Elevated liver enzymes, with elevation of aspartate aminotransferase in the hundreds
• Hypergammaglobulinemia, mainly elevation of IgG and IgA, although occasionally also elevation of IgM
• IgG levels >2,000 mg/dL
• IgA levels >500 mg/dL and as high as 850 mg/dL
• IgM concentrations as high as 568 mg/dL
• Note: Reference ranges for immunoglobulins are age dependent, but upper limits of normal at any age are: IgG = ~1600 mg/dL, IgA = 350 mg/dL, and IgM = 280 mg/dL.
• IgG levels >2,000 mg/dL
• IgA levels >500 mg/dL and as high as 850 mg/dL
• IgM concentrations as high as 568 mg/dL
• Hypocomplementemia, with levels of C3 ranging from 30 to 74 mg/dL (normal: 75-175 mg/dL) and C4 as low as 9 mg/dL (normal: 20-40 mg/dL)
• IgG levels >2,000 mg/dL
• IgA levels >500 mg/dL and as high as 850 mg/dL
• IgM concentrations as high as 568 mg/dL
## Establishing the Diagnosis
The clinical diagnosis of prolidase deficiency
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 laboratory findings suggest the diagnosis of prolidase deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first for Amish individuals from Geauga County, Ohio, and Druze and Arab Muslim individuals from northern Israel (see
For an introduction to multigene panels click
When the diagnosis of prolidase deficiency has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Prolidase 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
Sequence analysis should also be able to detect the founder
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.
Click
• Note: Targeted analysis for pathogenic variants can be performed first for Amish individuals from Geauga County, Ohio, and Druze and Arab Muslim individuals from northern Israel (see
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of prolidase deficiency, molecular genetic testing approaches can include
Note: Targeted analysis for pathogenic variants can be performed first for Amish individuals from Geauga County, Ohio, and Druze and Arab Muslim individuals from northern Israel (see
For an introduction to multigene panels click
• Note: Targeted analysis for pathogenic variants can be performed first for Amish individuals from Geauga County, Ohio, and Druze and Arab Muslim individuals from northern Israel (see
• For an introduction to multigene panels click
## Option 2
When the diagnosis of prolidase deficiency has not been considered because an individual has atypical phenotypic features, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Prolidase 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
Sequence analysis should also be able to detect the founder
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.
Click
## Clinical Characteristics
To date, more than 175 individuals from more than 90 families have been identified with prolidase deficiency, as recently reviewed by
Note: A minority of individuals (n=5) have remained asymptomatic, despite biochemical or molecular confirmation of prolidase deficiency [
Prolidase Deficiency: Frequency of Select Features
DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; IgG = immunoglobulin G; IgE = immunoglobulin E; SLE = systemic lupus erythematosus
The formal medical definition of intellectual disability is an IQ score lower than 70. Individuals with an IQ score equal to or above 70 may still have delays in the acquisition of milestones but would not be considered to have intellectual disability.
Rhupus is a condition in which individuals have features of both rheumatoid arthritis and SLE, often in a sequential manner.
Although not a universal finding, facial features typically described include prominent forehead, widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairlines [
The hallmark of prolidase deficiency is severe, chronic, recalcitrant, and painful skin ulcers (see
Skin ulcers can begin as early as age six months or as late as age 30 years. Half of affected individuals have ulcers by age 12 years and around 75% by age 18 years (see also
Ulceration is recurrent, and individual ulcers can take months to heal.
Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor.
A variety of skin findings can precede the appearance of ulcers by many years, including:
Telangiectasias of the face, shoulders, and hands
Scaly, erythematous, maculopapular lesions
Purpuric lesions in the absence of hematologic abnormalities
Premature graying of the hair
Occasional skin findings may also include:
Lymphedema
Hyperkeratosis of the elbows and knees
Hirsutism
Perioral pitted scars or radial scars
As prolidase deficiency is associated with chronic recalcitrant lower extremity ulcers, an increased risk of squamous cell carcinoma of the skin could be expected, and indeed has been reported in one individual [
DD of variable degree has been described in approximately 60% of individuals with prolidase deficiency [
The reported spectrum varies widely, from normal development to mild-to-moderate DD or, less frequently, severe ID [
Reported IQ values (n=18) ranged from 30 to 90.
Multiple microthromboses bilaterally in the cerebral white matter [
Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) [
Findings compatible with vasculitis [
Rarely, an axonal neuropathy can occur [
Splenomegaly is common and variable in severity; in one instance massive splenomegaly (spleen measuring 35 cm) was reported [
Liver enzymes may be mildly elevated [
Only a few individuals have progressed to more severe liver disease, including cirrhosis or hepatitis, sometimes in the context of autoimmune disease [
Anemia is present in around 30% of affected individuals and can be either mild microcytic hypochromic anemia or normocytic normochromic anemia [
Hemolysis has been described, with reticulocytosis varying from 5.9% [
Thrombocytopenia is present in around 18% of affected individuals, but recurrent bleeding episodes or easy bruising has been rarely reported in the literature.
Recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis are common. A few affected individuals have been reported with hemophagocytic lymphohistiocytosis / macrophage activation syndrome, which required emergent management (see
Immunologic studies may reveal the following (see also
Elevated levels of IgG, IgA, and IgM
Hypocomplementemia
Decreased neutrophil chemotaxis
Increased serum IgE levels, ranging from 20,000 IU/mL to 77,600 IU/mL
Grimbacher scores for hyper IgE syndrome were 34 (possible) for one affected individual [
Asthma-like chronic reactive airway disease has been described in approximately 7% of affected individuals.
Other forms of chronic pulmonary disease occasionally seen:
Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis-like phenotype with elevated sweat chloride and transepithelial potential difference. One man developed severe progressive restrictive lung disease at age 45 years [
Progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity in a Druze woman age 24 years [
Pulmonary hypertension requiring supplemental oxygen in an Amish child age six years [
Pulmonary fibrosis with pulmonary capillaritis and cystic lung changes in two individuals age five years [
About one fifth of individuals with prolidase deficiency develop an autoimmune disorder. Various manifestations of these disorders may comprise arthritis, nephritis, pericarditis, cytopenias, mouth ulcers, malar rash, and hypocomplementemia (low C3, C4, and CH50 levels).
The most common autoimmune disorder associated with prolidase deficiency is systemic lupus erythematosus (SLE), although not all individuals fulfill the American College of Rheumatology criteria for a diagnosis of SLE.
Reported positive markers include rheumatoid factor, antinuclear antibodies, ANCA, anti-dsDNA, anti-cardiolipin, anti-SSA/Ro, anti-SSB/La, anti-chromatin, anti-RNP, and/or anti-Sm antibodies.
A couple of cases of cryoglobulinemia have been reported [
Sometimes, these antibodies have been reported in the absence of SLE-like clinical findings [
Other autoimmune conditions may include:
Autoimmune arthritis, including psoriatic arthritis or juvenile idiopathic arthritis
Vasculitis, including central nervous system vasculitis
Rhupus (a condition in which individuals have features of both rheumatoid arthritis and SLE, often in a sequential manner)
Coombs-positive hemolytic anemia
Crohn-like disease
Autoimmune adrenal failure (in one affected individual) [
Among 12 affected individuals reported by
Other primary bone/limb findings (reported in a few cases each) include:
Spina bifida of C3 and 13 thoracic vertebrae [
Fusion of C2 and C3 [
Delayed bone age [
Syndactyly of the hands and/or feet
Pes planus
Pes cavus
Short fingers / brachydactyly
Arachnodactyly
Ocular abnormalities have been found in approximately 15% of affected individuals and include varied phenomena including optic and chorioretinal atrophy in two individuals [
Dental abnormalities were present in more than 20 affected individuals. Dental findings have included multiple caries with or without enamel hypoplasia, misaligned teeth, and hypodontia.
Diarrhea has been reported in 19 affected individuals, even in the absence of Crohn-like inflammatory bowel disease (reported in only 5 individuals).
Both poor weight gain (14%) and short stature (12%) as well as overweight/obesity (9%) have been reported.
The severity of prolidase deficiency is quite variable: in some individuals skin ulcerations lead to amputation of one or all toes, whereas others remain entirely asymptomatic [
In many instances, however, individuals with prolidase deficiency experience severe morbidity and sometimes early death, usually as a result of infection or respiratory failure. The youngest reported death was at age three months [
In general, individuals with biallelic loss-of-function pathogenic variants in
By age 20 years, 100% of individuals with loss-of-function pathogenic variants reported ulcers, whereas fewer than 50% of individuals with biallelic pathogenic missense variants reported having ulcers by this age.
However, marked phenotypic variability has been found among affected individuals even from the same family (who have the same pathogenic variants) [
Prolidase deficiency was also known as hyperimidodipeptiduria, although increased excretion of imidodipeptides is not exclusive to prolidase deficiency. Other names used in the past include imidodipeptidase deficiency and peptidase D deficiency.
Approximately 175 affected individuals have been reported in the literature; however, prolidase deficiency likely remains underdiagnosed as a result of underrecognition by physicians.
The Québec Newborn Urine Screening Program (Programme québécois de dépistage neonatal urinaire, PQDNU) identified two affected infants out of 2,469,929 screened between 1973 and 2006, for an incidence of 1:1,235,000 [
Prolidase deficiency has been diagnosed throughout the world [
A founder variant has been described in the Geauga County Amish settlement in Ohio [
• Skin ulcers can begin as early as age six months or as late as age 30 years. Half of affected individuals have ulcers by age 12 years and around 75% by age 18 years (see also
• Ulceration is recurrent, and individual ulcers can take months to heal.
• Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor.
• Telangiectasias of the face, shoulders, and hands
• Scaly, erythematous, maculopapular lesions
• Purpuric lesions in the absence of hematologic abnormalities
• Premature graying of the hair
• Lymphedema
• Hyperkeratosis of the elbows and knees
• Hirsutism
• Perioral pitted scars or radial scars
• The reported spectrum varies widely, from normal development to mild-to-moderate DD or, less frequently, severe ID [
• Reported IQ values (n=18) ranged from 30 to 90.
• Multiple microthromboses bilaterally in the cerebral white matter [
• Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) [
• Findings compatible with vasculitis [
• Liver enzymes may be mildly elevated [
• Only a few individuals have progressed to more severe liver disease, including cirrhosis or hepatitis, sometimes in the context of autoimmune disease [
• Elevated levels of IgG, IgA, and IgM
• Hypocomplementemia
• Decreased neutrophil chemotaxis
• Increased serum IgE levels, ranging from 20,000 IU/mL to 77,600 IU/mL
• Grimbacher scores for hyper IgE syndrome were 34 (possible) for one affected individual [
• Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis-like phenotype with elevated sweat chloride and transepithelial potential difference. One man developed severe progressive restrictive lung disease at age 45 years [
• Progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity in a Druze woman age 24 years [
• Pulmonary hypertension requiring supplemental oxygen in an Amish child age six years [
• Pulmonary fibrosis with pulmonary capillaritis and cystic lung changes in two individuals age five years [
• Reported positive markers include rheumatoid factor, antinuclear antibodies, ANCA, anti-dsDNA, anti-cardiolipin, anti-SSA/Ro, anti-SSB/La, anti-chromatin, anti-RNP, and/or anti-Sm antibodies.
• A couple of cases of cryoglobulinemia have been reported [
• Sometimes, these antibodies have been reported in the absence of SLE-like clinical findings [
• Autoimmune arthritis, including psoriatic arthritis or juvenile idiopathic arthritis
• Vasculitis, including central nervous system vasculitis
• Rhupus (a condition in which individuals have features of both rheumatoid arthritis and SLE, often in a sequential manner)
• Coombs-positive hemolytic anemia
• Crohn-like disease
• Autoimmune adrenal failure (in one affected individual) [
• Spina bifida of C3 and 13 thoracic vertebrae [
• Fusion of C2 and C3 [
• Delayed bone age [
• Syndactyly of the hands and/or feet
• Pes planus
• Pes cavus
• Short fingers / brachydactyly
• Arachnodactyly
• By age 20 years, 100% of individuals with loss-of-function pathogenic variants reported ulcers, whereas fewer than 50% of individuals with biallelic pathogenic missense variants reported having ulcers by this age.
• However, marked phenotypic variability has been found among affected individuals even from the same family (who have the same pathogenic variants) [
## Clinical Description
To date, more than 175 individuals from more than 90 families have been identified with prolidase deficiency, as recently reviewed by
Note: A minority of individuals (n=5) have remained asymptomatic, despite biochemical or molecular confirmation of prolidase deficiency [
Prolidase Deficiency: Frequency of Select Features
DD = developmental delay; GI = gastrointestinal; ID = intellectual disability; IgG = immunoglobulin G; IgE = immunoglobulin E; SLE = systemic lupus erythematosus
The formal medical definition of intellectual disability is an IQ score lower than 70. Individuals with an IQ score equal to or above 70 may still have delays in the acquisition of milestones but would not be considered to have intellectual disability.
Rhupus is a condition in which individuals have features of both rheumatoid arthritis and SLE, often in a sequential manner.
Although not a universal finding, facial features typically described include prominent forehead, widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairlines [
The hallmark of prolidase deficiency is severe, chronic, recalcitrant, and painful skin ulcers (see
Skin ulcers can begin as early as age six months or as late as age 30 years. Half of affected individuals have ulcers by age 12 years and around 75% by age 18 years (see also
Ulceration is recurrent, and individual ulcers can take months to heal.
Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor.
A variety of skin findings can precede the appearance of ulcers by many years, including:
Telangiectasias of the face, shoulders, and hands
Scaly, erythematous, maculopapular lesions
Purpuric lesions in the absence of hematologic abnormalities
Premature graying of the hair
Occasional skin findings may also include:
Lymphedema
Hyperkeratosis of the elbows and knees
Hirsutism
Perioral pitted scars or radial scars
As prolidase deficiency is associated with chronic recalcitrant lower extremity ulcers, an increased risk of squamous cell carcinoma of the skin could be expected, and indeed has been reported in one individual [
DD of variable degree has been described in approximately 60% of individuals with prolidase deficiency [
The reported spectrum varies widely, from normal development to mild-to-moderate DD or, less frequently, severe ID [
Reported IQ values (n=18) ranged from 30 to 90.
Multiple microthromboses bilaterally in the cerebral white matter [
Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) [
Findings compatible with vasculitis [
Rarely, an axonal neuropathy can occur [
Splenomegaly is common and variable in severity; in one instance massive splenomegaly (spleen measuring 35 cm) was reported [
Liver enzymes may be mildly elevated [
Only a few individuals have progressed to more severe liver disease, including cirrhosis or hepatitis, sometimes in the context of autoimmune disease [
Anemia is present in around 30% of affected individuals and can be either mild microcytic hypochromic anemia or normocytic normochromic anemia [
Hemolysis has been described, with reticulocytosis varying from 5.9% [
Thrombocytopenia is present in around 18% of affected individuals, but recurrent bleeding episodes or easy bruising has been rarely reported in the literature.
Recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis are common. A few affected individuals have been reported with hemophagocytic lymphohistiocytosis / macrophage activation syndrome, which required emergent management (see
Immunologic studies may reveal the following (see also
Elevated levels of IgG, IgA, and IgM
Hypocomplementemia
Decreased neutrophil chemotaxis
Increased serum IgE levels, ranging from 20,000 IU/mL to 77,600 IU/mL
Grimbacher scores for hyper IgE syndrome were 34 (possible) for one affected individual [
Asthma-like chronic reactive airway disease has been described in approximately 7% of affected individuals.
Other forms of chronic pulmonary disease occasionally seen:
Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis-like phenotype with elevated sweat chloride and transepithelial potential difference. One man developed severe progressive restrictive lung disease at age 45 years [
Progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity in a Druze woman age 24 years [
Pulmonary hypertension requiring supplemental oxygen in an Amish child age six years [
Pulmonary fibrosis with pulmonary capillaritis and cystic lung changes in two individuals age five years [
About one fifth of individuals with prolidase deficiency develop an autoimmune disorder. Various manifestations of these disorders may comprise arthritis, nephritis, pericarditis, cytopenias, mouth ulcers, malar rash, and hypocomplementemia (low C3, C4, and CH50 levels).
The most common autoimmune disorder associated with prolidase deficiency is systemic lupus erythematosus (SLE), although not all individuals fulfill the American College of Rheumatology criteria for a diagnosis of SLE.
Reported positive markers include rheumatoid factor, antinuclear antibodies, ANCA, anti-dsDNA, anti-cardiolipin, anti-SSA/Ro, anti-SSB/La, anti-chromatin, anti-RNP, and/or anti-Sm antibodies.
A couple of cases of cryoglobulinemia have been reported [
Sometimes, these antibodies have been reported in the absence of SLE-like clinical findings [
Other autoimmune conditions may include:
Autoimmune arthritis, including psoriatic arthritis or juvenile idiopathic arthritis
Vasculitis, including central nervous system vasculitis
Rhupus (a condition in which individuals have features of both rheumatoid arthritis and SLE, often in a sequential manner)
Coombs-positive hemolytic anemia
Crohn-like disease
Autoimmune adrenal failure (in one affected individual) [
Among 12 affected individuals reported by
Other primary bone/limb findings (reported in a few cases each) include:
Spina bifida of C3 and 13 thoracic vertebrae [
Fusion of C2 and C3 [
Delayed bone age [
Syndactyly of the hands and/or feet
Pes planus
Pes cavus
Short fingers / brachydactyly
Arachnodactyly
Ocular abnormalities have been found in approximately 15% of affected individuals and include varied phenomena including optic and chorioretinal atrophy in two individuals [
Dental abnormalities were present in more than 20 affected individuals. Dental findings have included multiple caries with or without enamel hypoplasia, misaligned teeth, and hypodontia.
Diarrhea has been reported in 19 affected individuals, even in the absence of Crohn-like inflammatory bowel disease (reported in only 5 individuals).
Both poor weight gain (14%) and short stature (12%) as well as overweight/obesity (9%) have been reported.
The severity of prolidase deficiency is quite variable: in some individuals skin ulcerations lead to amputation of one or all toes, whereas others remain entirely asymptomatic [
In many instances, however, individuals with prolidase deficiency experience severe morbidity and sometimes early death, usually as a result of infection or respiratory failure. The youngest reported death was at age three months [
• Skin ulcers can begin as early as age six months or as late as age 30 years. Half of affected individuals have ulcers by age 12 years and around 75% by age 18 years (see also
• Ulceration is recurrent, and individual ulcers can take months to heal.
• Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor.
• Telangiectasias of the face, shoulders, and hands
• Scaly, erythematous, maculopapular lesions
• Purpuric lesions in the absence of hematologic abnormalities
• Premature graying of the hair
• Lymphedema
• Hyperkeratosis of the elbows and knees
• Hirsutism
• Perioral pitted scars or radial scars
• The reported spectrum varies widely, from normal development to mild-to-moderate DD or, less frequently, severe ID [
• Reported IQ values (n=18) ranged from 30 to 90.
• Multiple microthromboses bilaterally in the cerebral white matter [
• Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) [
• Findings compatible with vasculitis [
• Liver enzymes may be mildly elevated [
• Only a few individuals have progressed to more severe liver disease, including cirrhosis or hepatitis, sometimes in the context of autoimmune disease [
• Elevated levels of IgG, IgA, and IgM
• Hypocomplementemia
• Decreased neutrophil chemotaxis
• Increased serum IgE levels, ranging from 20,000 IU/mL to 77,600 IU/mL
• Grimbacher scores for hyper IgE syndrome were 34 (possible) for one affected individual [
• Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis-like phenotype with elevated sweat chloride and transepithelial potential difference. One man developed severe progressive restrictive lung disease at age 45 years [
• Progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity in a Druze woman age 24 years [
• Pulmonary hypertension requiring supplemental oxygen in an Amish child age six years [
• Pulmonary fibrosis with pulmonary capillaritis and cystic lung changes in two individuals age five years [
• Reported positive markers include rheumatoid factor, antinuclear antibodies, ANCA, anti-dsDNA, anti-cardiolipin, anti-SSA/Ro, anti-SSB/La, anti-chromatin, anti-RNP, and/or anti-Sm antibodies.
• A couple of cases of cryoglobulinemia have been reported [
• Sometimes, these antibodies have been reported in the absence of SLE-like clinical findings [
• Autoimmune arthritis, including psoriatic arthritis or juvenile idiopathic arthritis
• Vasculitis, including central nervous system vasculitis
• Rhupus (a condition in which individuals have features of both rheumatoid arthritis and SLE, often in a sequential manner)
• Coombs-positive hemolytic anemia
• Crohn-like disease
• Autoimmune adrenal failure (in one affected individual) [
• Spina bifida of C3 and 13 thoracic vertebrae [
• Fusion of C2 and C3 [
• Delayed bone age [
• Syndactyly of the hands and/or feet
• Pes planus
• Pes cavus
• Short fingers / brachydactyly
• Arachnodactyly
## Dysmorphic Facial Features
Although not a universal finding, facial features typically described include prominent forehead, widely spaced eyes, proptosis, depressed nasal bridge, prognathism, thin vermilion of the upper lip, and low anterior and posterior hairlines [
## Skin
The hallmark of prolidase deficiency is severe, chronic, recalcitrant, and painful skin ulcers (see
Skin ulcers can begin as early as age six months or as late as age 30 years. Half of affected individuals have ulcers by age 12 years and around 75% by age 18 years (see also
Ulceration is recurrent, and individual ulcers can take months to heal.
Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor.
A variety of skin findings can precede the appearance of ulcers by many years, including:
Telangiectasias of the face, shoulders, and hands
Scaly, erythematous, maculopapular lesions
Purpuric lesions in the absence of hematologic abnormalities
Premature graying of the hair
Occasional skin findings may also include:
Lymphedema
Hyperkeratosis of the elbows and knees
Hirsutism
Perioral pitted scars or radial scars
As prolidase deficiency is associated with chronic recalcitrant lower extremity ulcers, an increased risk of squamous cell carcinoma of the skin could be expected, and indeed has been reported in one individual [
• Skin ulcers can begin as early as age six months or as late as age 30 years. Half of affected individuals have ulcers by age 12 years and around 75% by age 18 years (see also
• Ulceration is recurrent, and individual ulcers can take months to heal.
• Typically, no precipitating factors are identified with the appearance of an ulcer, although trauma has been reported as a triggering factor.
• Telangiectasias of the face, shoulders, and hands
• Scaly, erythematous, maculopapular lesions
• Purpuric lesions in the absence of hematologic abnormalities
• Premature graying of the hair
• Lymphedema
• Hyperkeratosis of the elbows and knees
• Hirsutism
• Perioral pitted scars or radial scars
## Developmental Delay (DD) and Intellectual Disability (ID)
DD of variable degree has been described in approximately 60% of individuals with prolidase deficiency [
The reported spectrum varies widely, from normal development to mild-to-moderate DD or, less frequently, severe ID [
Reported IQ values (n=18) ranged from 30 to 90.
• The reported spectrum varies widely, from normal development to mild-to-moderate DD or, less frequently, severe ID [
• Reported IQ values (n=18) ranged from 30 to 90.
## Other Neurologic/Brain Findings
Multiple microthromboses bilaterally in the cerebral white matter [
Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) [
Findings compatible with vasculitis [
Rarely, an axonal neuropathy can occur [
• Multiple microthromboses bilaterally in the cerebral white matter [
• Multiple bilateral subcortical white matter lesions (mainly in the parieto-occipital area), accompanied by leptomeningeal enhancement (one affected individual) [
• Findings compatible with vasculitis [
## Organomegaly
Splenomegaly is common and variable in severity; in one instance massive splenomegaly (spleen measuring 35 cm) was reported [
Liver enzymes may be mildly elevated [
Only a few individuals have progressed to more severe liver disease, including cirrhosis or hepatitis, sometimes in the context of autoimmune disease [
• Liver enzymes may be mildly elevated [
• Only a few individuals have progressed to more severe liver disease, including cirrhosis or hepatitis, sometimes in the context of autoimmune disease [
## Hematologic Manifestations
Anemia is present in around 30% of affected individuals and can be either mild microcytic hypochromic anemia or normocytic normochromic anemia [
Hemolysis has been described, with reticulocytosis varying from 5.9% [
Thrombocytopenia is present in around 18% of affected individuals, but recurrent bleeding episodes or easy bruising has been rarely reported in the literature.
## Immunologic Manifestations
Recurrent episodes of otitis media, sinusitis, pneumonia, and gastroenteritis are common. A few affected individuals have been reported with hemophagocytic lymphohistiocytosis / macrophage activation syndrome, which required emergent management (see
Immunologic studies may reveal the following (see also
Elevated levels of IgG, IgA, and IgM
Hypocomplementemia
Decreased neutrophil chemotaxis
Increased serum IgE levels, ranging from 20,000 IU/mL to 77,600 IU/mL
Grimbacher scores for hyper IgE syndrome were 34 (possible) for one affected individual [
• Elevated levels of IgG, IgA, and IgM
• Hypocomplementemia
• Decreased neutrophil chemotaxis
• Increased serum IgE levels, ranging from 20,000 IU/mL to 77,600 IU/mL
• Grimbacher scores for hyper IgE syndrome were 34 (possible) for one affected individual [
## Pulmonary Manifestations
Asthma-like chronic reactive airway disease has been described in approximately 7% of affected individuals.
Other forms of chronic pulmonary disease occasionally seen:
Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis-like phenotype with elevated sweat chloride and transepithelial potential difference. One man developed severe progressive restrictive lung disease at age 45 years [
Progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity in a Druze woman age 24 years [
Pulmonary hypertension requiring supplemental oxygen in an Amish child age six years [
Pulmonary fibrosis with pulmonary capillaritis and cystic lung changes in two individuals age five years [
• Bronchiectasis, chronic lipoid pneumonia, and a cystic fibrosis-like phenotype with elevated sweat chloride and transepithelial potential difference. One man developed severe progressive restrictive lung disease at age 45 years [
• Progressive lung disease with chest CT findings of mainly cystic lung lesions and ground glass opacity in a Druze woman age 24 years [
• Pulmonary hypertension requiring supplemental oxygen in an Amish child age six years [
• Pulmonary fibrosis with pulmonary capillaritis and cystic lung changes in two individuals age five years [
## Autoimmune Disorders and Systemic Lupus Erythematosus-Like Findings
About one fifth of individuals with prolidase deficiency develop an autoimmune disorder. Various manifestations of these disorders may comprise arthritis, nephritis, pericarditis, cytopenias, mouth ulcers, malar rash, and hypocomplementemia (low C3, C4, and CH50 levels).
The most common autoimmune disorder associated with prolidase deficiency is systemic lupus erythematosus (SLE), although not all individuals fulfill the American College of Rheumatology criteria for a diagnosis of SLE.
Reported positive markers include rheumatoid factor, antinuclear antibodies, ANCA, anti-dsDNA, anti-cardiolipin, anti-SSA/Ro, anti-SSB/La, anti-chromatin, anti-RNP, and/or anti-Sm antibodies.
A couple of cases of cryoglobulinemia have been reported [
Sometimes, these antibodies have been reported in the absence of SLE-like clinical findings [
Other autoimmune conditions may include:
Autoimmune arthritis, including psoriatic arthritis or juvenile idiopathic arthritis
Vasculitis, including central nervous system vasculitis
Rhupus (a condition in which individuals have features of both rheumatoid arthritis and SLE, often in a sequential manner)
Coombs-positive hemolytic anemia
Crohn-like disease
Autoimmune adrenal failure (in one affected individual) [
• Reported positive markers include rheumatoid factor, antinuclear antibodies, ANCA, anti-dsDNA, anti-cardiolipin, anti-SSA/Ro, anti-SSB/La, anti-chromatin, anti-RNP, and/or anti-Sm antibodies.
• A couple of cases of cryoglobulinemia have been reported [
• Sometimes, these antibodies have been reported in the absence of SLE-like clinical findings [
• Autoimmune arthritis, including psoriatic arthritis or juvenile idiopathic arthritis
• Vasculitis, including central nervous system vasculitis
• Rhupus (a condition in which individuals have features of both rheumatoid arthritis and SLE, often in a sequential manner)
• Coombs-positive hemolytic anemia
• Crohn-like disease
• Autoimmune adrenal failure (in one affected individual) [
## Bone/Limb Manifestations
Among 12 affected individuals reported by
Other primary bone/limb findings (reported in a few cases each) include:
Spina bifida of C3 and 13 thoracic vertebrae [
Fusion of C2 and C3 [
Delayed bone age [
Syndactyly of the hands and/or feet
Pes planus
Pes cavus
Short fingers / brachydactyly
Arachnodactyly
• Spina bifida of C3 and 13 thoracic vertebrae [
• Fusion of C2 and C3 [
• Delayed bone age [
• Syndactyly of the hands and/or feet
• Pes planus
• Pes cavus
• Short fingers / brachydactyly
• Arachnodactyly
## Other Manifestations
Ocular abnormalities have been found in approximately 15% of affected individuals and include varied phenomena including optic and chorioretinal atrophy in two individuals [
Dental abnormalities were present in more than 20 affected individuals. Dental findings have included multiple caries with or without enamel hypoplasia, misaligned teeth, and hypodontia.
Diarrhea has been reported in 19 affected individuals, even in the absence of Crohn-like inflammatory bowel disease (reported in only 5 individuals).
Both poor weight gain (14%) and short stature (12%) as well as overweight/obesity (9%) have been reported.
## Prognosis
The severity of prolidase deficiency is quite variable: in some individuals skin ulcerations lead to amputation of one or all toes, whereas others remain entirely asymptomatic [
In many instances, however, individuals with prolidase deficiency experience severe morbidity and sometimes early death, usually as a result of infection or respiratory failure. The youngest reported death was at age three months [
## Genotype-Phenotype Correlations
In general, individuals with biallelic loss-of-function pathogenic variants in
By age 20 years, 100% of individuals with loss-of-function pathogenic variants reported ulcers, whereas fewer than 50% of individuals with biallelic pathogenic missense variants reported having ulcers by this age.
However, marked phenotypic variability has been found among affected individuals even from the same family (who have the same pathogenic variants) [
• By age 20 years, 100% of individuals with loss-of-function pathogenic variants reported ulcers, whereas fewer than 50% of individuals with biallelic pathogenic missense variants reported having ulcers by this age.
• However, marked phenotypic variability has been found among affected individuals even from the same family (who have the same pathogenic variants) [
## Nomenclature
Prolidase deficiency was also known as hyperimidodipeptiduria, although increased excretion of imidodipeptides is not exclusive to prolidase deficiency. Other names used in the past include imidodipeptidase deficiency and peptidase D deficiency.
## Prevalence
Approximately 175 affected individuals have been reported in the literature; however, prolidase deficiency likely remains underdiagnosed as a result of underrecognition by physicians.
The Québec Newborn Urine Screening Program (Programme québécois de dépistage neonatal urinaire, PQDNU) identified two affected infants out of 2,469,929 screened between 1973 and 2006, for an incidence of 1:1,235,000 [
Prolidase deficiency has been diagnosed throughout the world [
A founder variant has been described in the Geauga County Amish settlement in Ohio [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genetic Disorders with Skin Ulcers and/or Immune Deficiency in the Differential Diagnosis of Prolidase Deficiency
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; HIES = hyper IgE syndrome; MOI = mode of inheritance
## Management
No clinical practice guidelines for prolidase deficiency have been published.
To establish the extent of disease and needs in an individual diagnosed with prolidase deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Prolidase Deficiency
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI if clinically indicated.
Consider EEG if seizures are a concern.
Chest imaging, including chest x-ray;
Pulmonary function tests;
Echocardiogram to assess for pulmonary hypertension.
Gross motor & fine motor skills
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.
ALT = alanine transaminase; AST = aspartate aminotransferase; BCVA = best corrected visual acuity; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Care is preferably provided by a multidisciplinary team.
Treatment of Manifestations in Individuals with Prolidase Deficiency
Consider PRBC transfusion in those w/severe anemia.
Consider platelet transfusion in those w/severe thrombocytopenia or low platelet counts who require any (incl dental) surgical procedures.
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, DD = developmental delay; HLH = hemophagocytic lymphohistiocytosis; ID = intellectual disability; SLE = systemic lupus erythematosus
Many therapies have been tried but few are successful. Oral proline supplementation has not been successful. For a full list of treatments that have been trialed (with partial success in some), click
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).
Those who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection.
Antibiotic prophylaxis should also be considered in the appropriate setting.
Recommended Surveillance for Individuals with Prolidase Deficiency
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, & mvmt disorders.
Liver function tests
Abdominal ultrasound exam to assess liver & spleen size
OT = occupational therapy; PT = physical therapy
Individuals with prolidase deficiency who have splenomegaly should avoid contact sports given the increased risk for splenic rupture.
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI if clinically indicated.
• Consider EEG if seizures are a concern.
• Chest imaging, including chest x-ray;
• Pulmonary function tests;
• Echocardiogram to assess for pulmonary hypertension.
• Gross motor & fine motor skills
• 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.
• Consider PRBC transfusion in those w/severe anemia.
• Consider platelet transfusion in those w/severe thrombocytopenia or low platelet counts who require any (incl dental) surgical procedures.
• 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).
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, & mvmt disorders.
• Liver function tests
• Abdominal ultrasound exam to assess liver & spleen size
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with prolidase deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Prolidase Deficiency
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI if clinically indicated.
Consider EEG if seizures are a concern.
Chest imaging, including chest x-ray;
Pulmonary function tests;
Echocardiogram to assess for pulmonary hypertension.
Gross motor & fine motor skills
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.
ALT = alanine transaminase; AST = aspartate aminotransferase; BCVA = best corrected visual acuity; DXA = dual-energy x-ray absorptiometry; 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
• Eval for early intervention / special education
• Consider brain MRI if clinically indicated.
• Consider EEG if seizures are a concern.
• Chest imaging, including chest x-ray;
• Pulmonary function tests;
• Echocardiogram to assess for pulmonary hypertension.
• Gross motor & fine motor skills
• 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
Care is preferably provided by a multidisciplinary team.
Treatment of Manifestations in Individuals with Prolidase Deficiency
Consider PRBC transfusion in those w/severe anemia.
Consider platelet transfusion in those w/severe thrombocytopenia or low platelet counts who require any (incl dental) surgical procedures.
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, DD = developmental delay; HLH = hemophagocytic lymphohistiocytosis; ID = intellectual disability; SLE = systemic lupus erythematosus
Many therapies have been tried but few are successful. Oral proline supplementation has not been successful. For a full list of treatments that have been trialed (with partial success in some), click
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).
• Consider PRBC transfusion in those w/severe anemia.
• Consider platelet transfusion in those w/severe thrombocytopenia or low platelet counts who require any (incl dental) surgical procedures.
• 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).
## 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).
• 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).
## Prevention of Secondary Complications
Those who have undergone splenectomy should be appropriately immunized and treated promptly with antibiotics at the first sign of infection.
Antibiotic prophylaxis should also be considered in the appropriate setting.
## Surveillance
Recommended Surveillance for Individuals with Prolidase Deficiency
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, & mvmt disorders.
Liver function tests
Abdominal ultrasound exam to assess liver & spleen size
OT = occupational therapy; PT = physical therapy
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, & mvmt disorders.
• Liver function tests
• Abdominal ultrasound exam to assess liver & spleen size
## Agents/Circumstances to Avoid
Individuals with prolidase deficiency who have splenomegaly should avoid contact sports given the increased risk for splenic rupture.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Prolidase deficiency is inherited in an autosomal recessive manner.
The parents of an affected child are presumed to be heterozygous for a
If a molecular diagnosis has been established in the proband, 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 asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Significant clinical variability may be observed between sibs with the same
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Note: Urine amino acid analysis of carriers for detection of imidodipeptiduria is uninformative.
A high carrier rate for prolidase deficiency exists in certain populations, increasing the risk that an affected individual may have a reproductive partner who is heterozygous (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.
Note: Results of prenatal testing cannot be used to predict age of onset or clinical course. Severity of the condition can vary among affected individuals within the same family.
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
• If a molecular diagnosis has been established in the proband, 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 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
• Significant clinical variability may be observed between sibs with the same
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• A high carrier rate for prolidase deficiency exists in certain populations, increasing the risk that an affected individual may have a reproductive partner who is heterozygous (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
Prolidase 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
If a molecular diagnosis has been established in the proband, 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 asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Significant clinical variability may be observed between sibs with the same
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
• If a molecular diagnosis has been established in the proband, 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 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
• Significant clinical variability may be observed between sibs with the same
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## Carrier Detection
Note: Urine amino acid analysis of carriers for detection of imidodipeptiduria is uninformative.
## Related Genetic Counseling Issues
A high carrier rate for prolidase deficiency exists in certain populations, increasing the risk that an affected individual may have a reproductive partner who is heterozygous (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.
• A high carrier rate for prolidase deficiency exists in certain populations, increasing the risk that an affected individual may have a reproductive partner who is heterozygous (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
Note: Results of prenatal testing cannot be used to predict age of onset or clinical course. Severity of the condition can vary among affected individuals within the same family.
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
Prolidase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Prolidase Deficiency (
Prolidase contains 493 amino acids. It is a homodimer, with each subunit binding two manganese ions that are required for full enzymatic activity. The enzyme is required in the final catabolic steps of endogenous and dietary proteins, as it cleaves proline or hydroxyproline when these amino acids are in the C-terminal position. It is thus particularly important in the metabolism of proteins rich in proline and hydroxyproline, such as collagen. The deficiency of prolidase leads to accumulation of imidodipeptides, or peptides with two amino acids, with a C-terminal proline or hydroxyproline.
Several pathophysiologic hypotheses have been proposed, many involving abnormal collagen recycling or complement abnormalities. Prolidase is released from damaged cells and has some roles in the regulation of transforming growth factor beta, hypoxia-induced factor 1-alpha, and epidermal growth factor receptor. Both the imidodipeptidase activity and non-enzymatic roles of prolidase may be responsible for the findings.
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Prolidase contains 493 amino acids. It is a homodimer, with each subunit binding two manganese ions that are required for full enzymatic activity. The enzyme is required in the final catabolic steps of endogenous and dietary proteins, as it cleaves proline or hydroxyproline when these amino acids are in the C-terminal position. It is thus particularly important in the metabolism of proteins rich in proline and hydroxyproline, such as collagen. The deficiency of prolidase leads to accumulation of imidodipeptides, or peptides with two amino acids, with a C-terminal proline or hydroxyproline.
Several pathophysiologic hypotheses have been proposed, many involving abnormal collagen recycling or complement abnormalities. Prolidase is released from damaged cells and has some roles in the regulation of transforming growth factor beta, hypoxia-induced factor 1-alpha, and epidermal growth factor receptor. Both the imidodipeptidase activity and non-enzymatic roles of prolidase may be responsible for the findings.
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
7 July 2022 (ma) Comprehensive update posted live
25 June 2015 (me) Review posted live
20 January 2015 (cf) Original submission
• 7 July 2022 (ma) Comprehensive update posted live
• 25 June 2015 (me) Review posted live
• 20 January 2015 (cf) Original submission
## Revision History
7 July 2022 (ma) Comprehensive update posted live
25 June 2015 (me) Review posted live
20 January 2015 (cf) Original submission
• 7 July 2022 (ma) Comprehensive update posted live
• 25 June 2015 (me) Review posted live
• 20 January 2015 (cf) Original submission
## References
## Literature Cited
Typical skin ulcerations in individuals with prolidase deficiency
Typical facial features of prolidase deficiency: prominent forehead, proptosis, depressed nasal bridge, and thin vermilion of the upper lip
|
[] |
25/6/2015
|
7/7/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
prop1
|
prop1
|
[
"PROP1-Related CPHD",
"PROP1-Related CPHD",
"Homeobox protein prophet of Pit-1",
"PROP1",
"PROP1-Related Combined Pituitary Hormone Deficiency"
] |
Luciani Renata Carvalho, Mirian Yumie Nishi, Fernanda Azevedo Correa, Juliana Moreira Marques, Ivo Jorge Prado Arnhold, Berenice B Mendonca
|
Summary Most affected individuals are ascertained because of short stature during childhood. Although TSH deficiency can present shortly after birth, TSH deficiency usually occurs with or after the onset of GH deficiency. Hypothyroidism is usually mild. FSH and LH deficiencies are typically identified at the age of onset of puberty. Affected individuals can have absent or delayed and incomplete secondary sexual development with infertility. Untreated males usually have a small penis and small testes. Some females experience menarche but subsequently require hormone replacement therapy. ACTH deficiency is less common and, when present, usually occurs in adolescence or adulthood. Neuroimaging of hypothalamic-pituitary region usually demonstrates a hypoplastic or normal anterior pituitary lobe and a normal posterior pituitary lobe. The diagnosis of
|
## Diagnosis
Thyroid-stimulating hormone (TSH)
The two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
Prolactin (PrL)
Adrenocorticotropic hormone (ACTH) (Deficiency develops in ~50% of individuals.)
Delayed bone maturation on x-ray examination
On head MRI, normal pituitary stalk and normal position of posterior lobe; anterior lobe may appear hypoplastic, normal, or diffusely enlarged [
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. Individuals with the distinctive findings described in
Note: Targeted analysis can be considered for founder variants in individuals of Hutterite, Indian, and/or Eastern European ancestry or for individuals from the Iberian Peninsula. See
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by CPHD,
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
The common recurring
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.
• Thyroid-stimulating hormone (TSH)
• The two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
• Prolactin (PrL)
• Adrenocorticotropic hormone (ACTH) (Deficiency develops in ~50% of individuals.)
• Delayed bone maturation on x-ray examination
• On head MRI, normal pituitary stalk and normal position of posterior lobe; anterior lobe may appear hypoplastic, normal, or diffusely enlarged [
## Suggestive Findings
Thyroid-stimulating hormone (TSH)
The two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
Prolactin (PrL)
Adrenocorticotropic hormone (ACTH) (Deficiency develops in ~50% of individuals.)
Delayed bone maturation on x-ray examination
On head MRI, normal pituitary stalk and normal position of posterior lobe; anterior lobe may appear hypoplastic, normal, or diffusely enlarged [
• Thyroid-stimulating hormone (TSH)
• The two gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH)
• Prolactin (PrL)
• Adrenocorticotropic hormone (ACTH) (Deficiency develops in ~50% of individuals.)
• Delayed bone maturation on x-ray examination
• On head MRI, normal pituitary stalk and normal position of posterior lobe; anterior lobe may appear hypoplastic, normal, or diffusely enlarged [
## 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. Individuals with the distinctive findings described in
Note: Targeted analysis can be considered for founder variants in individuals of Hutterite, Indian, and/or Eastern European ancestry or for individuals from the Iberian Peninsula. See
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by CPHD,
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
The common recurring
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
Note: Targeted analysis can be considered for founder variants in individuals of Hutterite, Indian, and/or Eastern European ancestry or for individuals from the Iberian Peninsula. See
For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by CPHD,
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
The common recurring
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
ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; GH = growth hormone; LH = luteinizing hormone; PrL = prolactin; TSH = thyroid-stimulating hormone
Clinical response to exogenous GH usually depends on the severity of GH deficiency, deficiencies of other pituitary hormones, age of onset of growth failure, the time interval between the onset of growth failure and the onset of GH therapy, duration of replacement therapy, and the sex of the affected individual.
If treatment is started early in life, GH therapy is very effective for linear growth to achieve familial expected height. GH therapy has also improved body composition and quality of life in older individuals [
Affected individuals with later onset can have absent or delayed and incomplete secondary sexual development and infertility. Adolescent males may present with small penis, small testes, onset of puberty after age 14 years, and/or cessation of secondary sexual development. Adolescent females may present with lack of breast development or delayed menarche. Some females experience menarche before requiring hormone replacement therapy [
Gonadotropin deficiency can be the presenting feature, with GH deficiency and TSH deficiency developing later in adulthood [
Facies are characterized as "immature," with a depressed nasal bridge and relative decrease in the vertical dimensions of the face [
Obesity, rare in childhood, is more common in adulthood.
Limited genotype-phenotype correlations have been identified. Phenotypic variability was observed among individuals with the same pathogenic variants, particularly the presence and age of onset of hypocortisolism, the levels of prolactin, and the results of pituitary imaging [
There are reports of spontaneous puberty with decline of gonadotropic function in individuals with
Impaired gonadotropic function occurs in all individuals with the most common
The prevalence of
• Facies are characterized as "immature," with a depressed nasal bridge and relative decrease in the vertical dimensions of the face [
• Obesity, rare in childhood, is more common in adulthood.
• There are reports of spontaneous puberty with decline of gonadotropic function in individuals with
• Impaired gonadotropic function occurs in all individuals with the most common
## Clinical Description
ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; GH = growth hormone; LH = luteinizing hormone; PrL = prolactin; TSH = thyroid-stimulating hormone
Clinical response to exogenous GH usually depends on the severity of GH deficiency, deficiencies of other pituitary hormones, age of onset of growth failure, the time interval between the onset of growth failure and the onset of GH therapy, duration of replacement therapy, and the sex of the affected individual.
If treatment is started early in life, GH therapy is very effective for linear growth to achieve familial expected height. GH therapy has also improved body composition and quality of life in older individuals [
Affected individuals with later onset can have absent or delayed and incomplete secondary sexual development and infertility. Adolescent males may present with small penis, small testes, onset of puberty after age 14 years, and/or cessation of secondary sexual development. Adolescent females may present with lack of breast development or delayed menarche. Some females experience menarche before requiring hormone replacement therapy [
Gonadotropin deficiency can be the presenting feature, with GH deficiency and TSH deficiency developing later in adulthood [
Facies are characterized as "immature," with a depressed nasal bridge and relative decrease in the vertical dimensions of the face [
Obesity, rare in childhood, is more common in adulthood.
• Facies are characterized as "immature," with a depressed nasal bridge and relative decrease in the vertical dimensions of the face [
• Obesity, rare in childhood, is more common in adulthood.
## Genotype-Phenotype Correlations
Limited genotype-phenotype correlations have been identified. Phenotypic variability was observed among individuals with the same pathogenic variants, particularly the presence and age of onset of hypocortisolism, the levels of prolactin, and the results of pituitary imaging [
There are reports of spontaneous puberty with decline of gonadotropic function in individuals with
Impaired gonadotropic function occurs in all individuals with the most common
• There are reports of spontaneous puberty with decline of gonadotropic function in individuals with
• Impaired gonadotropic function occurs in all individuals with the most common
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Selected genes associated with CPHD;*
Isolated growth hormone deficiency (which may evolve into CPHD);
Isolated hypogonadotropic hypogonadism (which may overlap molecularly with CPHD and/or evolve in CPHD).
* More than 30 genes are known to be associated CPHD. Based on 21 studies, pathogenic variants in five genes –
Note: Some CPHD conditions may present with extrapituitary abnormalities that have not been systematically reported in
Genetic Disorders of Interest in the Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; CPHD = combined pituitary hormone deficiency
Pathogenic variants in more than 30 genes account for about half of all isolated GnRH deficiency; the genetic cause is unknown in about 50% of persons with isolated GnRH deficiency.
• Selected genes associated with CPHD;*
• Isolated growth hormone deficiency (which may evolve into CPHD);
• Isolated hypogonadotropic hypogonadism (which may overlap molecularly with CPHD and/or evolve in CPHD).
## Management
To establish the extent of disease and needs in each individual with newly diagnosed
Recommended Evaluations Following Initial Diagnosis in Individuals with
Basal IGF1
Basal & stimulated GH
Clinical assessment for micropenis in newborn males
Clinical assessment of pubertal development & secondary sexual characteristics in newly diagnosed adolescents/adults
Assessment of amenorrhea or irregular menses in women
Assessment of infertility
LH & FSH measured at beginning of pubertal age
ITT = insulin tolerance test; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
The main principle of treatment in
Treatment of Manifestations in Individuals with
The initial dose of rhGH is based on body weight in childhood.
The dose ↑s w/↑ body weight to a maximum during puberty.
When final height is achieved, rhGH dose is ↓ to 0.2-0.4 mg/d for persons age 60 yrs.
The ideal rhGH dose will raise & maintain IGF1 levels to between mean & upper limit of normal.
There is ↑ support for rhGH treatment in young adults because of possible effects on fat metabolism, lean body mass, & bone mineral density.
In males: starting at 12-13 yrs, monthly injections of 100 mg testosterone enanthate, gradually ↑ by 50 mg every 6 mos to a dose of 200-300 mg/mo
In females: starting at 11-12 yrs, 17 beta-estradiol or estradiol valerate, cycling w/progesterone (medroxyprogesterone acetate, 5-10 mg/d) & micronized progesterone (200 mg/d from 1st to 12th day of each month)
Long-term mgmt: 8-10 mg/m
For minor stress (e.g., fever, minor illness), hydrocortisone dose is doubled or tripled until illness has resolved.
For major stress (e.g., surgery, significant illness), hydrocortisone is ↑ to 50-100 mg & administered parenterally w/fluid replacement.
Recommended Surveillance for Individuals with
ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; GH = growth hormone; LH = luteinizing hormone; PrL = prolactin; TSH = thyroid-stimulating hormone
Thyroid hormone replacement should not be initiated until adrenal function has been assessed and adrenal insufficiency is treated if present.
For individuals with GH deficiency, the lowest safe dose of hydrocortisone is used to avoid interfering with the growth response to growth hormone therapy.
It is appropriate to clarify the genetic status of younger sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of hormone replacement therapy and surveillance.
For younger sibs who have not undergone molecular genetic testing, monitoring growth for evidence of growth failure is appropriate. Of note, affected sibs usually have extreme short stature because of thyroid hormone deficiency and GH deficiency.
See
Long-acting GH preparations are being developed to improve adherence by decreasing the frequency of GH injections from daily to weekly, biweekly, or monthly. However, several questions need to be addressed including the methods of dose adjustment, the timing of IGF1 monitoring, safety, efficacy, and cost effectiveness [
Newer glucocorticoid replacement alternatives are under development. Medications with a modified release (Chonocort
Search
• Basal IGF1
• Basal & stimulated GH
• Clinical assessment for micropenis in newborn males
• Clinical assessment of pubertal development & secondary sexual characteristics in newly diagnosed adolescents/adults
• Assessment of amenorrhea or irregular menses in women
• Assessment of infertility
• LH & FSH measured at beginning of pubertal age
• The initial dose of rhGH is based on body weight in childhood.
• The dose ↑s w/↑ body weight to a maximum during puberty.
• When final height is achieved, rhGH dose is ↓ to 0.2-0.4 mg/d for persons age 60 yrs.
• The ideal rhGH dose will raise & maintain IGF1 levels to between mean & upper limit of normal.
• There is ↑ support for rhGH treatment in young adults because of possible effects on fat metabolism, lean body mass, & bone mineral density.
• In males: starting at 12-13 yrs, monthly injections of 100 mg testosterone enanthate, gradually ↑ by 50 mg every 6 mos to a dose of 200-300 mg/mo
• In females: starting at 11-12 yrs, 17 beta-estradiol or estradiol valerate, cycling w/progesterone (medroxyprogesterone acetate, 5-10 mg/d) & micronized progesterone (200 mg/d from 1st to 12th day of each month)
• Long-term mgmt: 8-10 mg/m
• For minor stress (e.g., fever, minor illness), hydrocortisone dose is doubled or tripled until illness has resolved.
• For major stress (e.g., surgery, significant illness), hydrocortisone is ↑ to 50-100 mg & administered parenterally w/fluid replacement.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in each individual with newly diagnosed
Recommended Evaluations Following Initial Diagnosis in Individuals with
Basal IGF1
Basal & stimulated GH
Clinical assessment for micropenis in newborn males
Clinical assessment of pubertal development & secondary sexual characteristics in newly diagnosed adolescents/adults
Assessment of amenorrhea or irregular menses in women
Assessment of infertility
LH & FSH measured at beginning of pubertal age
ITT = insulin tolerance test; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Basal IGF1
• Basal & stimulated GH
• Clinical assessment for micropenis in newborn males
• Clinical assessment of pubertal development & secondary sexual characteristics in newly diagnosed adolescents/adults
• Assessment of amenorrhea or irregular menses in women
• Assessment of infertility
• LH & FSH measured at beginning of pubertal age
## Treatment of Manifestations
The main principle of treatment in
Treatment of Manifestations in Individuals with
The initial dose of rhGH is based on body weight in childhood.
The dose ↑s w/↑ body weight to a maximum during puberty.
When final height is achieved, rhGH dose is ↓ to 0.2-0.4 mg/d for persons age 60 yrs.
The ideal rhGH dose will raise & maintain IGF1 levels to between mean & upper limit of normal.
There is ↑ support for rhGH treatment in young adults because of possible effects on fat metabolism, lean body mass, & bone mineral density.
In males: starting at 12-13 yrs, monthly injections of 100 mg testosterone enanthate, gradually ↑ by 50 mg every 6 mos to a dose of 200-300 mg/mo
In females: starting at 11-12 yrs, 17 beta-estradiol or estradiol valerate, cycling w/progesterone (medroxyprogesterone acetate, 5-10 mg/d) & micronized progesterone (200 mg/d from 1st to 12th day of each month)
Long-term mgmt: 8-10 mg/m
For minor stress (e.g., fever, minor illness), hydrocortisone dose is doubled or tripled until illness has resolved.
For major stress (e.g., surgery, significant illness), hydrocortisone is ↑ to 50-100 mg & administered parenterally w/fluid replacement.
• The initial dose of rhGH is based on body weight in childhood.
• The dose ↑s w/↑ body weight to a maximum during puberty.
• When final height is achieved, rhGH dose is ↓ to 0.2-0.4 mg/d for persons age 60 yrs.
• The ideal rhGH dose will raise & maintain IGF1 levels to between mean & upper limit of normal.
• There is ↑ support for rhGH treatment in young adults because of possible effects on fat metabolism, lean body mass, & bone mineral density.
• In males: starting at 12-13 yrs, monthly injections of 100 mg testosterone enanthate, gradually ↑ by 50 mg every 6 mos to a dose of 200-300 mg/mo
• In females: starting at 11-12 yrs, 17 beta-estradiol or estradiol valerate, cycling w/progesterone (medroxyprogesterone acetate, 5-10 mg/d) & micronized progesterone (200 mg/d from 1st to 12th day of each month)
• Long-term mgmt: 8-10 mg/m
• For minor stress (e.g., fever, minor illness), hydrocortisone dose is doubled or tripled until illness has resolved.
• For major stress (e.g., surgery, significant illness), hydrocortisone is ↑ to 50-100 mg & administered parenterally w/fluid replacement.
## Surveillance
Recommended Surveillance for Individuals with
ACTH = adrenocorticotropic hormone; FSH = follicle-stimulating hormone; GH = growth hormone; LH = luteinizing hormone; PrL = prolactin; TSH = thyroid-stimulating hormone
## Agents/Circumstances to Avoid
Thyroid hormone replacement should not be initiated until adrenal function has been assessed and adrenal insufficiency is treated if present.
For individuals with GH deficiency, the lowest safe dose of hydrocortisone is used to avoid interfering with the growth response to growth hormone therapy.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of younger sibs of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of hormone replacement therapy and surveillance.
For younger sibs who have not undergone molecular genetic testing, monitoring growth for evidence of growth failure is appropriate. Of note, affected sibs usually have extreme short stature because of thyroid hormone deficiency and GH deficiency.
See
## Therapies Under Investigation
Long-acting GH preparations are being developed to improve adherence by decreasing the frequency of GH injections from daily to weekly, biweekly, or monthly. However, several questions need to be addressed including the methods of dose adjustment, the timing of IGF1 monitoring, safety, efficacy, and cost effectiveness [
Newer glucocorticoid replacement alternatives are under development. Medications with a modified release (Chonocort
Search
## Genetic Counseling
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
Intrafamilial clinical variability may be observed between sibs with the same pathogenic variants [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Fertility in both females and males with
The offspring of an individual with
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 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
• Intrafamilial clinical variability may be observed between sibs with the same pathogenic variants [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Fertility in both females and males with
• The offspring 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 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 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
Intrafamilial clinical variability may be observed between sibs with the same pathogenic variants [
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Fertility in both females and males with
The offspring of an individual with
• 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
• Intrafamilial clinical variability may be observed between sibs with the same pathogenic variants [
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Fertility in both females and males with
• The offspring of an individual 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 and discussion of the availability of prenatal/preimplantation genetic testing is before 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
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## Molecular Genetics
PROP1-Related Combined Pituitary Hormone Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for PROP1-Related Combined Pituitary Hormone Deficiency (
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Chapter Notes
Fundação de amparo a Pesquisa do Estado de São Paulo (Fapesp)Conselho nacional de apoio à Pesquisa (CNPq)
Ivo Jorge Prado Arnhold, MD (2022-present)Fernanda Azevedo Correa, MD (2022-present)Berenice B Mendonca, MD (2022-present)Luciani Renata Carvalho, MD, PhD (2022-present)Laura CG de Graaff, MD, PhD; Erasmus Medical Center (2011-2022)Lawrence C Layman, MD; Medical College of Georgia (1999-2011)Juliana Moreira Marques, PhD (2022-present)Mirian Yumie Nishi, MD, PhD (2022-present)John A Phillips III, MD; Vanderbilt University Medical Center (1999-2011)Cindy Vnencak-Jones, PhD; Vanderbilt University Medical Center (1999-2011)
24 February 2022 (sw) Comprehensive update posted live
7 August 2014 (me) Comprehensive update posted live
6 October 2011 (me) Comprehensive update posted live
21 November 2005 (me) Comprehensive update posted live
16 June 2003 (ca) Comprehensive update posted live
7 December 2000 (me) Review posted live
18 October 1999 (jp) Original submission
• 24 February 2022 (sw) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 6 October 2011 (me) Comprehensive update posted live
• 21 November 2005 (me) Comprehensive update posted live
• 16 June 2003 (ca) Comprehensive update posted live
• 7 December 2000 (me) Review posted live
• 18 October 1999 (jp) Original submission
## Author Notes
## Acknowledgments
Fundação de amparo a Pesquisa do Estado de São Paulo (Fapesp)Conselho nacional de apoio à Pesquisa (CNPq)
## Author History
Ivo Jorge Prado Arnhold, MD (2022-present)Fernanda Azevedo Correa, MD (2022-present)Berenice B Mendonca, MD (2022-present)Luciani Renata Carvalho, MD, PhD (2022-present)Laura CG de Graaff, MD, PhD; Erasmus Medical Center (2011-2022)Lawrence C Layman, MD; Medical College of Georgia (1999-2011)Juliana Moreira Marques, PhD (2022-present)Mirian Yumie Nishi, MD, PhD (2022-present)John A Phillips III, MD; Vanderbilt University Medical Center (1999-2011)Cindy Vnencak-Jones, PhD; Vanderbilt University Medical Center (1999-2011)
## Revision History
24 February 2022 (sw) Comprehensive update posted live
7 August 2014 (me) Comprehensive update posted live
6 October 2011 (me) Comprehensive update posted live
21 November 2005 (me) Comprehensive update posted live
16 June 2003 (ca) Comprehensive update posted live
7 December 2000 (me) Review posted live
18 October 1999 (jp) Original submission
• 24 February 2022 (sw) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 6 October 2011 (me) Comprehensive update posted live
• 21 November 2005 (me) Comprehensive update posted live
• 16 June 2003 (ca) Comprehensive update posted live
• 7 December 2000 (me) Review posted live
• 18 October 1999 (jp) Original submission
## References
Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab. Available
Ho KK, et al. GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Available
• Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab. Available
• Ho KK, et al. GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Available
## Published Guidelines / Consensus Statements
Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab. Available
Ho KK, et al. GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Available
• Growth Hormone Research Society. Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab. Available
• Ho KK, et al. GH Deficiency Consensus Workshop Participants. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia. Available
## Literature Cited
|
[
"RV Araujo, CV Chang, VA Cescato, MC Fragoso, MD Bronstein, BB Mendonca, IJ Arnhold, LR Carvalho. PROP1 overexpression in corticotrophinomas: evidence for the role of PROP1 in the maintenance of cells committed to corticotrophic differentiation.. Clinics (Sao Paulo) 2013;68:887-91",
"K Bajuk Studen, MA Stefanija, A Saveanu, A Barlier, T Brue, M Pfeifer. Genetic analysis of adult Slovenian patients with combined pituitary hormone deficiency.. Endocrine. 2019;65:379-85",
"F Baş, ZO Uyguner, F Darendeliler, Z Aycan, E Çetinkaya, M Berberoğlu, Z Şiklar, G Öcal, Ş Darcan, D Gökşen, AK Topaloğlu, B Yüksel, MN Özbek, O Ercan, O Evliyaoğlu, S Çetinkaya, Y Şen, E Atabek, G Toksoy, BK Aydin, R Bundak. Molecular analysis of PROP1, POU1F1, LHX3, and HESX1 in Turkish patients with combined pituitary hormone deficiency: a multicenter study.. Endocrine. 2015;49:479-91",
"FD Bulut, S Özdemir Dilek, D Kotan, E Mengen, F Gürbüz, B Yüksel. Mutations within the transcription factor PROP1 in a cohort of Turkish patients with combined pituitary hormone deficiency.. J Clin Res Pediatr Endocrinol. 2020;12:261-8",
"FA Correa, M Nakaguma, JLO Madeira, MY Nishi, MG Abrão, AAL Jorge, LR Carvalho, IJP Arnhold, BB Mendonça. Combined pituitary hormone deficiency caused by PROP1 mutations: update 20 years post-discovery.. Arch Endocrinol Metab. 2019;63:167-74",
"F De Rienzo, S Mellone, S Bellone, D Babu, I Fusco, F Prodam, A Petri, R Muniswamy, F De Luca, M Salerno, P Momigliano-Richardi, G Bona, M Giordano. Frequency of genetic defects in combined pituitary hormone deficiency: a systematic review and analysis of a multicentre Italian cohort.. Clin Endocrinol (Oxf) 2015;83:849-60",
"M Doknic, V Gasic, M Stojanovic, S Pavlovic, S Marinkovic, D Miljic, S Pekic, E Manojlovic-Gacic, D Damjanovic, I Soldatovic, M. Petakov. Hypopituitarism in five PROP1 mutation siblings: long-lasting natural course and the effects of growth hormone replacement introduction in middle adulthood.. Pituitary. 2020;23:400-8",
"P Dusatkova, R Pfäffle, MR Brown, N Akulevich, IJ Arnhold, MA Kalina, K Kot, C Krzisnik, MC Lemos, J Malikova, R Navardauskaite, B Obermannova, Z Pribilincova, A Sallai, G Stipancic, R Verkauskiene, O Cinek, WF Blum, JS Parks, F Austerlitz, J Lebl. Genesis of two most prevalent PROP1 gene variants causing combined pituitary hormone deficiency in 21 populations.. Eur J Hum Genet. 2016;24:415-20",
"M Fleseriu, IA Hashim, N Karavitaki, S Melmed, MH Murad, R Salvatori, MH Samuels. Hormonal replacement in hypopituitarism in adults: an Endocrine Society Clinical Practice Guideline.. J Clin Endocrinol Metab. 2016;101:3888-921",
"C Flück, J Deladoey, K Rutishauser, A Eblé, U Marti, W Wu, PE Mullis. Phenotypic variability in familial combined pituitary hormone deficiency caused by a PROP1 gene mutation resulting in the substitution of Arg-->Cys at codon 120 (R120C).. J Clin Endocrinol Metab. 1998;83:3727-34",
"N Fritez, ML Sobrier, H Iraqi, MP Vié-Luton, I Netchine, A El Annas, J Pantel, N Collot, S Rose, W Piterboth, M Legendre, A Chraibi, S Amselem, A Kadiri, L Hilal. Molecular screening of a large cohort of Moroccan patients with congenital hypopituitarism.. Clin Endocrinol (Oxf) 2015;82:876-84",
"HM Garmes, CL Boguszewski, PAC Miranda, MRA Martins, SRC da Silva, JZ Abucham. Filho, de Castro Musolino NR, Vilar L, Portari LHC, Gadelha MR, Kasuki L, Naves LA, Czepielewski MA, de Almeida TS, Duarte FHG, Glezer A, Bronstein MD. Management of hypopituitarism: a perspective from the Brazilian Society of Endocrinology and Metabolism.. Arch Endocrinol Metab. 2021;65:212-30",
"S Gorar, D Turkkahraman, K. Yararbas. A large PROP1 gene deletion in a Turkish pedigree.. Case Rep Endocrinol. 2018;2018",
"Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. GH Research Society.. J Clin Endocrinol Metab. 2000;85:3990-3",
"JC Guy, CS Hunter, AD Showalter, TP Smith, K Charoonpatrapong, KW Sloop, JP Bidwell, SJ Rhodes. Conserved amino acid sequences confer nuclear localization upon the Prophet of Pit-1 pituitary transcription factor protein.. Gene 2004;336:263-73",
"KK Ho. Consensus guidelines for the diagnosis and treatment of adults with GH deficiency II: a statement of the GH Research Society in association with the European Society for Pediatric Endocrinology, Lawson Wilkins Society, European Society of Endocrinology, Japan Endocrine Society, and Endocrine Society of Australia.. Eur J Endocrinol. 2007;157:695-700",
"SR Howard, L Guasti, G Ruiz-Babot, A Mancini, A David, HL Storr, LA Metherell, MJ Sternberg, CP Cabrera, HR Warren, MR Barnes, R Quinton, N de Roux, J Young, A Guiochon-Mantel, K Wehkalampi, V André, Y Gothilf, A Cariboni, L Dunkel. IGSF10 mutations dysregulate gonadotropin-releasing hormone neuronal migration resulting in delayed puberty.. EMBO Mol Med. 2016;8:626-42",
"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",
"C Krzisnik, Z Kolacio, T Battelino, M Brown, JS Parks, Z Laron. The \"little people\" of the island of Krk - revisited. Etiology of hypopituitarism revealed.. J Endocrine Genet. 1999;1:9-19",
"MC Lemos, L Gomes, M Bastos, V Leite, E Limbert, D Carvalho, C Bacelar, M Monteiro, F Fonseca, A Agapito, JJ Castro, FJ Regateiro, M Carvalheiro. PROP1 gene analysis in Portuguese patients with combined pituitary hormone deficiency.. Clin Endocrinol (Oxf) 2006;65:479-85",
"JL Madeira, MY Nishi, M Nakaguma, AF Benedetti, IP Biscotto, T Fernandes, T Pequeno, T Figueiredo, MM Franca, FA Correa, AP Otto, M Abrão, MB Miras, S Santos, AA Jorge, EF Costalonga, BB Mendonca, IJ Arnhold, LR Carvalho. Molecular analysis of brazilian patients with combined pituitary hormone deficiency and orthotopic posterior pituitary lobe reveals eight different PROP1 alterations with three novel mutations.. Clin Endocrinol (Oxf) 2017;87:725-32",
"BS Miller, E Velazquez, KCJ Yuen. Long-acting growth hormone preparations - current status and future considerations.. J Clin Endocrinol Metab. 2020;105:e2121-33",
"R Navardauskaite, P Dusatkova, B Obermannova, RW Pfaeffle, WF Blum, D Adukauskiene, N Smetanina, O Cinek, R Verkauskiene, J Lebl. High prevalence of PROP1 defects in Lithuania: phenotypic findings in an ethnically homogenous cohort of patients with multiple pituitary hormone deficiency.. J Clin Endocrinol Metab. 2014;99:299-306",
"MG Osorio, P Kopp, S Marui, AC Latronico, BB Mendonca, IJ Arnhold. Combined pituitary hormone deficiency caused by a novel mutation of a highly conserved residue (F88S) in the homeodomain of PROP-1.. J Clin Endocrinol Metab. 2000;85:2779-85",
"RM Paragliola, SM Corsello. Secondary adrenal insufficiency: from the physiopathology to the possible role of modified-release hydrocortisone treatment.. Minerva Endocrinol. 2018;43:183-97",
"S Pirinen, A Majurin, HL Lenko, K Koski. Craniofacial features in patients with deficient and excessive growth hormone.. J Craniofac Genet Dev Biol. 1994;14:144-52",
"R Reynaud, A Barlier, S Vallette-Kasic, A Saveanu, MP Guillet, G Simonin, A Enjalbert, P Valensi, T Brue. An uncommon phenotype with familial central hypogonadism caused by a novel PROP1 gene mutant truncated in the transactivation domain.. J Clin Endocrinol Metab. 2005;90:4880-7",
"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 Rohayem, H Drechsel, B Tittel, G Hahn, R Pfaeffle, A Huebner. Long-term outcomes, genetics, and pituitary morphology in patients with isolated growth hormone deficiency and multiple pituitary hormone deficiencies: a single-centre experience of four decades of growth hormone replacement.. Horm Res Paediatr. 2016;86:106-16",
"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",
"JP Turton, A Mehta, J Raza, KS Woods, A Tiulpakov, J Cassar, K Chong, PQ Thomas, M Eunice, AC Ammini, PM Bouloux, J Starzyk, PC Hindmarsh, MT Dattani. Mutations within the transcription factor PROP1 are rare in a cohort of patients with sporadic combined pituitary hormone deficiency (CPHD).. Clin Endocrinol (Oxf) 2005;63:10-8",
"A Voutetakis, A Sertedaki, S Livadas, M Maniati-Christidi, I Mademtzis, I Bossis, C Dacou-Voutetakis, IE Messinis. Ovulation induction and successful pregnancy outcome in two patients with Prop1 gene mutations.. Fertil Steril 2004;82:454-7",
"W Wu, JD Cogan, RW Pfäffle, JS Dasen, H Frisch, SM O'Connell, SE Flynn, MR Brown, PE Mullis, JS Parks, JA Phillips, MG Rosenfeld. Mutations in PROP1 cause familial combined pituitary hormone deficiency.. Nat Genet. 1998;18:147-9"
] |
7/12/2000
|
24/2/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
propionic-a
|
propionic-a
|
[
"Propionyl-CoA carboxylase alpha chain, mitochondrial",
"Propionyl-CoA carboxylase beta chain, mitochondrial",
"PCCA",
"PCCB",
"Propionic Acidemia"
] |
Propionic Acidemia
|
Carolina I Galarreta Aima, Oleg A Shchelochkov, Teodoro Jerves Serrano, Charles P Venditti
|
Summary The spectrum of propionic acidemia (PA) ranges from neonatal onset to late-onset disease. Neonatal-onset PA, the most common form, is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Without prompt diagnosis (often through newborn screening) and management, this is followed by progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death. It is frequently accompanied by metabolic acidosis with anion gap, lactic acidosis, ketonuria, hypoglycemia, hyperammonemia, and cytopenias. Individuals with late-onset PA may remain asymptomatic and suffer a metabolic crisis under catabolic stress (e.g., illness, surgery, fasting) or may experience a more insidious onset with the development of multiorgan complications including vomiting, protein intolerance, failure to thrive, hypotonia, developmental delays or regression, movement disorders, or cardiomyopathy. Isolated cardiomyopathy can be observed on rare occasions in the absence of clinical metabolic decompensation or neurocognitive deficits Manifestations of neonatal-onset and late-onset PA over time can include growth impairment, intellectual disability, seizures, basal ganglia lesions, pancreatitis, cardiomyopathy, and chronic kidney disease. Other rarely reported complications include optic atrophy, sensorineural hearing loss, and premature ovarian insufficiency. PA is caused by deficiency of propionyl-coenzyme A carboxylase (PCC), the enzyme that catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA. Newborns with PA tested by expanded newborn screening (NBS) have elevated C3 (propionylcarnitine). Testing of urine organic acids in persons who are symptomatic or those detected by NBS reveals elevated 3-hydroxypropionate and the presence of methylcitrate, tiglylglycine, propionylglycine, and lactic acid. Testing of plasma amino acids generally reveals elevated glycine. Confirmation of the diagnosis relies on detection of biallelic pathogenic variants in PA is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
NBS for propionic acidemia (PA) is primarily based on the quantification of propionylcarnitine (C3) and calculation of the C3/C2 ratio from the acylcarnitine profile on dried blood spots [
Propionylcarnitine (C3) and/or C3/C2 ratio values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see
If the follow-up biochemical testing supports the diagnosis of PA, confirmatory testing is required (see
The following medical interventions need to begin immediately upon receipt of an abnormal NBS result while additional testing is being performed:
Clinical evaluation of the newborn
Education of the caregivers to avoid prolonged fasting and identify concerning symptoms, including poor feeding, hypothermia, difficulty breathing, vomiting, seizures, or lethargy
Immediate intervention if concerning symptoms are present (see also
Admission to the hospital
Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
Infusion of IV glucose
Nutritional evaluation and consideration of dietary protein restriction
Carnitine supplementation
A symptomatic individual who has either (1) typical findings associated with late-onset PA or (2) untreated infantile-onset PA resulting from NBS not performed, false negative NBS result, symptoms prior to receiving NBS result, or caregivers not adherent to the recommended treatment after a positive NBS result may have the following nonspecific clinical findings, preliminary laboratory findings, and family history.
Developmental delay
Intellectual disability
Failure to thrive
Chronic gastrointestinal complaints
Protein intolerance
Acute psychosis
Hypotonia
Difficulty breathing
Seizures
Movement disorders such as dystonia and choreoathetosis
Apparently isolated dilated or hypertrophic cardiomyopathy without a known history of metabolic decompensation or neurocognitive deficits
Plasma acylcarnitine profile. Elevated propionylcarnitine (C3)
Urine organic acids
Elevated 3-hydroxypropionate
Elevated 2-methylcitrate
Presence of tiglylglycine and/or propionylglycine
Plasma amino acids. Elevated glycine and/or low glutamine
Pertinent negative findings. Individuals with propionic acidemia have normal methylmalonic acid and total plasma homocysteine levels.
Note: Because elevations of PA metabolites individually are not entirely specific to PA, follow-up molecular or enzymatic testing is required to establish or rule out the diagnosis of PA (see
High-anion gap metabolic acidosis
Lactic acidosis
Hyperammonemia
Elevated plasma and urinary ketones
Low-to-normal blood glucose
Neutropenia, anemia, and/or thrombocytopenia
The diagnosis of propionic acidemia
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 Propionic Acidemia
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 [
Exon deletions account for to ~20% of
Fewer than 10
• Clinical evaluation of the newborn
• Education of the caregivers to avoid prolonged fasting and identify concerning symptoms, including poor feeding, hypothermia, difficulty breathing, vomiting, seizures, or lethargy
• Immediate intervention if concerning symptoms are present (see also
• Admission to the hospital
• Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
• Infusion of IV glucose
• Nutritional evaluation and consideration of dietary protein restriction
• Carnitine supplementation
• Admission to the hospital
• Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
• Infusion of IV glucose
• Nutritional evaluation and consideration of dietary protein restriction
• Carnitine supplementation
• Admission to the hospital
• Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
• Infusion of IV glucose
• Nutritional evaluation and consideration of dietary protein restriction
• Carnitine supplementation
• Developmental delay
• Intellectual disability
• Failure to thrive
• Chronic gastrointestinal complaints
• Protein intolerance
• Acute psychosis
• Hypotonia
• Difficulty breathing
• Seizures
• Movement disorders such as dystonia and choreoathetosis
• Apparently isolated dilated or hypertrophic cardiomyopathy without a known history of metabolic decompensation or neurocognitive deficits
• Plasma acylcarnitine profile. Elevated propionylcarnitine (C3)
• Urine organic acids
• Elevated 3-hydroxypropionate
• Elevated 2-methylcitrate
• Presence of tiglylglycine and/or propionylglycine
• Elevated 3-hydroxypropionate
• Elevated 2-methylcitrate
• Presence of tiglylglycine and/or propionylglycine
• Plasma amino acids. Elevated glycine and/or low glutamine
• Pertinent negative findings. Individuals with propionic acidemia have normal methylmalonic acid and total plasma homocysteine levels.
• Elevated 3-hydroxypropionate
• Elevated 2-methylcitrate
• Presence of tiglylglycine and/or propionylglycine
• High-anion gap metabolic acidosis
• Lactic acidosis
• Hyperammonemia
• Elevated plasma and urinary ketones
• Low-to-normal blood glucose
• Neutropenia, anemia, and/or thrombocytopenia
## Suggestive Findings
NBS for propionic acidemia (PA) is primarily based on the quantification of propionylcarnitine (C3) and calculation of the C3/C2 ratio from the acylcarnitine profile on dried blood spots [
Propionylcarnitine (C3) and/or C3/C2 ratio values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see
If the follow-up biochemical testing supports the diagnosis of PA, confirmatory testing is required (see
The following medical interventions need to begin immediately upon receipt of an abnormal NBS result while additional testing is being performed:
Clinical evaluation of the newborn
Education of the caregivers to avoid prolonged fasting and identify concerning symptoms, including poor feeding, hypothermia, difficulty breathing, vomiting, seizures, or lethargy
Immediate intervention if concerning symptoms are present (see also
Admission to the hospital
Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
Infusion of IV glucose
Nutritional evaluation and consideration of dietary protein restriction
Carnitine supplementation
A symptomatic individual who has either (1) typical findings associated with late-onset PA or (2) untreated infantile-onset PA resulting from NBS not performed, false negative NBS result, symptoms prior to receiving NBS result, or caregivers not adherent to the recommended treatment after a positive NBS result may have the following nonspecific clinical findings, preliminary laboratory findings, and family history.
Developmental delay
Intellectual disability
Failure to thrive
Chronic gastrointestinal complaints
Protein intolerance
Acute psychosis
Hypotonia
Difficulty breathing
Seizures
Movement disorders such as dystonia and choreoathetosis
Apparently isolated dilated or hypertrophic cardiomyopathy without a known history of metabolic decompensation or neurocognitive deficits
Plasma acylcarnitine profile. Elevated propionylcarnitine (C3)
Urine organic acids
Elevated 3-hydroxypropionate
Elevated 2-methylcitrate
Presence of tiglylglycine and/or propionylglycine
Plasma amino acids. Elevated glycine and/or low glutamine
Pertinent negative findings. Individuals with propionic acidemia have normal methylmalonic acid and total plasma homocysteine levels.
Note: Because elevations of PA metabolites individually are not entirely specific to PA, follow-up molecular or enzymatic testing is required to establish or rule out the diagnosis of PA (see
High-anion gap metabolic acidosis
Lactic acidosis
Hyperammonemia
Elevated plasma and urinary ketones
Low-to-normal blood glucose
Neutropenia, anemia, and/or thrombocytopenia
• Clinical evaluation of the newborn
• Education of the caregivers to avoid prolonged fasting and identify concerning symptoms, including poor feeding, hypothermia, difficulty breathing, vomiting, seizures, or lethargy
• Immediate intervention if concerning symptoms are present (see also
• Admission to the hospital
• Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
• Infusion of IV glucose
• Nutritional evaluation and consideration of dietary protein restriction
• Carnitine supplementation
• Admission to the hospital
• Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
• Infusion of IV glucose
• Nutritional evaluation and consideration of dietary protein restriction
• Carnitine supplementation
• Admission to the hospital
• Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
• Infusion of IV glucose
• Nutritional evaluation and consideration of dietary protein restriction
• Carnitine supplementation
• Developmental delay
• Intellectual disability
• Failure to thrive
• Chronic gastrointestinal complaints
• Protein intolerance
• Acute psychosis
• Hypotonia
• Difficulty breathing
• Seizures
• Movement disorders such as dystonia and choreoathetosis
• Apparently isolated dilated or hypertrophic cardiomyopathy without a known history of metabolic decompensation or neurocognitive deficits
• Plasma acylcarnitine profile. Elevated propionylcarnitine (C3)
• Urine organic acids
• Elevated 3-hydroxypropionate
• Elevated 2-methylcitrate
• Presence of tiglylglycine and/or propionylglycine
• Elevated 3-hydroxypropionate
• Elevated 2-methylcitrate
• Presence of tiglylglycine and/or propionylglycine
• Plasma amino acids. Elevated glycine and/or low glutamine
• Pertinent negative findings. Individuals with propionic acidemia have normal methylmalonic acid and total plasma homocysteine levels.
• Elevated 3-hydroxypropionate
• Elevated 2-methylcitrate
• Presence of tiglylglycine and/or propionylglycine
• High-anion gap metabolic acidosis
• Lactic acidosis
• Hyperammonemia
• Elevated plasma and urinary ketones
• Low-to-normal blood glucose
• Neutropenia, anemia, and/or thrombocytopenia
## Scenario 1: Abnormal Newborn Screening (NBS) Result
NBS for propionic acidemia (PA) is primarily based on the quantification of propionylcarnitine (C3) and calculation of the C3/C2 ratio from the acylcarnitine profile on dried blood spots [
Propionylcarnitine (C3) and/or C3/C2 ratio values above the cutoff reported by the screening laboratory are considered positive and require follow-up biochemical testing (see
If the follow-up biochemical testing supports the diagnosis of PA, confirmatory testing is required (see
The following medical interventions need to begin immediately upon receipt of an abnormal NBS result while additional testing is being performed:
Clinical evaluation of the newborn
Education of the caregivers to avoid prolonged fasting and identify concerning symptoms, including poor feeding, hypothermia, difficulty breathing, vomiting, seizures, or lethargy
Immediate intervention if concerning symptoms are present (see also
Admission to the hospital
Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
Infusion of IV glucose
Nutritional evaluation and consideration of dietary protein restriction
Carnitine supplementation
• Clinical evaluation of the newborn
• Education of the caregivers to avoid prolonged fasting and identify concerning symptoms, including poor feeding, hypothermia, difficulty breathing, vomiting, seizures, or lethargy
• Immediate intervention if concerning symptoms are present (see also
• Admission to the hospital
• Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
• Infusion of IV glucose
• Nutritional evaluation and consideration of dietary protein restriction
• Carnitine supplementation
• Admission to the hospital
• Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
• Infusion of IV glucose
• Nutritional evaluation and consideration of dietary protein restriction
• Carnitine supplementation
• Admission to the hospital
• Obtain complete blood count (CBC), glucose, electrolytes, blood gas, ammonia, and urinary ketones
• Infusion of IV glucose
• Nutritional evaluation and consideration of dietary protein restriction
• Carnitine supplementation
## Scenario 2: Symptomatic Individual
A symptomatic individual who has either (1) typical findings associated with late-onset PA or (2) untreated infantile-onset PA resulting from NBS not performed, false negative NBS result, symptoms prior to receiving NBS result, or caregivers not adherent to the recommended treatment after a positive NBS result may have the following nonspecific clinical findings, preliminary laboratory findings, and family history.
Developmental delay
Intellectual disability
Failure to thrive
Chronic gastrointestinal complaints
Protein intolerance
Acute psychosis
Hypotonia
Difficulty breathing
Seizures
Movement disorders such as dystonia and choreoathetosis
Apparently isolated dilated or hypertrophic cardiomyopathy without a known history of metabolic decompensation or neurocognitive deficits
Plasma acylcarnitine profile. Elevated propionylcarnitine (C3)
Urine organic acids
Elevated 3-hydroxypropionate
Elevated 2-methylcitrate
Presence of tiglylglycine and/or propionylglycine
Plasma amino acids. Elevated glycine and/or low glutamine
Pertinent negative findings. Individuals with propionic acidemia have normal methylmalonic acid and total plasma homocysteine levels.
Note: Because elevations of PA metabolites individually are not entirely specific to PA, follow-up molecular or enzymatic testing is required to establish or rule out the diagnosis of PA (see
High-anion gap metabolic acidosis
Lactic acidosis
Hyperammonemia
Elevated plasma and urinary ketones
Low-to-normal blood glucose
Neutropenia, anemia, and/or thrombocytopenia
• Developmental delay
• Intellectual disability
• Failure to thrive
• Chronic gastrointestinal complaints
• Protein intolerance
• Acute psychosis
• Hypotonia
• Difficulty breathing
• Seizures
• Movement disorders such as dystonia and choreoathetosis
• Apparently isolated dilated or hypertrophic cardiomyopathy without a known history of metabolic decompensation or neurocognitive deficits
• Plasma acylcarnitine profile. Elevated propionylcarnitine (C3)
• Urine organic acids
• Elevated 3-hydroxypropionate
• Elevated 2-methylcitrate
• Presence of tiglylglycine and/or propionylglycine
• Elevated 3-hydroxypropionate
• Elevated 2-methylcitrate
• Presence of tiglylglycine and/or propionylglycine
• Plasma amino acids. Elevated glycine and/or low glutamine
• Pertinent negative findings. Individuals with propionic acidemia have normal methylmalonic acid and total plasma homocysteine levels.
• Elevated 3-hydroxypropionate
• Elevated 2-methylcitrate
• Presence of tiglylglycine and/or propionylglycine
• High-anion gap metabolic acidosis
• Lactic acidosis
• Hyperammonemia
• Elevated plasma and urinary ketones
• Low-to-normal blood glucose
• Neutropenia, anemia, and/or thrombocytopenia
## Establishing the Diagnosis
The diagnosis of propionic acidemia
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 Propionic Acidemia
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 [
Exon deletions account for to ~20% of
Fewer than 10
## Clinical Characteristics
Propionic acidemia (PA) presents with a wide spectrum of symptoms and age of onset. The onset of symptoms in PA varies depending on several factors, including residual enzymatic activity, intake of propiogenic precursors, and the occurrence of catabolic stressors.
A common presentation of PA in the neonatal period is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Most individuals eventually diagnosed with PA become symptomatic in the first weeks of life, with 50%-60% exhibiting clinical signs at the time of the newborn screen (NBS) report. Without prompt diagnosis and management, neonates can develop progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death (see
Propionic Acidemia: Findings During Initial Metabolic Crisis
The differences in the reported prevalence of findings may reflect variable sizes of the cohorts, age of the last evaluation, length of follow up, differences in therapeutic approaches, availability, turnaround time and sensitivity of NBS, screening method (NBS vs selective metabolic screen), overlap of affected individuals in the reported cohorts, and ascertainment and recall bias.
Prevalences derived from
The mean plasma ammonia levels in people with neonatal-onset PA was reported to vary between 207 and 697 μmol/L [
Following initial clinical and biochemical stabilization, individuals with neonatal-onset PA may experience metabolic decompensations and can develop a range of symptoms affecting different organ systems.
These episodes can be life-threatening and are often precipitated by illnesses, infections, surgery, or any physiologic stress that can trigger a catabolic state.
Infectious complications (e.g., sepsis or bacterial meningitis) often accompany metabolic crises and are the major contributors to mortality.
The long-term cognitive outcome of individuals with PA is negatively correlated with the number of metabolic decompensations [
Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
Early clinical manifestations of cardiomyopathy include increased fatigue, tachypnea, hepatomegaly, hypotension, tachycardia, or bradycardia.
The median age of onset of cardiomyopathy ranges from 7 to 14.4 years [
The age of PA diagnosis and frequency of metabolic decompensation do not correlate with presence/absence of cardiomyopathy in individuals with PA [
Rarely, cardiomyopathy can occur as an apparently isolated clinical phenomenon in previously healthy individuals without documented episodes of metabolic decompensation or neurocognitive deficits [
Cardiomyopathy can progress to cardiac failure and may be associated with sudden death.
Pancreatitis (reported in 3%-18% of individuals with PA) may be recurrent and present with anorexia, recurrent nausea, and abdominal pain. In some individuals, recurrent pancreatitis can lead to insulin-dependent diabetes [
Poor feeding and lack of appetite are common, affecting up to 76% of affected individuals.
Emesis and diarrhea are commonly reported in individuals with PA, and are a recurrent problem in approximately 6% [
Liver manifestations include hepatomegaly, hypoalbuminemia, and abnormal liver function tests (ALT, AST, GGT, INR, and bilirubin) [
Hypogammaglobulinemia, B-cell lymphopenia, neutropenia, decreased CD4 and CD8 counts, decreased naïve T cells, and abnormal CD4/CD8 ratio have been described [
Optic neuropathy occurs in 11%-25% of affected individuals [
Relatively high residual activity of propionyl-CoA carboxylase may delay the onset of symptoms beyond the neonatal period.
Individuals with late-onset PA may remain asymptomatic during infancy [
Features of Late-Onset Propionic Acidemia
Encephalopathy, coma, weakness, gait abnormalities, &/or seizures precipitated by catabolic stressors (e.g., intercurrent illness, surgery)
Vomiting, protein intolerance, failure to thrive, hypotonia, developmental regression, movement disorders
Cardiomyopathy
Long QT syndrome
Psychiatric symptoms
Pancreatitis
± metabolic acidosis or hyperammonemia
Missed
Normal
Hyperglycinemia
MRI abnormalities incl basal ganglia lesions
PA is associated with a high risk of mortality. However, reported mortality rates appear to be on the decline: 41%-90% in the 1980-1990s, 17%-72% in the 2000s, and 7%-18% in the 2010s [
Although there is no evidence that identification of the underlying pathogenic variants in
Some homozygous missense pathogenic variants, in which partial enzymatic activity is retained, have been associated with a less severe phenotype.
The homozygous
The homozygous pathogenic variant
However, some
The homozygous
Propionic acidemia and propionyl-coenzyme A carboxylase deficiency are the two most common terms used to describe this condition. Ketotic hyperglycinemia was used in the 1960s before defects in PCC were determined to be the underlying cause of PA. The term propionic aciduria is used infrequently.
PA is an ultrarare metabolic disorder, and its prevalence varies by population. While PA is included in routine NBS in the United States, many countries still rely on clinical presentation for diagnosis, and therefore, the worldwide incidence of PA remains unknown. However, PA is more frequent in certain ancestral groups due to the founder effect of specific pathogenic variants.
In the US, the birth incidence of PA is estimated to be ~0.14-0.77 in 100,000 (1 in 129,792 to 1 in 733,000) [
The incidence in other parts of the world is generally higher [
0.32-2.20 in 100,000 in Europe
0.05-5.05 in 100,000 in the Asia-Pacific
3.6-8.14 in 100,000 in the Middle East and North Africa
• These episodes can be life-threatening and are often precipitated by illnesses, infections, surgery, or any physiologic stress that can trigger a catabolic state.
• Infectious complications (e.g., sepsis or bacterial meningitis) often accompany metabolic crises and are the major contributors to mortality.
• The long-term cognitive outcome of individuals with PA is negatively correlated with the number of metabolic decompensations [
• Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
• The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
• A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
• Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
• Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
• Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
• Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
• The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
• A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
• Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
• Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
• Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
• Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
• The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
• A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
• Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
• Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
• Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
• Early clinical manifestations of cardiomyopathy include increased fatigue, tachypnea, hepatomegaly, hypotension, tachycardia, or bradycardia.
• The median age of onset of cardiomyopathy ranges from 7 to 14.4 years [
• The age of PA diagnosis and frequency of metabolic decompensation do not correlate with presence/absence of cardiomyopathy in individuals with PA [
• Rarely, cardiomyopathy can occur as an apparently isolated clinical phenomenon in previously healthy individuals without documented episodes of metabolic decompensation or neurocognitive deficits [
• Cardiomyopathy can progress to cardiac failure and may be associated with sudden death.
• Pancreatitis (reported in 3%-18% of individuals with PA) may be recurrent and present with anorexia, recurrent nausea, and abdominal pain. In some individuals, recurrent pancreatitis can lead to insulin-dependent diabetes [
• Poor feeding and lack of appetite are common, affecting up to 76% of affected individuals.
• Emesis and diarrhea are commonly reported in individuals with PA, and are a recurrent problem in approximately 6% [
• Liver manifestations include hepatomegaly, hypoalbuminemia, and abnormal liver function tests (ALT, AST, GGT, INR, and bilirubin) [
• Encephalopathy, coma, weakness, gait abnormalities, &/or seizures precipitated by catabolic stressors (e.g., intercurrent illness, surgery)
• Vomiting, protein intolerance, failure to thrive, hypotonia, developmental regression, movement disorders
• Cardiomyopathy
• Long QT syndrome
• Psychiatric symptoms
• Pancreatitis
• ± metabolic acidosis or hyperammonemia
• Missed
• Normal
• Hyperglycinemia
• MRI abnormalities incl basal ganglia lesions
• Some homozygous missense pathogenic variants, in which partial enzymatic activity is retained, have been associated with a less severe phenotype.
• The homozygous
• The homozygous pathogenic variant
• The homozygous
• The homozygous pathogenic variant
• However, some
• The homozygous
• The homozygous
• The homozygous pathogenic variant
• In the US, the birth incidence of PA is estimated to be ~0.14-0.77 in 100,000 (1 in 129,792 to 1 in 733,000) [
• The incidence in other parts of the world is generally higher [
• 0.32-2.20 in 100,000 in Europe
• 0.05-5.05 in 100,000 in the Asia-Pacific
• 3.6-8.14 in 100,000 in the Middle East and North Africa
• 0.32-2.20 in 100,000 in Europe
• 0.05-5.05 in 100,000 in the Asia-Pacific
• 3.6-8.14 in 100,000 in the Middle East and North Africa
• 0.32-2.20 in 100,000 in Europe
• 0.05-5.05 in 100,000 in the Asia-Pacific
• 3.6-8.14 in 100,000 in the Middle East and North Africa
## Clinical Description
Propionic acidemia (PA) presents with a wide spectrum of symptoms and age of onset. The onset of symptoms in PA varies depending on several factors, including residual enzymatic activity, intake of propiogenic precursors, and the occurrence of catabolic stressors.
A common presentation of PA in the neonatal period is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Most individuals eventually diagnosed with PA become symptomatic in the first weeks of life, with 50%-60% exhibiting clinical signs at the time of the newborn screen (NBS) report. Without prompt diagnosis and management, neonates can develop progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death (see
Propionic Acidemia: Findings During Initial Metabolic Crisis
The differences in the reported prevalence of findings may reflect variable sizes of the cohorts, age of the last evaluation, length of follow up, differences in therapeutic approaches, availability, turnaround time and sensitivity of NBS, screening method (NBS vs selective metabolic screen), overlap of affected individuals in the reported cohorts, and ascertainment and recall bias.
Prevalences derived from
The mean plasma ammonia levels in people with neonatal-onset PA was reported to vary between 207 and 697 μmol/L [
Following initial clinical and biochemical stabilization, individuals with neonatal-onset PA may experience metabolic decompensations and can develop a range of symptoms affecting different organ systems.
These episodes can be life-threatening and are often precipitated by illnesses, infections, surgery, or any physiologic stress that can trigger a catabolic state.
Infectious complications (e.g., sepsis or bacterial meningitis) often accompany metabolic crises and are the major contributors to mortality.
The long-term cognitive outcome of individuals with PA is negatively correlated with the number of metabolic decompensations [
Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
Early clinical manifestations of cardiomyopathy include increased fatigue, tachypnea, hepatomegaly, hypotension, tachycardia, or bradycardia.
The median age of onset of cardiomyopathy ranges from 7 to 14.4 years [
The age of PA diagnosis and frequency of metabolic decompensation do not correlate with presence/absence of cardiomyopathy in individuals with PA [
Rarely, cardiomyopathy can occur as an apparently isolated clinical phenomenon in previously healthy individuals without documented episodes of metabolic decompensation or neurocognitive deficits [
Cardiomyopathy can progress to cardiac failure and may be associated with sudden death.
Pancreatitis (reported in 3%-18% of individuals with PA) may be recurrent and present with anorexia, recurrent nausea, and abdominal pain. In some individuals, recurrent pancreatitis can lead to insulin-dependent diabetes [
Poor feeding and lack of appetite are common, affecting up to 76% of affected individuals.
Emesis and diarrhea are commonly reported in individuals with PA, and are a recurrent problem in approximately 6% [
Liver manifestations include hepatomegaly, hypoalbuminemia, and abnormal liver function tests (ALT, AST, GGT, INR, and bilirubin) [
Hypogammaglobulinemia, B-cell lymphopenia, neutropenia, decreased CD4 and CD8 counts, decreased naïve T cells, and abnormal CD4/CD8 ratio have been described [
Optic neuropathy occurs in 11%-25% of affected individuals [
Relatively high residual activity of propionyl-CoA carboxylase may delay the onset of symptoms beyond the neonatal period.
Individuals with late-onset PA may remain asymptomatic during infancy [
Features of Late-Onset Propionic Acidemia
Encephalopathy, coma, weakness, gait abnormalities, &/or seizures precipitated by catabolic stressors (e.g., intercurrent illness, surgery)
Vomiting, protein intolerance, failure to thrive, hypotonia, developmental regression, movement disorders
Cardiomyopathy
Long QT syndrome
Psychiatric symptoms
Pancreatitis
± metabolic acidosis or hyperammonemia
Missed
Normal
Hyperglycinemia
MRI abnormalities incl basal ganglia lesions
PA is associated with a high risk of mortality. However, reported mortality rates appear to be on the decline: 41%-90% in the 1980-1990s, 17%-72% in the 2000s, and 7%-18% in the 2010s [
• These episodes can be life-threatening and are often precipitated by illnesses, infections, surgery, or any physiologic stress that can trigger a catabolic state.
• Infectious complications (e.g., sepsis or bacterial meningitis) often accompany metabolic crises and are the major contributors to mortality.
• The long-term cognitive outcome of individuals with PA is negatively correlated with the number of metabolic decompensations [
• Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
• The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
• A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
• Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
• Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
• Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
• Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
• The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
• A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
• Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
• Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
• Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
• Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
• The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
• A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
• Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
• Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
• Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
• Early clinical manifestations of cardiomyopathy include increased fatigue, tachypnea, hepatomegaly, hypotension, tachycardia, or bradycardia.
• The median age of onset of cardiomyopathy ranges from 7 to 14.4 years [
• The age of PA diagnosis and frequency of metabolic decompensation do not correlate with presence/absence of cardiomyopathy in individuals with PA [
• Rarely, cardiomyopathy can occur as an apparently isolated clinical phenomenon in previously healthy individuals without documented episodes of metabolic decompensation or neurocognitive deficits [
• Cardiomyopathy can progress to cardiac failure and may be associated with sudden death.
• Pancreatitis (reported in 3%-18% of individuals with PA) may be recurrent and present with anorexia, recurrent nausea, and abdominal pain. In some individuals, recurrent pancreatitis can lead to insulin-dependent diabetes [
• Poor feeding and lack of appetite are common, affecting up to 76% of affected individuals.
• Emesis and diarrhea are commonly reported in individuals with PA, and are a recurrent problem in approximately 6% [
• Liver manifestations include hepatomegaly, hypoalbuminemia, and abnormal liver function tests (ALT, AST, GGT, INR, and bilirubin) [
• Encephalopathy, coma, weakness, gait abnormalities, &/or seizures precipitated by catabolic stressors (e.g., intercurrent illness, surgery)
• Vomiting, protein intolerance, failure to thrive, hypotonia, developmental regression, movement disorders
• Cardiomyopathy
• Long QT syndrome
• Psychiatric symptoms
• Pancreatitis
• ± metabolic acidosis or hyperammonemia
• Missed
• Normal
• Hyperglycinemia
• MRI abnormalities incl basal ganglia lesions
## Neonatal-Onset PA
A common presentation of PA in the neonatal period is characterized by a healthy newborn with poor feeding and decreased arousal in the first few days of life, followed by progressive encephalopathy of unexplained origin. Most individuals eventually diagnosed with PA become symptomatic in the first weeks of life, with 50%-60% exhibiting clinical signs at the time of the newborn screen (NBS) report. Without prompt diagnosis and management, neonates can develop progressive encephalopathy manifesting as lethargy, seizures, or coma that can result in death (see
Propionic Acidemia: Findings During Initial Metabolic Crisis
The differences in the reported prevalence of findings may reflect variable sizes of the cohorts, age of the last evaluation, length of follow up, differences in therapeutic approaches, availability, turnaround time and sensitivity of NBS, screening method (NBS vs selective metabolic screen), overlap of affected individuals in the reported cohorts, and ascertainment and recall bias.
Prevalences derived from
The mean plasma ammonia levels in people with neonatal-onset PA was reported to vary between 207 and 697 μmol/L [
Following initial clinical and biochemical stabilization, individuals with neonatal-onset PA may experience metabolic decompensations and can develop a range of symptoms affecting different organ systems.
These episodes can be life-threatening and are often precipitated by illnesses, infections, surgery, or any physiologic stress that can trigger a catabolic state.
Infectious complications (e.g., sepsis or bacterial meningitis) often accompany metabolic crises and are the major contributors to mortality.
The long-term cognitive outcome of individuals with PA is negatively correlated with the number of metabolic decompensations [
Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
Early clinical manifestations of cardiomyopathy include increased fatigue, tachypnea, hepatomegaly, hypotension, tachycardia, or bradycardia.
The median age of onset of cardiomyopathy ranges from 7 to 14.4 years [
The age of PA diagnosis and frequency of metabolic decompensation do not correlate with presence/absence of cardiomyopathy in individuals with PA [
Rarely, cardiomyopathy can occur as an apparently isolated clinical phenomenon in previously healthy individuals without documented episodes of metabolic decompensation or neurocognitive deficits [
Cardiomyopathy can progress to cardiac failure and may be associated with sudden death.
Pancreatitis (reported in 3%-18% of individuals with PA) may be recurrent and present with anorexia, recurrent nausea, and abdominal pain. In some individuals, recurrent pancreatitis can lead to insulin-dependent diabetes [
Poor feeding and lack of appetite are common, affecting up to 76% of affected individuals.
Emesis and diarrhea are commonly reported in individuals with PA, and are a recurrent problem in approximately 6% [
Liver manifestations include hepatomegaly, hypoalbuminemia, and abnormal liver function tests (ALT, AST, GGT, INR, and bilirubin) [
Hypogammaglobulinemia, B-cell lymphopenia, neutropenia, decreased CD4 and CD8 counts, decreased naïve T cells, and abnormal CD4/CD8 ratio have been described [
Optic neuropathy occurs in 11%-25% of affected individuals [
• These episodes can be life-threatening and are often precipitated by illnesses, infections, surgery, or any physiologic stress that can trigger a catabolic state.
• Infectious complications (e.g., sepsis or bacterial meningitis) often accompany metabolic crises and are the major contributors to mortality.
• The long-term cognitive outcome of individuals with PA is negatively correlated with the number of metabolic decompensations [
• Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
• The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
• A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
• Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
• Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
• Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
• Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
• The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
• A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
• Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
• Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
• Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
• Basal ganglia changes seen in 7%-56% of individuals may be preceded by an acute "stroke-like" episode and manifest as altered mental status, dystonia, choreoathetosis, or hemiplegia.
• The frequency of movement disorders in individuals with PA appears to be independent of the age of symptom onset [
• A unique pattern of cortical and subcortical diffusion restriction can be seen on brain MRI in some affected individuals [
• Other brain MRI findings can include delayed myelination, white matter changes, cerebral atrophy, cerebellar atrophy, and cerebellar hemorrhage.
• Clinically unstable individuals appear to be at higher risk of developing brain abnormalities. In a study of 17 individuals with PA who had clinical seizures, all had abnormal MRI findings and a history of more than ten metabolic decompensations [
• Magnetic resonance spectroscopy (MRS) can reveal decreased myoinositol and N-acetylaspartate and abnormal Glx (glutamine, glutamate, and gamma-aminobutyric acid) peaks in the basal ganglia.
• Early clinical manifestations of cardiomyopathy include increased fatigue, tachypnea, hepatomegaly, hypotension, tachycardia, or bradycardia.
• The median age of onset of cardiomyopathy ranges from 7 to 14.4 years [
• The age of PA diagnosis and frequency of metabolic decompensation do not correlate with presence/absence of cardiomyopathy in individuals with PA [
• Rarely, cardiomyopathy can occur as an apparently isolated clinical phenomenon in previously healthy individuals without documented episodes of metabolic decompensation or neurocognitive deficits [
• Cardiomyopathy can progress to cardiac failure and may be associated with sudden death.
• Pancreatitis (reported in 3%-18% of individuals with PA) may be recurrent and present with anorexia, recurrent nausea, and abdominal pain. In some individuals, recurrent pancreatitis can lead to insulin-dependent diabetes [
• Poor feeding and lack of appetite are common, affecting up to 76% of affected individuals.
• Emesis and diarrhea are commonly reported in individuals with PA, and are a recurrent problem in approximately 6% [
• Liver manifestations include hepatomegaly, hypoalbuminemia, and abnormal liver function tests (ALT, AST, GGT, INR, and bilirubin) [
## Late-Onset PA
Relatively high residual activity of propionyl-CoA carboxylase may delay the onset of symptoms beyond the neonatal period.
Individuals with late-onset PA may remain asymptomatic during infancy [
Features of Late-Onset Propionic Acidemia
Encephalopathy, coma, weakness, gait abnormalities, &/or seizures precipitated by catabolic stressors (e.g., intercurrent illness, surgery)
Vomiting, protein intolerance, failure to thrive, hypotonia, developmental regression, movement disorders
Cardiomyopathy
Long QT syndrome
Psychiatric symptoms
Pancreatitis
± metabolic acidosis or hyperammonemia
Missed
Normal
Hyperglycinemia
MRI abnormalities incl basal ganglia lesions
• Encephalopathy, coma, weakness, gait abnormalities, &/or seizures precipitated by catabolic stressors (e.g., intercurrent illness, surgery)
• Vomiting, protein intolerance, failure to thrive, hypotonia, developmental regression, movement disorders
• Cardiomyopathy
• Long QT syndrome
• Psychiatric symptoms
• Pancreatitis
• ± metabolic acidosis or hyperammonemia
• Missed
• Normal
• Hyperglycinemia
• MRI abnormalities incl basal ganglia lesions
## Life Span
PA is associated with a high risk of mortality. However, reported mortality rates appear to be on the decline: 41%-90% in the 1980-1990s, 17%-72% in the 2000s, and 7%-18% in the 2010s [
## Genotype-Phenotype Correlations
Although there is no evidence that identification of the underlying pathogenic variants in
Some homozygous missense pathogenic variants, in which partial enzymatic activity is retained, have been associated with a less severe phenotype.
The homozygous
The homozygous pathogenic variant
However, some
The homozygous
• Some homozygous missense pathogenic variants, in which partial enzymatic activity is retained, have been associated with a less severe phenotype.
• The homozygous
• The homozygous pathogenic variant
• The homozygous
• The homozygous pathogenic variant
• However, some
• The homozygous
• The homozygous
• The homozygous pathogenic variant
## Nomenclature
Propionic acidemia and propionyl-coenzyme A carboxylase deficiency are the two most common terms used to describe this condition. Ketotic hyperglycinemia was used in the 1960s before defects in PCC were determined to be the underlying cause of PA. The term propionic aciduria is used infrequently.
## Prevalence
PA is an ultrarare metabolic disorder, and its prevalence varies by population. While PA is included in routine NBS in the United States, many countries still rely on clinical presentation for diagnosis, and therefore, the worldwide incidence of PA remains unknown. However, PA is more frequent in certain ancestral groups due to the founder effect of specific pathogenic variants.
In the US, the birth incidence of PA is estimated to be ~0.14-0.77 in 100,000 (1 in 129,792 to 1 in 733,000) [
The incidence in other parts of the world is generally higher [
0.32-2.20 in 100,000 in Europe
0.05-5.05 in 100,000 in the Asia-Pacific
3.6-8.14 in 100,000 in the Middle East and North Africa
• In the US, the birth incidence of PA is estimated to be ~0.14-0.77 in 100,000 (1 in 129,792 to 1 in 733,000) [
• The incidence in other parts of the world is generally higher [
• 0.32-2.20 in 100,000 in Europe
• 0.05-5.05 in 100,000 in the Asia-Pacific
• 3.6-8.14 in 100,000 in the Middle East and North Africa
• 0.32-2.20 in 100,000 in Europe
• 0.05-5.05 in 100,000 in the Asia-Pacific
• 3.6-8.14 in 100,000 in the Middle East and North Africa
• 0.32-2.20 in 100,000 in Europe
• 0.05-5.05 in 100,000 in the Asia-Pacific
• 3.6-8.14 in 100,000 in the Middle East and North Africa
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Propionic Acidemia
AD = autosomal dominant; AR = autosomal recessive; CoA = coenzyme A; Mat = maternal; MOI = mode of inheritance; NBS = newborn screening; NL = normal; PA = propionic acidemia; XL = X-linked
Most disorders of intracellular cobalamin metabolism are inherited in an autosomal recessive manner.
Biallelic pathogenic variants in
Conditions included in the commonly used mnemonic
## Genetic Disorders
Genes of Interest in the Differential Diagnosis of Propionic Acidemia
AD = autosomal dominant; AR = autosomal recessive; CoA = coenzyme A; Mat = maternal; MOI = mode of inheritance; NBS = newborn screening; NL = normal; PA = propionic acidemia; XL = X-linked
Most disorders of intracellular cobalamin metabolism are inherited in an autosomal recessive manner.
Biallelic pathogenic variants in
## Acquired Disorders and Other Considerations
Conditions included in the commonly used mnemonic
## Management
Several proposed acute and chronic clinical management guidelines for individuals with propionic acidemia (PA) have been published and revised [
When PA is suspected (i.e., an abnormal newborn screening [NBS] result or suggestive symptoms), metabolic treatment should be initiated immediately.
To establish the extent of disease and needs in an individual diagnosed with PA, the evaluations summarized in
Propionic Acidemia: Recommended Evaluations Following Initial Diagnosis
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).
Consider short hospitalization at a center w/expertise for inherited metabolic conditions to provide caregivers with detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
Blood gas w/base balance
Electrolytes w/anion gap, calcium, & phosphorus
Glucose
Plasma ammonia level
Urine ketones
Plasma amino acids
Urine organic acids
Acylcarnitine profile
Total & free carnitine levels
Complete blood count
Amylase & lipase
Assessment of nutritional status (calcium, phosphorus, albumin, plasma amino acids, vitamin levels [incl thiamine & 25-hydroxyvitamin D])
Iron panel
Kidney function (e.g., cystatin C, parathyroid hormone, erythropoietin)
CBC to assess for cytopenias
Consider brain MRI if the neurologic eval is abnormal.
Consider EEG if seizures are a concern.
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk or significant feeding difficulties.
Consider in persons w/cytopenias or suspicion for immunodeficiency.
To assess for hypogammaglobulinemia, B-cell lymphopenia, & ↓ CD4 & CD8 counts
Complete adherence to regional immunization schedules & influenza vaccination is indicated.
Consultation w/PT, OT, & speech therapist
Consider referral to developmental pediatrician.
Consider in persons w/history of fractures or nutritional concerns.
DXA scan might aid in eval in persons age ≥3 yrs.
CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OT = occupational therapist; PA = propionic acidemia; PT = physical therapist
After a new diagnosis of PA in a child, the closest hospital and local pediatrician should also be informed.
To evaluate for cytopenias. Consider initiating an evaluation for sepsis if the CBC and clinical signs are suggestive of an infection.
To evaluate for pancreatitis
Consider ambulatory EKG monitoring.
Medical geneticist, certified genetic counselor, and certified advanced genetic nurse
The mainstay nutritional intervention is modification of diet to control the intake of propiogenic substrates (isoleucine, valine, methionine, and threonine), while ensuring normal protein synthesis and preventing protein catabolism, amino acid deficiencies, and growth restriction.
Propionic Acidemia: Routine Daily Treatment
Dietary restriction of propiogenic amino acids (isoleucine, valine, methionine, & threonine) by using specialized medical foods
Specific dietary protein prescription might vary based on multiple factors incl disease severity & growth rate.
Additional calories can be provided using protein-free formulas.
Dietary mgmt needs to be directed by experienced physician & metabolic dietician.
Recommended protein intake is age- & sex-dependent.
The ratio of natural source protein to medical foods varies depending on clinical status, laboratory parameters, & growth trajectory.
Screening laboratory studies to guide nutritional intervention are listed in
1 regimen uses a 1-week-on, 3-weeks off approach.
Possible benefits may need to be balanced against known side effects (constipation, diarrhea, optic neuropathy, & pancreatitis).
Oral levocarnintine, 100 mg/kg/day
Dose is adjusted on individual basis to maintain plasma free L-carnitine concentration w/in reference range.
There is no consensus re use of biotin supplementation or optimal dose in treatment of PA.
There is no evidence that a biotin-responsive form of PA exists.
Advanced kidney disease may require dialysis &/or kidney transplant.
Avoidance of nephrotoxic drugs
Liver transplant (LT) has been proposed as therapeutic measure in persons w/heart failure, w/improvement of LVEF reported in some persons.
However, recurrence of cardiomyopathy after LT has also been reported.
Successful cases of combined heart & liver transplantation & isolated heart transplantation have been reported.
Consider speech therapy, PT, &/or OT as needed.
Rehab therapy
Care must be taken when using antipsychotic medications, as they can mask clinical signs of encephalopathy or cause adverse effects in persons w/PA.
Special caution should be exercised w/antipsychotic medications that have QT interval prolongation potential.
CNS = central nervous system; LVEF = left ventricular ejection fraction; OT = occupational therapy; PA = propionic acidemia; PT = physical therapy
For protein restriction, the authors suggest adherence to the recommended age- and sex-specific safe levels of protein and energy intake [
See
The optimal dose of levocarnitine has not been established.
When calculating the daily dose of levocarnitine, one needs to consider the presence of this pharmaceutic compound in medical foods and the maximum daily dose in older affected individuals.
Propionic Acidemia: Home Management of Mild Metabolic Status
Carbohydrate supplementation orally or via tube feed
Reduce natural protein intake
Increasing carnitine supplementation
Trial of outpatient treatment at home for up to 12 hrs
Reassessment (every ~2 hrs) for clinical changes
At-home detection & monitoring of urine ketones may be considered.
Fever; 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, with some centers recommending 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) may be considered.
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
More aggressive fever management might be indicated in individuals with history of arrythmias and/or prolonged QT interval.
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 (see
Propionic Acidemia: Acute Inpatient Treatment
Address electrolytes & pH imbalances w/IV fluid mgmt.
Administration of high-energy fluids &, if hyperglycemia develops, insulin
IV intralipids
↓ or omit natural protein for <24 hours
L-carnitine supplementation (100 mg/kg/day IV divided in 3 doses)
The volume, glucose content, & electrolyte composition of IV fluids is determined by age, target glucose infusion rates, cardiovascular status, kidney condition, & coadministration of other medications.
Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine levels, urine pH, & ketone screening may all be of use in guiding mgmt.
Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
Inadequate or delayed start of emergency treatment is a risk factor for basal ganglia injury, dystonia, & consequent long-term disability.
Sodium benzoate has been used in mgmt of acute hyperammonemia in persons w/PA.
Oral carglumic acid (150 mg/kg/day in persons <15 kg & 3.3 gm/m
Extracorporeal detoxification can be considered (see
Correction of metabolic acidosis using IV fluids
Extracorporeal detoxification may be required for persistent acidosis & hyperammonemia (plasma ammonia level >250-300 μmol/L) not responding to fluid & drug treatment.
Judicious use of IV sodium bicarbonate to improve acid-base balance under control of fluid status & electrolyte balance
Methods of extracorporeal detoxification incl continuous venovenous hemofiltration, extracorporeal membrane oxygenation, or hemodialysis.
ICU = intensive care unit; IV = intravenous; PA = propionic acidemia
Inpatient 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.
Intravenous D10 ½ normal saline typically between 100% and 150% of the maintenance requirements is a common starting fluid. Dextrose solutions exceeding the concentration of 12.5% require a central line placement. The target glucose infusion rates vary by age [
Use of insulin if hyperglycemia emerges; intravenous insulin given at a starting dose of 0.01-0.02 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma) or glucosuria.
Protein intake can be gradually advanced as tolerated; careful introduction of non-propiogenic amino acids from medical foods might be needed to achieve a positive nitrogen balance [
If transition to enteral feedings within 48 hours is not possible, total parenteral nutrition is required.
Parenteral amino acid solutions are prescribed based on the recommended daily intake of age-appropriate energy and protein needs and adjusted using daily and weekly growth data and plasma amino acid concentrations.
L-carnitine (with options to increase the dose) can be given intravenously, which enhances bioavailability.
Carnitine supplementation may enhance the detoxification of propionic acid by conjugating into propionylcarnitine, which is excreted by the kidneys. Alternatively, it may relieve intracellular coenzyme A accretion.
For a discussion regarding the use of sodium benzoate vs sodium phenylacetate and sodium phenylbutyrate in PA, see
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PA together with pediatric metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise in metabolic diseases is essential.
Prevention and proactive management of metabolic crises (see
The indication of liver transplantation for dilated cardiomyopathy with severe heart dysfunction is less clear, with reports showing a short-term improvement or stabilization of heart function [
The current evidence with short- or medium-term follow up has not demonstrated superiority of unrelated donors compared to heterozygous related donors for liver transplant [
Close monitoring of metabolic and nutritional status around the perioperative period by a highly specialized team is recommended. Disease-specific metabolites such as 3-hydroxypropionate can be elevated during the anhepatic phase [
Metabolic decompensation during liver transplantation poses a higher mortality risk [
Benefits of OLT include decrease in the frequency of metabolic decompensations and potential stabilization of the neurodevelopmental decline [
Complications of liver transplantation were summarized in a meta-analysis with the following pooled estimated rates [
Patient survival of 0.95 (95% CI: 0.80-1)
Allograft survival of 0.91 (95% CI: 0.72-1)
Rejection of 0.20 (95% CI: 0.05-0.39)
Hepatic artery thrombosis of 0.08 (95% CI: 0.00-0.21)
Biliary complications of 0.03 (95% CI: 0.00-0.15)
Cytomegalovirus / Epstein-Barr virus infection of 0.14 (95% CI: 0.00-0.37)
Lifelong post-transplant management is recommended, as well as continuation of L-carnitine supplementation after liver transplantation. The authors recommend continued protein restriction after transplant using the WHO/FAO/UNU recommendations for energy and protein intake [
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 offered expediently during intercurrent illnesses or other catabolic stressors (see also
Propionic Acidemia: Prevention of Secondary Manifestations
Education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute metabolic crises
Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while traveling
MedicAlert
Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources), specialized amino acid formula, & medication required for maintenance & emergency treatment (carnitine, antipyretics) should always be maintained at home & during travel.
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 info & principles of emergency treatment for PA & containing contact info for primary treating metabolic center.
For any planned travel or vacations, consider contacting a center of expertise near destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Emergency surgeries & elective procedures require input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
Reassessment of dietary therapy to identify essential amino acid deficiencies or other vitamin or mineral deficiencies
Rule out iatrogenic overrestriction of essential amino acid intake.
Essential information including written treatment protocols should be provided
Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for affected individuals deemed to be at high risk for perioperative complications (see
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in
Propionic Acidemia: Recommended Surveillance
Measurement of weight, length, & head circumference
Eval of nutritional status & safety of oral intake
Plasma ammonia
Quantitative plasma acylcarnitine profile
Electrolytes & venous blood gas
Urinary ketones, plasma lactic acid, & 2-methylcitric acid
Plasma amino acids (esp isoleucine, leucine, valine, threonine, & methionine) collected 2 hrs after last typical meal
Plasma free & total carnitine
Mineral panel (calcium, phosphorus)
Hemoglobin &/or CBC
Vitamin D
Iron studies
Essential fatty acids
Trace minerals (selenium & zinc)
Plasma creatinine
Serum cystatin C may be more sensitive than plasma creatinine to identify chronic kidney disease.
Neuropsychological testing using age-appropriate standardized assessment batteries
Standardized quality-of-life assessment tools for affected persons & parents/caregivers
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
CBC = complete blood count; DXA = dual-energy x-ray absorptiometry
This should also include interval assessment for the need for a gastrostomy tube in those who do not already have one.
The following evaluations are performed at different intervals depending on factors such as age, disease severity, and presence of catabolic stressors; evaluation frequency can range from every three months to annually.
To monitor and adjust nutritional management
To monitor for cytopenias
To screen for cardiomyopathy and arrythmia
To assess for optic nerve and retinal changes
Avoid prolonged fasting, catabolic stressors, and excessive protein intake.
Lactated Ringer's solution is not recommended in individuals with organic acidemias.
In individuals with QT interval abnormalities, avoid medications that can prolong the QT interval.
Ondansetron, an antiemetic drug used to control nausea, has been associated with QT interval prolongation on EKG [
Nephrotoxic medications (e.g., aminoglycosides) should be avoided.
Neuroleptic antiemetics (e.g., promethazine) can mask symptoms of progressive encephalopathy and are best avoided.
Testing of at-risk sibs is warranted to allow for early diagnosis and treatment. If prenatal testing has not been performed on at-risk sibs, measure urine organic acids, plasma amino acids, and acylcarnitine profile immediately in the newborn period in parallel with newborn screening.
See
Although successful pregnancy outcomes have been reported in individuals with PA [
Search
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).
• Consider short hospitalization at a center w/expertise for inherited metabolic conditions to provide caregivers with detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
• Blood gas w/base balance
• Electrolytes w/anion gap, calcium, & phosphorus
• Glucose
• Plasma ammonia level
• Urine ketones
• Plasma amino acids
• Urine organic acids
• Acylcarnitine profile
• Total & free carnitine levels
• Complete blood count
• Amylase & lipase
• Assessment of nutritional status (calcium, phosphorus, albumin, plasma amino acids, vitamin levels [incl thiamine & 25-hydroxyvitamin D])
• Iron panel
• Kidney function (e.g., cystatin C, parathyroid hormone, erythropoietin)
• CBC to assess for cytopenias
• Consider brain MRI if the neurologic eval is abnormal.
• Consider EEG if seizures are a concern.
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk or significant feeding difficulties.
• Consider in persons w/cytopenias or suspicion for immunodeficiency.
• To assess for hypogammaglobulinemia, B-cell lymphopenia, & ↓ CD4 & CD8 counts
• Complete adherence to regional immunization schedules & influenza vaccination is indicated.
• Consultation w/PT, OT, & speech therapist
• Consider referral to developmental pediatrician.
• Consider in persons w/history of fractures or nutritional concerns.
• DXA scan might aid in eval in persons age ≥3 yrs.
• Dietary restriction of propiogenic amino acids (isoleucine, valine, methionine, & threonine) by using specialized medical foods
• Specific dietary protein prescription might vary based on multiple factors incl disease severity & growth rate.
• Additional calories can be provided using protein-free formulas.
• Dietary mgmt needs to be directed by experienced physician & metabolic dietician.
• Recommended protein intake is age- & sex-dependent.
• The ratio of natural source protein to medical foods varies depending on clinical status, laboratory parameters, & growth trajectory.
• Screening laboratory studies to guide nutritional intervention are listed in
• 1 regimen uses a 1-week-on, 3-weeks off approach.
• Possible benefits may need to be balanced against known side effects (constipation, diarrhea, optic neuropathy, & pancreatitis).
• Oral levocarnintine, 100 mg/kg/day
• Dose is adjusted on individual basis to maintain plasma free L-carnitine concentration w/in reference range.
• There is no consensus re use of biotin supplementation or optimal dose in treatment of PA.
• There is no evidence that a biotin-responsive form of PA exists.
• Advanced kidney disease may require dialysis &/or kidney transplant.
• Avoidance of nephrotoxic drugs
• Liver transplant (LT) has been proposed as therapeutic measure in persons w/heart failure, w/improvement of LVEF reported in some persons.
• However, recurrence of cardiomyopathy after LT has also been reported.
• Successful cases of combined heart & liver transplantation & isolated heart transplantation have been reported.
• Consider speech therapy, PT, &/or OT as needed.
• Rehab therapy
• Care must be taken when using antipsychotic medications, as they can mask clinical signs of encephalopathy or cause adverse effects in persons w/PA.
• Special caution should be exercised w/antipsychotic medications that have QT interval prolongation potential.
• Carbohydrate supplementation orally or via tube feed
• Reduce natural protein intake
• Increasing carnitine supplementation
• Trial of outpatient treatment at home for up to 12 hrs
• Reassessment (every ~2 hrs) for clinical changes
• At-home detection & monitoring of urine ketones may be considered.
• Address electrolytes & pH imbalances w/IV fluid mgmt.
• Administration of high-energy fluids &, if hyperglycemia develops, insulin
• IV intralipids
• ↓ or omit natural protein for <24 hours
• L-carnitine supplementation (100 mg/kg/day IV divided in 3 doses)
• The volume, glucose content, & electrolyte composition of IV fluids is determined by age, target glucose infusion rates, cardiovascular status, kidney condition, & coadministration of other medications.
• Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine levels, urine pH, & ketone screening may all be of use in guiding mgmt.
• Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
• Inadequate or delayed start of emergency treatment is a risk factor for basal ganglia injury, dystonia, & consequent long-term disability.
• Sodium benzoate has been used in mgmt of acute hyperammonemia in persons w/PA.
• Oral carglumic acid (150 mg/kg/day in persons <15 kg & 3.3 gm/m
• Extracorporeal detoxification can be considered (see
• Correction of metabolic acidosis using IV fluids
• Extracorporeal detoxification may be required for persistent acidosis & hyperammonemia (plasma ammonia level >250-300 μmol/L) not responding to fluid & drug treatment.
• Judicious use of IV sodium bicarbonate to improve acid-base balance under control of fluid status & electrolyte balance
• Methods of extracorporeal detoxification incl continuous venovenous hemofiltration, extracorporeal membrane oxygenation, or hemodialysis.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PA together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise in metabolic diseases is essential.
• Patient survival of 0.95 (95% CI: 0.80-1)
• Allograft survival of 0.91 (95% CI: 0.72-1)
• Rejection of 0.20 (95% CI: 0.05-0.39)
• Hepatic artery thrombosis of 0.08 (95% CI: 0.00-0.21)
• Biliary complications of 0.03 (95% CI: 0.00-0.15)
• Cytomegalovirus / Epstein-Barr virus infection of 0.14 (95% CI: 0.00-0.37)
• Education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute metabolic crises
• Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while traveling
• MedicAlert
• Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources), specialized amino acid formula, & medication required for maintenance & emergency treatment (carnitine, antipyretics) should always be maintained at home & during travel.
• 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 info & principles of emergency treatment for PA & containing contact info for primary treating metabolic center.
• For any planned travel or vacations, consider contacting a center of expertise near destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Emergency surgeries & elective procedures require input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
• Reassessment of dietary therapy to identify essential amino acid deficiencies or other vitamin or mineral deficiencies
• Rule out iatrogenic overrestriction of essential amino acid intake.
• Measurement of weight, length, & head circumference
• Eval of nutritional status & safety of oral intake
• Plasma ammonia
• Quantitative plasma acylcarnitine profile
• Electrolytes & venous blood gas
• Urinary ketones, plasma lactic acid, & 2-methylcitric acid
• Plasma amino acids (esp isoleucine, leucine, valine, threonine, & methionine) collected 2 hrs after last typical meal
• Plasma free & total carnitine
• Mineral panel (calcium, phosphorus)
• Hemoglobin &/or CBC
• Vitamin D
• Iron studies
• Essential fatty acids
• Trace minerals (selenium & zinc)
• Plasma creatinine
• Serum cystatin C may be more sensitive than plasma creatinine to identify chronic kidney disease.
• Neuropsychological testing using age-appropriate standardized assessment batteries
• Standardized quality-of-life assessment tools for affected persons & parents/caregivers
• 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 PA, the evaluations summarized in
Propionic Acidemia: Recommended Evaluations Following Initial Diagnosis
Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).
Consider short hospitalization at a center w/expertise for inherited metabolic conditions to provide caregivers with detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
Blood gas w/base balance
Electrolytes w/anion gap, calcium, & phosphorus
Glucose
Plasma ammonia level
Urine ketones
Plasma amino acids
Urine organic acids
Acylcarnitine profile
Total & free carnitine levels
Complete blood count
Amylase & lipase
Assessment of nutritional status (calcium, phosphorus, albumin, plasma amino acids, vitamin levels [incl thiamine & 25-hydroxyvitamin D])
Iron panel
Kidney function (e.g., cystatin C, parathyroid hormone, erythropoietin)
CBC to assess for cytopenias
Consider brain MRI if the neurologic eval is abnormal.
Consider EEG if seizures are a concern.
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk or significant feeding difficulties.
Consider in persons w/cytopenias or suspicion for immunodeficiency.
To assess for hypogammaglobulinemia, B-cell lymphopenia, & ↓ CD4 & CD8 counts
Complete adherence to regional immunization schedules & influenza vaccination is indicated.
Consultation w/PT, OT, & speech therapist
Consider referral to developmental pediatrician.
Consider in persons w/history of fractures or nutritional concerns.
DXA scan might aid in eval in persons age ≥3 yrs.
CBC = complete blood count; DXA = dual-energy x-ray absorptiometry; MOI = mode of inheritance; OT = occupational therapist; PA = propionic acidemia; PT = physical therapist
After a new diagnosis of PA in a child, the closest hospital and local pediatrician should also be informed.
To evaluate for cytopenias. Consider initiating an evaluation for sepsis if the CBC and clinical signs are suggestive of an infection.
To evaluate for pancreatitis
Consider ambulatory EKG monitoring.
Medical geneticist, certified genetic counselor, and certified advanced genetic nurse
• Transfer to specialist center w/experience in mgmt of inherited metabolic diseases (strongly recommended).
• Consider short hospitalization at a center w/expertise for inherited metabolic conditions to provide caregivers with detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
• Blood gas w/base balance
• Electrolytes w/anion gap, calcium, & phosphorus
• Glucose
• Plasma ammonia level
• Urine ketones
• Plasma amino acids
• Urine organic acids
• Acylcarnitine profile
• Total & free carnitine levels
• Complete blood count
• Amylase & lipase
• Assessment of nutritional status (calcium, phosphorus, albumin, plasma amino acids, vitamin levels [incl thiamine & 25-hydroxyvitamin D])
• Iron panel
• Kidney function (e.g., cystatin C, parathyroid hormone, erythropoietin)
• CBC to assess for cytopenias
• Consider brain MRI if the neurologic eval is abnormal.
• Consider EEG if seizures are a concern.
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk or significant feeding difficulties.
• Consider in persons w/cytopenias or suspicion for immunodeficiency.
• To assess for hypogammaglobulinemia, B-cell lymphopenia, & ↓ CD4 & CD8 counts
• Complete adherence to regional immunization schedules & influenza vaccination is indicated.
• Consultation w/PT, OT, & speech therapist
• Consider referral to developmental pediatrician.
• Consider in persons w/history of fractures or nutritional concerns.
• DXA scan might aid in eval in persons age ≥3 yrs.
## Treatment of Manifestations
The mainstay nutritional intervention is modification of diet to control the intake of propiogenic substrates (isoleucine, valine, methionine, and threonine), while ensuring normal protein synthesis and preventing protein catabolism, amino acid deficiencies, and growth restriction.
Propionic Acidemia: Routine Daily Treatment
Dietary restriction of propiogenic amino acids (isoleucine, valine, methionine, & threonine) by using specialized medical foods
Specific dietary protein prescription might vary based on multiple factors incl disease severity & growth rate.
Additional calories can be provided using protein-free formulas.
Dietary mgmt needs to be directed by experienced physician & metabolic dietician.
Recommended protein intake is age- & sex-dependent.
The ratio of natural source protein to medical foods varies depending on clinical status, laboratory parameters, & growth trajectory.
Screening laboratory studies to guide nutritional intervention are listed in
1 regimen uses a 1-week-on, 3-weeks off approach.
Possible benefits may need to be balanced against known side effects (constipation, diarrhea, optic neuropathy, & pancreatitis).
Oral levocarnintine, 100 mg/kg/day
Dose is adjusted on individual basis to maintain plasma free L-carnitine concentration w/in reference range.
There is no consensus re use of biotin supplementation or optimal dose in treatment of PA.
There is no evidence that a biotin-responsive form of PA exists.
Advanced kidney disease may require dialysis &/or kidney transplant.
Avoidance of nephrotoxic drugs
Liver transplant (LT) has been proposed as therapeutic measure in persons w/heart failure, w/improvement of LVEF reported in some persons.
However, recurrence of cardiomyopathy after LT has also been reported.
Successful cases of combined heart & liver transplantation & isolated heart transplantation have been reported.
Consider speech therapy, PT, &/or OT as needed.
Rehab therapy
Care must be taken when using antipsychotic medications, as they can mask clinical signs of encephalopathy or cause adverse effects in persons w/PA.
Special caution should be exercised w/antipsychotic medications that have QT interval prolongation potential.
CNS = central nervous system; LVEF = left ventricular ejection fraction; OT = occupational therapy; PA = propionic acidemia; PT = physical therapy
For protein restriction, the authors suggest adherence to the recommended age- and sex-specific safe levels of protein and energy intake [
See
The optimal dose of levocarnitine has not been established.
When calculating the daily dose of levocarnitine, one needs to consider the presence of this pharmaceutic compound in medical foods and the maximum daily dose in older affected individuals.
Propionic Acidemia: Home Management of Mild Metabolic Status
Carbohydrate supplementation orally or via tube feed
Reduce natural protein intake
Increasing carnitine supplementation
Trial of outpatient treatment at home for up to 12 hrs
Reassessment (every ~2 hrs) for clinical changes
At-home detection & monitoring of urine ketones may be considered.
Fever; 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, with some centers recommending 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) may be considered.
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
More aggressive fever management might be indicated in individuals with history of arrythmias and/or prolonged QT interval.
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 (see
Propionic Acidemia: Acute Inpatient Treatment
Address electrolytes & pH imbalances w/IV fluid mgmt.
Administration of high-energy fluids &, if hyperglycemia develops, insulin
IV intralipids
↓ or omit natural protein for <24 hours
L-carnitine supplementation (100 mg/kg/day IV divided in 3 doses)
The volume, glucose content, & electrolyte composition of IV fluids is determined by age, target glucose infusion rates, cardiovascular status, kidney condition, & coadministration of other medications.
Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine levels, urine pH, & ketone screening may all be of use in guiding mgmt.
Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
Inadequate or delayed start of emergency treatment is a risk factor for basal ganglia injury, dystonia, & consequent long-term disability.
Sodium benzoate has been used in mgmt of acute hyperammonemia in persons w/PA.
Oral carglumic acid (150 mg/kg/day in persons <15 kg & 3.3 gm/m
Extracorporeal detoxification can be considered (see
Correction of metabolic acidosis using IV fluids
Extracorporeal detoxification may be required for persistent acidosis & hyperammonemia (plasma ammonia level >250-300 μmol/L) not responding to fluid & drug treatment.
Judicious use of IV sodium bicarbonate to improve acid-base balance under control of fluid status & electrolyte balance
Methods of extracorporeal detoxification incl continuous venovenous hemofiltration, extracorporeal membrane oxygenation, or hemodialysis.
ICU = intensive care unit; IV = intravenous; PA = propionic acidemia
Inpatient 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.
Intravenous D10 ½ normal saline typically between 100% and 150% of the maintenance requirements is a common starting fluid. Dextrose solutions exceeding the concentration of 12.5% require a central line placement. The target glucose infusion rates vary by age [
Use of insulin if hyperglycemia emerges; intravenous insulin given at a starting dose of 0.01-0.02 IU/kg/hour in the event of persistent hyperglycemia (>150-180 mg/dL in plasma) or glucosuria.
Protein intake can be gradually advanced as tolerated; careful introduction of non-propiogenic amino acids from medical foods might be needed to achieve a positive nitrogen balance [
If transition to enteral feedings within 48 hours is not possible, total parenteral nutrition is required.
Parenteral amino acid solutions are prescribed based on the recommended daily intake of age-appropriate energy and protein needs and adjusted using daily and weekly growth data and plasma amino acid concentrations.
L-carnitine (with options to increase the dose) can be given intravenously, which enhances bioavailability.
Carnitine supplementation may enhance the detoxification of propionic acid by conjugating into propionylcarnitine, which is excreted by the kidneys. Alternatively, it may relieve intracellular coenzyme A accretion.
For a discussion regarding the use of sodium benzoate vs sodium phenylacetate and sodium phenylbutyrate in PA, see
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PA together with pediatric metabolic experts, dietitians, psychologists, and social workers.
As the long-term course of metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise in metabolic diseases is essential.
• Dietary restriction of propiogenic amino acids (isoleucine, valine, methionine, & threonine) by using specialized medical foods
• Specific dietary protein prescription might vary based on multiple factors incl disease severity & growth rate.
• Additional calories can be provided using protein-free formulas.
• Dietary mgmt needs to be directed by experienced physician & metabolic dietician.
• Recommended protein intake is age- & sex-dependent.
• The ratio of natural source protein to medical foods varies depending on clinical status, laboratory parameters, & growth trajectory.
• Screening laboratory studies to guide nutritional intervention are listed in
• 1 regimen uses a 1-week-on, 3-weeks off approach.
• Possible benefits may need to be balanced against known side effects (constipation, diarrhea, optic neuropathy, & pancreatitis).
• Oral levocarnintine, 100 mg/kg/day
• Dose is adjusted on individual basis to maintain plasma free L-carnitine concentration w/in reference range.
• There is no consensus re use of biotin supplementation or optimal dose in treatment of PA.
• There is no evidence that a biotin-responsive form of PA exists.
• Advanced kidney disease may require dialysis &/or kidney transplant.
• Avoidance of nephrotoxic drugs
• Liver transplant (LT) has been proposed as therapeutic measure in persons w/heart failure, w/improvement of LVEF reported in some persons.
• However, recurrence of cardiomyopathy after LT has also been reported.
• Successful cases of combined heart & liver transplantation & isolated heart transplantation have been reported.
• Consider speech therapy, PT, &/or OT as needed.
• Rehab therapy
• Care must be taken when using antipsychotic medications, as they can mask clinical signs of encephalopathy or cause adverse effects in persons w/PA.
• Special caution should be exercised w/antipsychotic medications that have QT interval prolongation potential.
• Carbohydrate supplementation orally or via tube feed
• Reduce natural protein intake
• Increasing carnitine supplementation
• Trial of outpatient treatment at home for up to 12 hrs
• Reassessment (every ~2 hrs) for clinical changes
• At-home detection & monitoring of urine ketones may be considered.
• Address electrolytes & pH imbalances w/IV fluid mgmt.
• Administration of high-energy fluids &, if hyperglycemia develops, insulin
• IV intralipids
• ↓ or omit natural protein for <24 hours
• L-carnitine supplementation (100 mg/kg/day IV divided in 3 doses)
• The volume, glucose content, & electrolyte composition of IV fluids is determined by age, target glucose infusion rates, cardiovascular status, kidney condition, & coadministration of other medications.
• Blood glucose, electrolyte concentrations, blood gases, plasma amino acids, plasma carnitine levels, urine pH, & ketone screening may all be of use in guiding mgmt.
• Ongoing assessment of hemodynamic status & for new neurologic signs is critical.
• Inadequate or delayed start of emergency treatment is a risk factor for basal ganglia injury, dystonia, & consequent long-term disability.
• Sodium benzoate has been used in mgmt of acute hyperammonemia in persons w/PA.
• Oral carglumic acid (150 mg/kg/day in persons <15 kg & 3.3 gm/m
• Extracorporeal detoxification can be considered (see
• Correction of metabolic acidosis using IV fluids
• Extracorporeal detoxification may be required for persistent acidosis & hyperammonemia (plasma ammonia level >250-300 μmol/L) not responding to fluid & drug treatment.
• Judicious use of IV sodium bicarbonate to improve acid-base balance under control of fluid status & electrolyte balance
• Methods of extracorporeal detoxification incl continuous venovenous hemofiltration, extracorporeal membrane oxygenation, or hemodialysis.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PA together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• As the long-term course of metabolic diseases in this age group is not yet fully characterized, continuous supervision by a center of expertise in metabolic diseases is essential.
## Prevention of Primary Manifestations
Prevention and proactive management of metabolic crises (see
The indication of liver transplantation for dilated cardiomyopathy with severe heart dysfunction is less clear, with reports showing a short-term improvement or stabilization of heart function [
The current evidence with short- or medium-term follow up has not demonstrated superiority of unrelated donors compared to heterozygous related donors for liver transplant [
Close monitoring of metabolic and nutritional status around the perioperative period by a highly specialized team is recommended. Disease-specific metabolites such as 3-hydroxypropionate can be elevated during the anhepatic phase [
Metabolic decompensation during liver transplantation poses a higher mortality risk [
Benefits of OLT include decrease in the frequency of metabolic decompensations and potential stabilization of the neurodevelopmental decline [
Complications of liver transplantation were summarized in a meta-analysis with the following pooled estimated rates [
Patient survival of 0.95 (95% CI: 0.80-1)
Allograft survival of 0.91 (95% CI: 0.72-1)
Rejection of 0.20 (95% CI: 0.05-0.39)
Hepatic artery thrombosis of 0.08 (95% CI: 0.00-0.21)
Biliary complications of 0.03 (95% CI: 0.00-0.15)
Cytomegalovirus / Epstein-Barr virus infection of 0.14 (95% CI: 0.00-0.37)
Lifelong post-transplant management is recommended, as well as continuation of L-carnitine supplementation after liver transplantation. The authors recommend continued protein restriction after transplant using the WHO/FAO/UNU recommendations for energy and protein intake [
• Patient survival of 0.95 (95% CI: 0.80-1)
• Allograft survival of 0.91 (95% CI: 0.72-1)
• Rejection of 0.20 (95% CI: 0.05-0.39)
• Hepatic artery thrombosis of 0.08 (95% CI: 0.00-0.21)
• Biliary complications of 0.03 (95% CI: 0.00-0.15)
• Cytomegalovirus / Epstein-Barr virus infection of 0.14 (95% CI: 0.00-0.37)
## 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 offered expediently during intercurrent illnesses or other catabolic stressors (see also
Propionic Acidemia: Prevention of Secondary Manifestations
Education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute metabolic crises
Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while traveling
MedicAlert
Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources), specialized amino acid formula, & medication required for maintenance & emergency treatment (carnitine, antipyretics) should always be maintained at home & during travel.
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 info & principles of emergency treatment for PA & containing contact info for primary treating metabolic center.
For any planned travel or vacations, consider contacting a center of expertise near destination prior to travel dates.
Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
Emergency surgeries & elective procedures require input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
Reassessment of dietary therapy to identify essential amino acid deficiencies or other vitamin or mineral deficiencies
Rule out iatrogenic overrestriction of essential amino acid intake.
Essential information including written treatment protocols should be provided
Perioperative/perianesthetic management precautions may include visitations at specialist anesthetic clinics for affected individuals deemed to be at high risk for perioperative complications (see
• Education of affected persons & caregivers re natural history, maintenance & emergency treatment, prognosis, & risks of acute metabolic crises
• Treatment protocols & provision of emergency letters or cards to incl guidance for care in event of illness while traveling
• MedicAlert
• Adequate supplies of specialized dietary products (carbohydrate-only formulas or other caloric sources), specialized amino acid formula, & medication required for maintenance & emergency treatment (carnitine, antipyretics) should always be maintained at home & during travel.
• 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 info & principles of emergency treatment for PA & containing contact info for primary treating metabolic center.
• For any planned travel or vacations, consider contacting a center of expertise near destination prior to travel dates.
• Notify designated metabolic center in advance of procedure to discuss perioperative mgmt w/surgeons & anesthesiologists.
• Emergency surgeries & elective procedures require input from physicians w/expertise in inherited metabolic diseases (w/respect to perioperative fluid & nutritional mgmt).
• Reassessment of dietary therapy to identify essential amino acid deficiencies or other vitamin or mineral deficiencies
• Rule out iatrogenic overrestriction of essential amino acid intake.
## Surveillance
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in
Propionic Acidemia: Recommended Surveillance
Measurement of weight, length, & head circumference
Eval of nutritional status & safety of oral intake
Plasma ammonia
Quantitative plasma acylcarnitine profile
Electrolytes & venous blood gas
Urinary ketones, plasma lactic acid, & 2-methylcitric acid
Plasma amino acids (esp isoleucine, leucine, valine, threonine, & methionine) collected 2 hrs after last typical meal
Plasma free & total carnitine
Mineral panel (calcium, phosphorus)
Hemoglobin &/or CBC
Vitamin D
Iron studies
Essential fatty acids
Trace minerals (selenium & zinc)
Plasma creatinine
Serum cystatin C may be more sensitive than plasma creatinine to identify chronic kidney disease.
Neuropsychological testing using age-appropriate standardized assessment batteries
Standardized quality-of-life assessment tools for affected persons & parents/caregivers
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
CBC = complete blood count; DXA = dual-energy x-ray absorptiometry
This should also include interval assessment for the need for a gastrostomy tube in those who do not already have one.
The following evaluations are performed at different intervals depending on factors such as age, disease severity, and presence of catabolic stressors; evaluation frequency can range from every three months to annually.
To monitor and adjust nutritional management
To monitor for cytopenias
To screen for cardiomyopathy and arrythmia
To assess for optic nerve and retinal changes
• Measurement of weight, length, & head circumference
• Eval of nutritional status & safety of oral intake
• Plasma ammonia
• Quantitative plasma acylcarnitine profile
• Electrolytes & venous blood gas
• Urinary ketones, plasma lactic acid, & 2-methylcitric acid
• Plasma amino acids (esp isoleucine, leucine, valine, threonine, & methionine) collected 2 hrs after last typical meal
• Plasma free & total carnitine
• Mineral panel (calcium, phosphorus)
• Hemoglobin &/or CBC
• Vitamin D
• Iron studies
• Essential fatty acids
• Trace minerals (selenium & zinc)
• Plasma creatinine
• Serum cystatin C may be more sensitive than plasma creatinine to identify chronic kidney disease.
• Neuropsychological testing using age-appropriate standardized assessment batteries
• Standardized quality-of-life assessment tools for affected persons & parents/caregivers
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
## Agents/Circumstances to Avoid
Avoid prolonged fasting, catabolic stressors, and excessive protein intake.
Lactated Ringer's solution is not recommended in individuals with organic acidemias.
In individuals with QT interval abnormalities, avoid medications that can prolong the QT interval.
Ondansetron, an antiemetic drug used to control nausea, has been associated with QT interval prolongation on EKG [
Nephrotoxic medications (e.g., aminoglycosides) should be avoided.
Neuroleptic antiemetics (e.g., promethazine) can mask symptoms of progressive encephalopathy and are best avoided.
## Evaluation of Relatives at Risk
Testing of at-risk sibs is warranted to allow for early diagnosis and treatment. If prenatal testing has not been performed on at-risk sibs, measure urine organic acids, plasma amino acids, and acylcarnitine profile immediately in the newborn period in parallel with newborn screening.
See
## Pregnancy Management
Although successful pregnancy outcomes have been reported in individuals with PA [
## Therapies Under Investigation
Search
## Genetic Counseling
Propionic acidemia (PA) 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 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 (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.
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 known carriers and for the reproductive partners of individuals affected with PA, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see
Once the
If biallelic
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 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 (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
• 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 known carriers and for the reproductive partners of individuals affected with PA, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see
## Mode of Inheritance
Propionic acidemia (PA) 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 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 (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 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 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 (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
• 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.
Carrier testing should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with PA, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (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 should be considered for the reproductive partners of known carriers and for the reproductive partners of individuals affected with PA, particularly if both partners are of the same ancestry. Founder variants have been identified in several populations (see
## Prenatal Testing and Preimplantation Genetic Testing
Once the
If biallelic
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
Health Resources & Services Administration
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• Health Resources & Services Administration
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## Molecular Genetics
Propionic Acidemia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Propionic Acidemia (
Propionic acidemia (PA) is caused by deficiency of the mitochondrial multimeric enzyme propionyl-coenzyme A carboxylase (PCC), a biotin-dependent carboxylase located in the mitochondrial inner space that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. The enzyme is composed of alpha and beta subunits encoded by their respective genes,
PCC is a heterododecamer (α6β6) composed of six alpha subunits encoded by
PCC catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA, which eventually enters the Krebs cycle as succinyl-CoA. Propionyl-CoA is common to the pathway for degradation of some amino acids (isoleucine, valine, threonine, and methionine), odd-chain fatty acids, and a side chain of cholesterol. Gut bacteria (e.g.,
The deficiency of PCC enzymatic activity profoundly deranges metabolism at several levels. Possible explanations include:
The toxic effects of free organic acids and ammonia;
The accumulation of propionyl-CoA, which in turn can inhibit other enzyme systems including oxidative phosphorylation [
Decreased production of Krebs cycle intermediates.
Pathogenic Variants Referenced in This
NBS = newborn screening
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
For a list of variants reported as pathogenic for PA, see
• The toxic effects of free organic acids and ammonia;
• The accumulation of propionyl-CoA, which in turn can inhibit other enzyme systems including oxidative phosphorylation [
• Decreased production of Krebs cycle intermediates.
## Molecular Pathogenesis
Propionic acidemia (PA) is caused by deficiency of the mitochondrial multimeric enzyme propionyl-coenzyme A carboxylase (PCC), a biotin-dependent carboxylase located in the mitochondrial inner space that catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA. The enzyme is composed of alpha and beta subunits encoded by their respective genes,
PCC is a heterododecamer (α6β6) composed of six alpha subunits encoded by
PCC catalyzes the conversion of propionyl-CoA to D-methylmalonyl-CoA, which eventually enters the Krebs cycle as succinyl-CoA. Propionyl-CoA is common to the pathway for degradation of some amino acids (isoleucine, valine, threonine, and methionine), odd-chain fatty acids, and a side chain of cholesterol. Gut bacteria (e.g.,
The deficiency of PCC enzymatic activity profoundly deranges metabolism at several levels. Possible explanations include:
The toxic effects of free organic acids and ammonia;
The accumulation of propionyl-CoA, which in turn can inhibit other enzyme systems including oxidative phosphorylation [
Decreased production of Krebs cycle intermediates.
Pathogenic Variants Referenced in This
NBS = newborn screening
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
For a list of variants reported as pathogenic for PA, see
• The toxic effects of free organic acids and ammonia;
• The accumulation of propionyl-CoA, which in turn can inhibit other enzyme systems including oxidative phosphorylation [
• Decreased production of Krebs cycle intermediates.
## Chapter Notes
Dr Carolina Galarreta Aima, Dr Oleg A Shchelochkov, and Dr Venditti are physicians at the NIH Clinical Center and specialize in pediatrics and biochemical genetics. Dr Teodoro Jerves is a biochemical geneticist at Yale University. Dr Venditti is the Director of the Organic Acid Research Section at the National Human Genome Research Institute.
The authors wish to express their appreciation to Christopher P Jordan, MD, and Jennifer L Sloan, PhD, for their valuable contributions to this chapter.
Nuria Carrillo, MD; National Human Genome Research Institute (2012-2024)Carolina I Galarreta Aima, MD (2024-present)Teodoro Jerves Serrano, MD (2024-present)Oleg A Shchelochkov, MD (2016-present)Charles P Venditti, MD, PhD (2012-present)
26 September 2024 (gf) Comprehensive update posted live
6 October 2016 (ha) Comprehensive update posted live
17 May 2012 (me) Review posted live
28 October 2011 (nc) Original submission
• 26 September 2024 (gf) Comprehensive update posted live
• 6 October 2016 (ha) Comprehensive update posted live
• 17 May 2012 (me) Review posted live
• 28 October 2011 (nc) Original submission
## Author Notes
Dr Carolina Galarreta Aima, Dr Oleg A Shchelochkov, and Dr Venditti are physicians at the NIH Clinical Center and specialize in pediatrics and biochemical genetics. Dr Teodoro Jerves is a biochemical geneticist at Yale University. Dr Venditti is the Director of the Organic Acid Research Section at the National Human Genome Research Institute.
## Acknowledgements
The authors wish to express their appreciation to Christopher P Jordan, MD, and Jennifer L Sloan, PhD, for their valuable contributions to this chapter.
## Author History
Nuria Carrillo, MD; National Human Genome Research Institute (2012-2024)Carolina I Galarreta Aima, MD (2024-present)Teodoro Jerves Serrano, MD (2024-present)Oleg A Shchelochkov, MD (2016-present)Charles P Venditti, MD, PhD (2012-present)
## Revision History
26 September 2024 (gf) Comprehensive update posted live
6 October 2016 (ha) Comprehensive update posted live
17 May 2012 (me) Review posted live
28 October 2011 (nc) Original submission
• 26 September 2024 (gf) Comprehensive update posted live
• 6 October 2016 (ha) Comprehensive update posted live
• 17 May 2012 (me) Review posted live
• 28 October 2011 (nc) Original submission
## References
## Literature Cited
Immediate management and testing algorithm to be pursued simultaneously after abnormal newborn screening concerning for propionic acidemia
Metabolic pathway. Propionyl-coenzyme A carboxylase (PCC) catalyzes the conversion of propionyl-CoA to methylmalonyl-CoA, which enters the Krebs cycle via succinyl-CoA. Sources of propionate include: valine, isoleucine, threonine, methionine, odd-chain fatty acids, and cholesterol. Deficiency of PCC results in propionic acidemia (PA) and accumulation of 3-OH propionate, methylcitrate, and glycine, among other metabolites. PCC, located inside the mitochondrion, is a heterododecamer (α6β6) comprising six alpha subunits (orange) and six beta subunits (purple). Biotin (blue), bicarbonate, and ATP have binding sites in the alpha subunit. The beta subunits form a central core.
|
[] |
17/5/2012
|
26/9/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
proteus
|
proteus
|
[
"AKT1-Related Overgrowth Spectrum",
"AKT1-Related Proteus Syndrome",
"RAC-alpha serine/threonine-protein kinase",
"AKT1",
"Proteus Syndrome"
] |
Proteus Syndrome
|
Leslie G Biesecker, Julie C Sapp
|
Summary Proteus syndrome (PS) is characterized by progressive segmental or patchy overgrowth most commonly affecting the skeleton, skin, adipose, and central nervous systems. In most individuals PS has modest or no manifestations at birth, develops and progresses rapidly beginning in the toddler period, and relentlessly progresses through childhood, causing severe overgrowth and disfigurement. It is associated with a range of tumors, pulmonary complications, and a striking predisposition to deep vein thrombosis and pulmonary embolism. The diagnosis of PS is established in a proband with all three general criteria (mosaic distribution of lesions, sporadic occurrence, progressive course) and a clinical score based on positive and negative criteria of at least ten points in an individual PS and
|
Proteus syndrome
Proteus syndrome (clinical diagnosis)
• Proteus syndrome
• Proteus syndrome (clinical diagnosis)
• Proteus syndrome (clinical diagnosis)
• Proteus syndrome (clinical diagnosis)
## Diagnosis
Consensus clinical diagnostic criteria for Proteus syndrome (PS) have been published [
PS
Distorting, progressive overgrowth, typically of postnatal onset, often resulting in asymmetric distortion of the skeletal architecture. Hemimegencephaly can be prenatal.
Cerebriform connective tissue nevi characterized by deep grooves and gyrations as seen on the surface of the brain
Linear verrucous epidermal nevus, a streaky, pigmented, rough nevus that often follows the lines of Blaschko and can be present anywhere on the body
Adipose dysregulation, including lipomatous overgrowth and lipoatrophy
Vascular malformations, including cutaneous capillary malformations, prominent venous patterning or varicosities, and lymphatic malformations
Overgrowth of other tissues, most commonly spleen, liver, thymus, and gastrointestinal tract
Tumors, most commonly meningiomas. Ovarian cystadenomas, breast cancer, parotid monomorphic adenoma, mesothelioma, and others have also been reported.
Bullous pulmonary degeneration
Dysmorphic facial features including dolichocephaly, long face, downslanting palpebral fissures, and/or minor ptosis, depressed nasal bridge, wide or anteverted nares, and open mouth at rest
The diagnosis of PS
Mosaic distribution of lesions
Sporadic occurrence
Progressive course
A score of ≥10 points in an individual
A score of ≥15 points in an individual
Note: The diagnosis of
* Individuals without a mosaic
Positive and Negative Clinical Criteria Used in the Diagnosis of Proteus Syndrome
Molecular 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
Note: (1) Identification of an
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other overgrowth disorders,
For an introduction to comprehensive genomic testing click
Note: The methodology used for testing must be designed to detect mosaic variants (variant allele fraction <50%). Some individuals with
Molecular Genetic Testing Used in Proteus Syndrome
See
See
Somatic mosaicism for the
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.
To date, an
• Distorting, progressive overgrowth, typically of postnatal onset, often resulting in asymmetric distortion of the skeletal architecture. Hemimegencephaly can be prenatal.
• Cerebriform connective tissue nevi characterized by deep grooves and gyrations as seen on the surface of the brain
• Linear verrucous epidermal nevus, a streaky, pigmented, rough nevus that often follows the lines of Blaschko and can be present anywhere on the body
• Adipose dysregulation, including lipomatous overgrowth and lipoatrophy
• Vascular malformations, including cutaneous capillary malformations, prominent venous patterning or varicosities, and lymphatic malformations
• Overgrowth of other tissues, most commonly spleen, liver, thymus, and gastrointestinal tract
• Tumors, most commonly meningiomas. Ovarian cystadenomas, breast cancer, parotid monomorphic adenoma, mesothelioma, and others have also been reported.
• Bullous pulmonary degeneration
• Dysmorphic facial features including dolichocephaly, long face, downslanting palpebral fissures, and/or minor ptosis, depressed nasal bridge, wide or anteverted nares, and open mouth at rest
• Mosaic distribution of lesions
• Sporadic occurrence
• Progressive course
• A score of ≥10 points in an individual
• A score of ≥15 points in an individual
## Suggestive Findings
PS
Distorting, progressive overgrowth, typically of postnatal onset, often resulting in asymmetric distortion of the skeletal architecture. Hemimegencephaly can be prenatal.
Cerebriform connective tissue nevi characterized by deep grooves and gyrations as seen on the surface of the brain
Linear verrucous epidermal nevus, a streaky, pigmented, rough nevus that often follows the lines of Blaschko and can be present anywhere on the body
Adipose dysregulation, including lipomatous overgrowth and lipoatrophy
Vascular malformations, including cutaneous capillary malformations, prominent venous patterning or varicosities, and lymphatic malformations
Overgrowth of other tissues, most commonly spleen, liver, thymus, and gastrointestinal tract
Tumors, most commonly meningiomas. Ovarian cystadenomas, breast cancer, parotid monomorphic adenoma, mesothelioma, and others have also been reported.
Bullous pulmonary degeneration
Dysmorphic facial features including dolichocephaly, long face, downslanting palpebral fissures, and/or minor ptosis, depressed nasal bridge, wide or anteverted nares, and open mouth at rest
• Distorting, progressive overgrowth, typically of postnatal onset, often resulting in asymmetric distortion of the skeletal architecture. Hemimegencephaly can be prenatal.
• Cerebriform connective tissue nevi characterized by deep grooves and gyrations as seen on the surface of the brain
• Linear verrucous epidermal nevus, a streaky, pigmented, rough nevus that often follows the lines of Blaschko and can be present anywhere on the body
• Adipose dysregulation, including lipomatous overgrowth and lipoatrophy
• Vascular malformations, including cutaneous capillary malformations, prominent venous patterning or varicosities, and lymphatic malformations
• Overgrowth of other tissues, most commonly spleen, liver, thymus, and gastrointestinal tract
• Tumors, most commonly meningiomas. Ovarian cystadenomas, breast cancer, parotid monomorphic adenoma, mesothelioma, and others have also been reported.
• Bullous pulmonary degeneration
• Dysmorphic facial features including dolichocephaly, long face, downslanting palpebral fissures, and/or minor ptosis, depressed nasal bridge, wide or anteverted nares, and open mouth at rest
## Establishing the Diagnosis
The diagnosis of PS
Mosaic distribution of lesions
Sporadic occurrence
Progressive course
A score of ≥10 points in an individual
A score of ≥15 points in an individual
Note: The diagnosis of
* Individuals without a mosaic
Positive and Negative Clinical Criteria Used in the Diagnosis of Proteus Syndrome
Molecular 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
Note: (1) Identification of an
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other overgrowth disorders,
For an introduction to comprehensive genomic testing click
Note: The methodology used for testing must be designed to detect mosaic variants (variant allele fraction <50%). Some individuals with
Molecular Genetic Testing Used in Proteus Syndrome
See
See
Somatic mosaicism for the
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.
To date, an
• Mosaic distribution of lesions
• Sporadic occurrence
• Progressive course
• A score of ≥10 points in an individual
• A score of ≥15 points in an individual
## Molecular Genetic Testing
Molecular 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
Note: (1) Identification of an
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other overgrowth disorders,
For an introduction to comprehensive genomic testing click
Note: The methodology used for testing must be designed to detect mosaic variants (variant allele fraction <50%). Some individuals with
Molecular Genetic Testing Used in Proteus Syndrome
See
See
Somatic mosaicism for the
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.
To date, an
## Clinical Characteristics
Proteus syndrome (PS) displays a wide range of severity. Some individuals are minimally affected, but others are quite severely affected. Among the individuals in the NIH
Most affected individuals have few or no manifestations at birth. Most typically, the first manifestations of the disorder occur between age six and 18 months with the onset of asymmetric overgrowth; it is most commonly of the feet or hands but may occur anywhere. An exception is that a few individuals (probably <5%) first manifest PS with hemimegencephaly, often associated with central nervous system migration defects and later intellectual disability. This manifestation is prenatal. There is a single individual reported with prenatal diagnosis of generalized overgrowth, but this presentation is distinctly unusual [
Many individuals with PS have (often unilateral) overgrowth of the tonsils/adenoids. Splenic overgrowth and asymmetric enlargement of the kidneys and testes are also not uncommon in individuals with PS.
Linear verrucous epidermal nevi are streaky, pigmented, rough nevi that often follow the lines of Blaschko. They can be present anywhere on the body. They are most commonly recognized in the first months of life and are generally stable over time [
Less common dermatologic findings include hypertrichosis or acne in patterns that follow the lines of Blaschko [
The most urgent and life-threatening complication of PS can be deep vein thrombosis (DVT) and pulmonary embolism (PE) [
Those with PS manifest skeletal and other overgrowth in areas where no vascular malformations are present (unlike some other overgrowth conditions).
Importantly, arteriovenous malformation (AVM) is uncommon in PS.
Pulmonary venous dilatation on chest imaging is common [
Because PS is a mosaic disorder, it is axiomatic that there will be substantial interindividual phenotypic variation because every affected individual has the causative variant in a distinct spectrum of their tissues. This variation is in both the nature and the severity of the manifestations. Because this spectrum of variation is continuous, any definition of minimal diagnostic criteria for the Proteus phenotype must be arbitrary.
All but two individuals with
Incomplete penetrance cannot be assessed in a practical way in a mosaic genetic disorder that is not inherited. As it has been shown that unaffected tissues can contain the causative variant, it is theoretically possible that an individual with lower variant allele fraction levels could be asymptomatic. This is mainly of academic interest, as it is difficult to imagine a circumstance where this would be sought and detected.
Other descriptors used include elephant man disease. This descriptor is derived from the fact that Mr Joseph Carey Merrick, who held this unfortunate descriptor, is now thought to have had PS [
PS is very rare. The prevalence is difficult to measure, but approximately 100 individuals are known to the author [L Biesecker, personal observation]. A very rough estimate is that PS affects 1:1,000,000-10,000,000 persons.
## Clinical Description
Proteus syndrome (PS) displays a wide range of severity. Some individuals are minimally affected, but others are quite severely affected. Among the individuals in the NIH
Most affected individuals have few or no manifestations at birth. Most typically, the first manifestations of the disorder occur between age six and 18 months with the onset of asymmetric overgrowth; it is most commonly of the feet or hands but may occur anywhere. An exception is that a few individuals (probably <5%) first manifest PS with hemimegencephaly, often associated with central nervous system migration defects and later intellectual disability. This manifestation is prenatal. There is a single individual reported with prenatal diagnosis of generalized overgrowth, but this presentation is distinctly unusual [
Many individuals with PS have (often unilateral) overgrowth of the tonsils/adenoids. Splenic overgrowth and asymmetric enlargement of the kidneys and testes are also not uncommon in individuals with PS.
Linear verrucous epidermal nevi are streaky, pigmented, rough nevi that often follow the lines of Blaschko. They can be present anywhere on the body. They are most commonly recognized in the first months of life and are generally stable over time [
Less common dermatologic findings include hypertrichosis or acne in patterns that follow the lines of Blaschko [
The most urgent and life-threatening complication of PS can be deep vein thrombosis (DVT) and pulmonary embolism (PE) [
Those with PS manifest skeletal and other overgrowth in areas where no vascular malformations are present (unlike some other overgrowth conditions).
Importantly, arteriovenous malformation (AVM) is uncommon in PS.
Pulmonary venous dilatation on chest imaging is common [
Because PS is a mosaic disorder, it is axiomatic that there will be substantial interindividual phenotypic variation because every affected individual has the causative variant in a distinct spectrum of their tissues. This variation is in both the nature and the severity of the manifestations. Because this spectrum of variation is continuous, any definition of minimal diagnostic criteria for the Proteus phenotype must be arbitrary.
## Genotype-Phenotype Correlations
All but two individuals with
## Penetrance
Incomplete penetrance cannot be assessed in a practical way in a mosaic genetic disorder that is not inherited. As it has been shown that unaffected tissues can contain the causative variant, it is theoretically possible that an individual with lower variant allele fraction levels could be asymptomatic. This is mainly of academic interest, as it is difficult to imagine a circumstance where this would be sought and detected.
## Nomenclature
Other descriptors used include elephant man disease. This descriptor is derived from the fact that Mr Joseph Carey Merrick, who held this unfortunate descriptor, is now thought to have had PS [
## Prevalence
PS is very rare. The prevalence is difficult to measure, but approximately 100 individuals are known to the author [L Biesecker, personal observation]. A very rough estimate is that PS affects 1:1,000,000-10,000,000 persons.
## Genetically Related (Allelic) Disorders
The only other phenotypes associated with somatic pathogenic variants in
It is hypothesized that a germline
## Differential Diagnosis
Significant diagnostic confusion regarding Proteus syndrome (PS) exists. Although the following disorders share some features with PS, both the natural history (i.e., almost always postnatal onset) and manifestations (e.g., disproportionate and progressive distorting skeletal overgrowth, cerebriform connective tissue nevi) of PS are important distinctions that can aid in clinical diagnosis.
PHTS includes growth abnormalities with linear nevi and vascular malformations that are clinically and molecularly distinct from those of PS.
PHTS is inherited in an autosomal dominant manner; PS is not inherited. Thus, the genetic implications in the two disorders are quite distinct, providing further argument for a clear distinction between individuals affected with PS and those with PHTS.
Hemihyperplasia
• Hemihyperplasia
## Management
No clinical practice guidelines for Proteus syndrome (PS) have been published.
To establish the extent of disease and needs in an individual diagnosed with Proteus syndrome (PS), the evaluations summarized in
Proteus Syndrome: Recommended Evaluations Following Initial Diagnosis
Detailed & comprehensive orthopedic eval (incl general, spine, & limbs)
Skeletal survey as baseline study of extent & severity of overgrowth
Pulmonology consultation
Pulmonary function testing
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.
MOI = mode of inheritance; PS = Proteus syndrome; US = ultrasound
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
PS is a complex multisystem disorder and individuals benefit from a coordinated and multidisciplinary clinical approach tailored to the individual's specific needs and manifestations (see
Proteus Syndrome: Treatment of Manifestations
Mgmt per orthopedist
Epiphysiostasis & epiphysiodesis for overgrowth of tubular bones
Mgmt by rehab medicine, incl PT & OT
Custom-designed footwear or orthotics due to leg-length inequality
Referral to orthopedist if scoliosis is identified on clinical &/or radiographic exam
Frequent monitoring due to risk of rapid progression
Surgery is often indicated, as progressive nature of scoliosis can lead to fatal restrictive lung disease.
Mgmt by dermatologist
Monitor for pressure ulcerations & malodor (due to difficulty w/cleanliness of deepening sulci in late adolescence)
Pedorthic referral as needed for issues w/shoe fit
Treatment of DVT & PE should follow recommended anticoagulation guidelines for these disorders.
Persons w/PE can be asymptomatic; therefore, a person w/DVT should be evaluated for PE regardless of symptoms.
Note: Hematologic consultation for consideration of anticoagulant prophylaxis for persons undergoing surgery or other procedures that may predispose to DVT/PE is recommended.
Pulmonary eval for persons w/bullous pulmonary disease
Resection of large bullous lesions may be indicated in some persons.
CCTN = cerebriform connective tissue nevi; DVT = deep vein thrombosis; OT = occupational therapy; PE = pulmonary embolism; PS = Proteus syndrome; PT = physical therapy; US = ultrasound
Hematologic consultation for consideration of anticoagulant prophylaxis for individuals undergoing surgery or other procedures that may predispose to DVT/PE is recommended.
Authors, personal observation
Individualized surveillance plans for the skeletal, pulmonary, soft tissue, and other manifestations of PS should be developed according to the individual's specific needs (see
Proteus Syndrome: Recommended Surveillance
Orthopedic eval to assess for progression of overgrowth & scoliosis
Imaging per orthopedist
Rehab medicine, PT, &/or OT eval to assess mobility issues, footwear, & orthotics needs
Pulmonary eval
Pulmonary function testing
Directed medical history & exam w/primary care clinician for signs/symptoms of malignancy (e.g., pain, unexpected growths, signs of obstruction or compression)
Imaging as needed for signs/symptoms concerning for tumor(s); periodic imaging is not indicated.
OT = occupational therapy; PT = physical therapy
Medications that increase the risk of deep vein thrombosis or are procoagulant should be avoided.
Medications that increase growth (e.g., androgenic steroids, growth hormone) should be avoided.
Because PS is not inherited, relatives are not at increased risk and do not require evaluation for recurrence of this condition. Every individual has the same likelihood of having a somatic mutation that could cause Proteus syndrome, irrespective of whether they are related to someone with Proteus syndrome or not.
There are no data on the management of pregnancy in women with PS. Pregnancy presents theoretic risks, especially the risk of thrombosis of the pelvic veins.
A pilot Phase 0/I pharmacodynamic study of miransertib (formerly ARQ-092) has been completed and showed a favorable safety profile with some suggestions of efficacy [
Search
• Detailed & comprehensive orthopedic eval (incl general, spine, & limbs)
• Skeletal survey as baseline study of extent & severity of overgrowth
• Pulmonology consultation
• Pulmonary function testing
• 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.
• Mgmt per orthopedist
• Epiphysiostasis & epiphysiodesis for overgrowth of tubular bones
• Mgmt by rehab medicine, incl PT & OT
• Custom-designed footwear or orthotics due to leg-length inequality
• Referral to orthopedist if scoliosis is identified on clinical &/or radiographic exam
• Frequent monitoring due to risk of rapid progression
• Surgery is often indicated, as progressive nature of scoliosis can lead to fatal restrictive lung disease.
• Mgmt by dermatologist
• Monitor for pressure ulcerations & malodor (due to difficulty w/cleanliness of deepening sulci in late adolescence)
• Pedorthic referral as needed for issues w/shoe fit
• Treatment of DVT & PE should follow recommended anticoagulation guidelines for these disorders.
• Persons w/PE can be asymptomatic; therefore, a person w/DVT should be evaluated for PE regardless of symptoms.
• Note: Hematologic consultation for consideration of anticoagulant prophylaxis for persons undergoing surgery or other procedures that may predispose to DVT/PE is recommended.
• Pulmonary eval for persons w/bullous pulmonary disease
• Resection of large bullous lesions may be indicated in some persons.
• Orthopedic eval to assess for progression of overgrowth & scoliosis
• Imaging per orthopedist
• Rehab medicine, PT, &/or OT eval to assess mobility issues, footwear, & orthotics needs
• Pulmonary eval
• Pulmonary function testing
• Directed medical history & exam w/primary care clinician for signs/symptoms of malignancy (e.g., pain, unexpected growths, signs of obstruction or compression)
• Imaging as needed for signs/symptoms concerning for tumor(s); periodic imaging is not indicated.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Proteus syndrome (PS), the evaluations summarized in
Proteus Syndrome: Recommended Evaluations Following Initial Diagnosis
Detailed & comprehensive orthopedic eval (incl general, spine, & limbs)
Skeletal survey as baseline study of extent & severity of overgrowth
Pulmonology consultation
Pulmonary function testing
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.
MOI = mode of inheritance; PS = Proteus syndrome; US = ultrasound
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Detailed & comprehensive orthopedic eval (incl general, spine, & limbs)
• Skeletal survey as baseline study of extent & severity of overgrowth
• Pulmonology consultation
• Pulmonary function testing
• 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
PS is a complex multisystem disorder and individuals benefit from a coordinated and multidisciplinary clinical approach tailored to the individual's specific needs and manifestations (see
Proteus Syndrome: Treatment of Manifestations
Mgmt per orthopedist
Epiphysiostasis & epiphysiodesis for overgrowth of tubular bones
Mgmt by rehab medicine, incl PT & OT
Custom-designed footwear or orthotics due to leg-length inequality
Referral to orthopedist if scoliosis is identified on clinical &/or radiographic exam
Frequent monitoring due to risk of rapid progression
Surgery is often indicated, as progressive nature of scoliosis can lead to fatal restrictive lung disease.
Mgmt by dermatologist
Monitor for pressure ulcerations & malodor (due to difficulty w/cleanliness of deepening sulci in late adolescence)
Pedorthic referral as needed for issues w/shoe fit
Treatment of DVT & PE should follow recommended anticoagulation guidelines for these disorders.
Persons w/PE can be asymptomatic; therefore, a person w/DVT should be evaluated for PE regardless of symptoms.
Note: Hematologic consultation for consideration of anticoagulant prophylaxis for persons undergoing surgery or other procedures that may predispose to DVT/PE is recommended.
Pulmonary eval for persons w/bullous pulmonary disease
Resection of large bullous lesions may be indicated in some persons.
CCTN = cerebriform connective tissue nevi; DVT = deep vein thrombosis; OT = occupational therapy; PE = pulmonary embolism; PS = Proteus syndrome; PT = physical therapy; US = ultrasound
Hematologic consultation for consideration of anticoagulant prophylaxis for individuals undergoing surgery or other procedures that may predispose to DVT/PE is recommended.
Authors, personal observation
• Mgmt per orthopedist
• Epiphysiostasis & epiphysiodesis for overgrowth of tubular bones
• Mgmt by rehab medicine, incl PT & OT
• Custom-designed footwear or orthotics due to leg-length inequality
• Referral to orthopedist if scoliosis is identified on clinical &/or radiographic exam
• Frequent monitoring due to risk of rapid progression
• Surgery is often indicated, as progressive nature of scoliosis can lead to fatal restrictive lung disease.
• Mgmt by dermatologist
• Monitor for pressure ulcerations & malodor (due to difficulty w/cleanliness of deepening sulci in late adolescence)
• Pedorthic referral as needed for issues w/shoe fit
• Treatment of DVT & PE should follow recommended anticoagulation guidelines for these disorders.
• Persons w/PE can be asymptomatic; therefore, a person w/DVT should be evaluated for PE regardless of symptoms.
• Note: Hematologic consultation for consideration of anticoagulant prophylaxis for persons undergoing surgery or other procedures that may predispose to DVT/PE is recommended.
• Pulmonary eval for persons w/bullous pulmonary disease
• Resection of large bullous lesions may be indicated in some persons.
## Surveillance
Individualized surveillance plans for the skeletal, pulmonary, soft tissue, and other manifestations of PS should be developed according to the individual's specific needs (see
Proteus Syndrome: Recommended Surveillance
Orthopedic eval to assess for progression of overgrowth & scoliosis
Imaging per orthopedist
Rehab medicine, PT, &/or OT eval to assess mobility issues, footwear, & orthotics needs
Pulmonary eval
Pulmonary function testing
Directed medical history & exam w/primary care clinician for signs/symptoms of malignancy (e.g., pain, unexpected growths, signs of obstruction or compression)
Imaging as needed for signs/symptoms concerning for tumor(s); periodic imaging is not indicated.
OT = occupational therapy; PT = physical therapy
• Orthopedic eval to assess for progression of overgrowth & scoliosis
• Imaging per orthopedist
• Rehab medicine, PT, &/or OT eval to assess mobility issues, footwear, & orthotics needs
• Pulmonary eval
• Pulmonary function testing
• Directed medical history & exam w/primary care clinician for signs/symptoms of malignancy (e.g., pain, unexpected growths, signs of obstruction or compression)
• Imaging as needed for signs/symptoms concerning for tumor(s); periodic imaging is not indicated.
## Agents/Circumstances to Avoid
Medications that increase the risk of deep vein thrombosis or are procoagulant should be avoided.
Medications that increase growth (e.g., androgenic steroids, growth hormone) should be avoided.
## Evaluation of Relatives at Risk
Because PS is not inherited, relatives are not at increased risk and do not require evaluation for recurrence of this condition. Every individual has the same likelihood of having a somatic mutation that could cause Proteus syndrome, irrespective of whether they are related to someone with Proteus syndrome or not.
## Pregnancy Management
There are no data on the management of pregnancy in women with PS. Pregnancy presents theoretic risks, especially the risk of thrombosis of the pelvic veins.
## Therapies Under Investigation
A pilot Phase 0/I pharmacodynamic study of miransertib (formerly ARQ-092) has been completed and showed a favorable safety profile with some suggestions of efficacy [
Search
## Genetic Counseling
Proteus syndrome (PS) and
There are no confirmed occurrences of vertical transmission or sib recurrence.
The molecular data show that all persons with a molecular diagnosis are mosaic for
Counseling for recurrence risks in PS and
The optimal time for determination of genetic risk is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• There are no confirmed occurrences of vertical transmission or sib recurrence.
• The molecular data show that all persons with a molecular diagnosis are mosaic for
• Counseling for recurrence risks in PS and
• The optimal time for determination of genetic risk is before 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
Proteus syndrome (PS) and
There are no confirmed occurrences of vertical transmission or sib recurrence.
The molecular data show that all persons with a molecular diagnosis are mosaic for
• There are no confirmed occurrences of vertical transmission or sib recurrence.
• The molecular data show that all persons with a molecular diagnosis are mosaic for
## Risk to Family Members
## Related Genetic Counseling Issues
Counseling for recurrence risks in PS and
The optimal time for determination of genetic risk is before pregnancy.
It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected.
• Counseling for recurrence risks in PS and
• The optimal time for determination of genetic risk is before 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
## Resources
•
•
•
•
## Molecular Genetics
Proteus Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Proteus Syndrome (
The PI3KCA/AKT pathway includes a number of other gene products that have been implicated in oncogenesis and/or overgrowth. This pathway is a key mediator of signal transduction from receptor tyrosine kinase growth-promoting and apoptosis-inhibiting factors. In addition to
It has been shown that
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The PI3KCA/AKT pathway includes a number of other gene products that have been implicated in oncogenesis and/or overgrowth. This pathway is a key mediator of signal transduction from receptor tyrosine kinase growth-promoting and apoptosis-inhibiting factors. In addition to
It has been shown that
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Leslie G Biesecker, Christopher Ours, and Julie Sapp are actively involved in clinical research regarding individuals with
Leslie G Biesecker, Christopher Ours, and Julie Sapp are also interested in hearing from clinicians treating families affected by PS in whom no causative variant has been identified through molecular genetic testing of appropriate tissues for
Contact Leslie G Biesecker to inquire about review of
25 May 2023 (sw) Comprehensive update posted live
10 January 2019 (lgb) Revision: Category C criteria corrected (added bullous pulmonary degeneration)
4 January 2018 (sw) Comprehensive update posted live
9 August 2012 (me) Review posted live
19 April 2012 (lgb) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 25 May 2023 (sw) Comprehensive update posted live
• 10 January 2019 (lgb) Revision: Category C criteria corrected (added bullous pulmonary degeneration)
• 4 January 2018 (sw) Comprehensive update posted live
• 9 August 2012 (me) Review posted live
• 19 April 2012 (lgb) Original submission
## Author Notes
Leslie G Biesecker, Christopher Ours, and Julie Sapp are actively involved in clinical research regarding individuals with
Leslie G Biesecker, Christopher Ours, and Julie Sapp are also interested in hearing from clinicians treating families affected by PS in whom no causative variant has been identified through molecular genetic testing of appropriate tissues for
Contact Leslie G Biesecker to inquire about review of
## Revision History
25 May 2023 (sw) Comprehensive update posted live
10 January 2019 (lgb) Revision: Category C criteria corrected (added bullous pulmonary degeneration)
4 January 2018 (sw) Comprehensive update posted live
9 August 2012 (me) Review posted live
19 April 2012 (lgb) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 25 May 2023 (sw) Comprehensive update posted live
• 10 January 2019 (lgb) Revision: Category C criteria corrected (added bullous pulmonary degeneration)
• 4 January 2018 (sw) Comprehensive update posted live
• 9 August 2012 (me) Review posted live
• 19 April 2012 (lgb) Original submission
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## Literature Cited
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"M. Cohen. The elephant man did not have neurofibromatosis.. Proc Greenwood Genet Cen. 1987;6:187-92",
"ME Doucet, HM Bloomhardt, K Moroz, MJ Lindhurst, LG Biesecker. Lack of mutation-histopathology correlation in a patient with Proteus syndrome.. Am J Med Genet A. 2016;170:1422-32",
"H Hannoush, V Sachdev, A Brofferio, AE Arai, G LaRocca, J Sapp, S Sidenko, C Brenneman, LG Biesecker, K Keppler-Noreuil. Myocardial fat overgrowth in Proteus syndrome.. Am J Med Genet A. 2015;167A:103-10",
"R. Happle. Cutaneous manifestation of lethal genes.. Hum Genet. 1986;72:280",
"K Hussain, B Challis, N Rocha, F Payne, M Minic, A Thompson, A Daly, C Scott, J Harris, BJ Smillie, DB Savage, U Ramaswami, P De Lonlay, S O'Rahilly, I Barroso, RK Semple. An activating mutation of AKT2 and human hypoglycemia.. Science. 2011;334:474",
"KM Keppler-Noreuil, JC Sapp, MJ Lindhurst, TN Darling, J Burton-Akright, M Bagheri, E Dombi, A Gruber, PF Jarosinski, S Martin, N Nathan, SM Paul, RE Savage, PL Wolters, B Schwartz, BC Widemann, LG Biesecker. Pharmacodynamic study of miransertib in individuals with Proteus syndrome.. Am J Hum Genet. 2019;104:484-91",
"KM Keppler-Noreuil, JC Sapp, MJ Lindhurst, VE Parker, C Blumhorst, T Darling, LL Tosi, SM Huson, RW Whitehouse, E Jakkula, I Grant, M Balasubramanian, KE Chandler, JL Fraser, Z Gucev, YJ Crow, LM Brennan, R Clark, EA Sellars, LD Pena, V Krishnamurty, A Shuen, N Braverman, ML Cunningham, VR Sutton, V Tasic, JM Graham, J Geer, A Henderson, RK Semple, LG Biesecker. Clinical delineation and natural history of the PIK3CA-related overgrowth spectrum.. Am J Med Genet A. 2014;164A:1713-33",
"KC Kurek, VL Luks, UM Ayturk, AI Alomari, SJ Fishman, SA Spencer, JB Mulliken, ME Bowen, GL Yamamoto, HP Kozakewich, ML Warman. Somatic mosaic activating mutations in PIK3CA cause CLOVES syndrome.. Am J Hum Genet. 2012;90:1108-15",
"C Leoni, G Gullo, N Resta, A Fagotti, R Onesimo, B Schwartz, J Kazakin, G Abbadessa, J Crown, CD Collins, C Ranieri, G Scambia, G Zampino. First evidence of a therapeutic effect of miransertib in a teenager with Proteus syndrome and ovarian carcinoma.. Am J Med Genet A. 2019;179:1319-24",
"GY Lim, OH Kim, HW Kim, KS Lee, KH Kang, HR Song, TJ Cho. Pulmonary manifestations in Proteus syndrome: pulmonary varicosities and bullous lung disease.. Am J Med Genet A. 2011;155A:865-9",
"MJ Lindhurst, W Li, N Laughner, JJ Shwetar, HC Kondolf, X Ma, YS Mukouyama, LG Biesecker. Ubiquitous expression of Akt1 p.(E17K) results in vascular defects and embryonic lethality in mice.. Hum Mol Genet. 2020;29:3350-60",
"MJ Lindhurst, VER Parker, F Payne, JC Sapp, S Rudge, J Harris, AM Witkowski, Q Zhang, MP Groeneveld, CE Scott, A Daly, SM Huson, LL Tosi, ML Cunningham, TN Darling, J Geer, Z Gucev, VR Sutton, MR Walters, AK Dixon, T Helliwell, S O'Rahilly, DB Savage, MJO Wakelam, I Barroso, LG Biesecker, RK Semple. Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA.. Nat Genet. 2012;44:928-33",
"MJ Lindhurst, JC Sapp, JK Teer, JJ Johnston, EM Finn, K Peters, J Turner, JL Cannons, D Bick, L Blakemore, C Blumhorst, K Brockmann, P Calder, N Cherman, MA Deardorff, DB Everman, G Golas, RM Greenstein, BM Kato, KM Keppler-Noreuil, SA Kuznetsov, RT Miyamoto, K Newman, D Ng, K O'Brien, S Rothenberg, DJ Schwartzentruber, V Singhal, R Tirabosco, J Upton, S Wientroub, EH Zackai, K Hoag, T Whitewood-Neal, PG Robey, PL Schwartzberg, TN Darling, LL Tosi, JC Mullikin, LG Biesecker. A mosaic activating mutation in AKT1 associated with the proteus syndrome.. N Engl J Med. 2011;365:611-9",
"SM Mirmomen, AE Arai, EB Turkbey, AJ Bradley, JC Sapp, LG Biesecker, A Sirajuddin. Cardiothoracic imaging findings of Proteus syndrome.. Sci Rep. 2021;11:6577",
"CA Ours, JC Sapp, MB Hodges, AJ de Moya, LG Biesecker. Case report: five-year experience of AKT inhibition with miransertib (MK-7075) in an individual with Proteus syndrome.. Cold Spring Harb Mol Case Stud. 2021;7",
"DJ Pithadia, JW Roman, JC Sapp, LG Biesecker, TN Darling. Hypertrichotic patches as a mosaic manifestation of Proteus syndrome.. J Am Acad Dermatol. 2021;84:415-24",
"A Poduri, GD Evrony, X Cai, PC Elhosary, R Beroukhim, MK Lehtinen, LB Hills, EL Heinzen, A Hill, RS Hill, BJ Barry, BF Bourgeois, JJ Riviello, AJ Barkovich, PM Black, KL Ligon, CA Walsh. Somatic activation of AKT3 causes hemispheric developmental brain malformations.. Neuron 2012;74:41-8",
"JC Sapp, A Buser, J Burton-Akright, KM Keppler-Noreuil, LG Biesecker. A dyadic genotype-phenotype approach to diagnostic criteria for Proteus syndrome.. Am J Med Genet C Semin Med Genet. 2019;181:565-70",
"JC Sapp, L Hu, J Zhao, A Gruber, B Schwartz, D Ferrari, LG Biesecker. Quantifying survival in patients with Proteus syndrome.. Genet Med 2017;19:1376-9",
"JC Sapp, JT Turner, JM van de Kamp, FS van Dijk, RB Lowry, LG Biesecker. Newly delineated syndrome of congenital lipomatous overgrowth, vascular malformations, and epidermal nevi (clove syndrome) in seven patients.. Am J Med Genet A. 2007;143A:2944-58",
"M Severino-Freire, A Maza, P Kuentz, Y Duffourd, L Faivre, E Brazet, N Chassaing, E Mery-Lemarche, P Vabres, J. Mazereeuw-Hautier. Severe gynaecological involvement in Proteus syndrome.. Eur J Med Genet. 2019;62:270-2",
"AM Slavotinek, SJ Vacha, KF Peters, LG Biesecker. Sudden death caused by pulmonary thromboembolism in Proteus syndrome.. Clin Genet. 2000;58:386-9",
"LL Tosi, JC Sapp, ES Allen, RJ O'Keefe, LG Biesecker. Assessment and management of the orthopedic and other complications of Proteus syndrome. J Child Orthop. 2011;5:319-27",
"J Turner, B Biesecker, J Leib, L Biesecker, KF Peters. Parenting children with Proteus syndrome: Experiences with, and adaptation to, courtesy stigma.. Am J Med Genet A. 2007;143A:2089-97",
"JV Twede, JT Turner, LG Biesecker, TN Darling. Evolution of skin lesions in Proteus syndrome.. J Am Acad Dermatol. 2005;52:834-8",
"W Uller, SJ Fishman, AI Alomari. Overgrowth syndromes with complex vascular anomalies.. Semin Pediatr Surg. 2014;23:208-15"
] |
9/8/2012
|
25/5/2023
|
10/1/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
prrt2-parox
|
prrt2-parox
|
[
"PRRT2-Related Paroxysmal Kinesigenic Dyskinesia (PKD)",
"PRRT2-Related Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (PKD/IC)",
"PRRT2-Related Hemiplegic Migraine",
"PRRT2-Related Self-Limited (Familial) Infantile Epilepsy (SeLIE)",
"Proline-rich transmembrane protein 2",
"PRRT2",
"PRRT2-Related Disorder"
] |
Kathryn Yang, Vincente Quiroz, Darius Ebrahimi-Fakhari
|
Summary The diagnosis of
|
## Diagnosis
SeLIE is characterized by the following clinical and supportive findings [
Onset in first year of life (usually age 4-7 months)
Spontaneous or in context of fever
Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
Excellent response to anti-seizure medications
Resolution by age two years
Normal development & developmental outcome
Normal neurologic exam
Normal interictal EEG (with sporadic focal epileptiform activity)
Normal brain MRI
PKD is characterized by the following clinical and supportive findings [
Onset between ages 1-18 years
A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
An aura preceding attacks (10% of persons)
Short duration (typically <1 min)
High frequency (can be as many as 100 times per day)
No loss of consciousness or pain
Prevention or control w/carbamazepine
Normal neurologic exam between attacks
Normal brain MRI
No EEG changes during attacks
PKD/IC is characterized by symptoms fulfilling the below criteria:
In first year of life: seizures meeting criteria for SeLIE
In childhood or adolescence: paroxysmal movements meeting criteria for PKD
HM, as defined by the International Classification of Headache Disorders, 3rd edition [
Average age of onset 12-17 years
Migraine during or after motor aura
Presence of other manifestations incl visual, sensory, and/or speech impairment
Triggered by stress, anxiety, light, and/or heat
Frequency from a few per week to one per month
Duration can be prolonged >72 hours
Normal neurologic exam between attacks
Normal brain MRI
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
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
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.
• Onset in first year of life (usually age 4-7 months)
• Spontaneous or in context of fever
• Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
• Excellent response to anti-seizure medications
• Resolution by age two years
• Onset in first year of life (usually age 4-7 months)
• Spontaneous or in context of fever
• Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
• Excellent response to anti-seizure medications
• Resolution by age two years
•
• Normal development & developmental outcome
• Normal neurologic exam
• Normal interictal EEG (with sporadic focal epileptiform activity)
• Normal brain MRI
• Normal development & developmental outcome
• Normal neurologic exam
• Normal interictal EEG (with sporadic focal epileptiform activity)
• Normal brain MRI
• Onset in first year of life (usually age 4-7 months)
• Spontaneous or in context of fever
• Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
• Excellent response to anti-seizure medications
• Resolution by age two years
• Normal development & developmental outcome
• Normal neurologic exam
• Normal interictal EEG (with sporadic focal epileptiform activity)
• Normal brain MRI
• Onset between ages 1-18 years
• A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
• An aura preceding attacks (10% of persons)
• Short duration (typically <1 min)
• High frequency (can be as many as 100 times per day)
• No loss of consciousness or pain
• Prevention or control w/carbamazepine
• Onset between ages 1-18 years
• A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
• An aura preceding attacks (10% of persons)
• Short duration (typically <1 min)
• High frequency (can be as many as 100 times per day)
• No loss of consciousness or pain
• Prevention or control w/carbamazepine
•
• Normal neurologic exam between attacks
• Normal brain MRI
• No EEG changes during attacks
• Normal neurologic exam between attacks
• Normal brain MRI
• No EEG changes during attacks
• Onset between ages 1-18 years
• A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
• An aura preceding attacks (10% of persons)
• Short duration (typically <1 min)
• High frequency (can be as many as 100 times per day)
• No loss of consciousness or pain
• Prevention or control w/carbamazepine
• Normal neurologic exam between attacks
• Normal brain MRI
• No EEG changes during attacks
• In first year of life: seizures meeting criteria for SeLIE
• In childhood or adolescence: paroxysmal movements meeting criteria for PKD
• Average age of onset 12-17 years
• Migraine during or after motor aura
• Presence of other manifestations incl visual, sensory, and/or speech impairment
• Triggered by stress, anxiety, light, and/or heat
• Frequency from a few per week to one per month
• Duration can be prolonged >72 hours
• Average age of onset 12-17 years
• Migraine during or after motor aura
• Presence of other manifestations incl visual, sensory, and/or speech impairment
• Triggered by stress, anxiety, light, and/or heat
• Frequency from a few per week to one per month
• Duration can be prolonged >72 hours
•
• Normal neurologic exam between attacks
• Normal brain MRI
• Normal neurologic exam between attacks
• Normal brain MRI
• Average age of onset 12-17 years
• Migraine during or after motor aura
• Presence of other manifestations incl visual, sensory, and/or speech impairment
• Triggered by stress, anxiety, light, and/or heat
• Frequency from a few per week to one per month
• Duration can be prolonged >72 hours
• Normal neurologic exam between attacks
• Normal brain MRI
## Suggestive Findings
SeLIE is characterized by the following clinical and supportive findings [
Onset in first year of life (usually age 4-7 months)
Spontaneous or in context of fever
Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
Excellent response to anti-seizure medications
Resolution by age two years
Normal development & developmental outcome
Normal neurologic exam
Normal interictal EEG (with sporadic focal epileptiform activity)
Normal brain MRI
PKD is characterized by the following clinical and supportive findings [
Onset between ages 1-18 years
A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
An aura preceding attacks (10% of persons)
Short duration (typically <1 min)
High frequency (can be as many as 100 times per day)
No loss of consciousness or pain
Prevention or control w/carbamazepine
Normal neurologic exam between attacks
Normal brain MRI
No EEG changes during attacks
PKD/IC is characterized by symptoms fulfilling the below criteria:
In first year of life: seizures meeting criteria for SeLIE
In childhood or adolescence: paroxysmal movements meeting criteria for PKD
HM, as defined by the International Classification of Headache Disorders, 3rd edition [
Average age of onset 12-17 years
Migraine during or after motor aura
Presence of other manifestations incl visual, sensory, and/or speech impairment
Triggered by stress, anxiety, light, and/or heat
Frequency from a few per week to one per month
Duration can be prolonged >72 hours
Normal neurologic exam between attacks
Normal brain MRI
• Onset in first year of life (usually age 4-7 months)
• Spontaneous or in context of fever
• Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
• Excellent response to anti-seizure medications
• Resolution by age two years
• Onset in first year of life (usually age 4-7 months)
• Spontaneous or in context of fever
• Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
• Excellent response to anti-seizure medications
• Resolution by age two years
•
• Normal development & developmental outcome
• Normal neurologic exam
• Normal interictal EEG (with sporadic focal epileptiform activity)
• Normal brain MRI
• Normal development & developmental outcome
• Normal neurologic exam
• Normal interictal EEG (with sporadic focal epileptiform activity)
• Normal brain MRI
• Onset in first year of life (usually age 4-7 months)
• Spontaneous or in context of fever
• Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
• Excellent response to anti-seizure medications
• Resolution by age two years
• Normal development & developmental outcome
• Normal neurologic exam
• Normal interictal EEG (with sporadic focal epileptiform activity)
• Normal brain MRI
• Onset between ages 1-18 years
• A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
• An aura preceding attacks (10% of persons)
• Short duration (typically <1 min)
• High frequency (can be as many as 100 times per day)
• No loss of consciousness or pain
• Prevention or control w/carbamazepine
• Onset between ages 1-18 years
• A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
• An aura preceding attacks (10% of persons)
• Short duration (typically <1 min)
• High frequency (can be as many as 100 times per day)
• No loss of consciousness or pain
• Prevention or control w/carbamazepine
•
• Normal neurologic exam between attacks
• Normal brain MRI
• No EEG changes during attacks
• Normal neurologic exam between attacks
• Normal brain MRI
• No EEG changes during attacks
• Onset between ages 1-18 years
• A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
• An aura preceding attacks (10% of persons)
• Short duration (typically <1 min)
• High frequency (can be as many as 100 times per day)
• No loss of consciousness or pain
• Prevention or control w/carbamazepine
• Normal neurologic exam between attacks
• Normal brain MRI
• No EEG changes during attacks
• In first year of life: seizures meeting criteria for SeLIE
• In childhood or adolescence: paroxysmal movements meeting criteria for PKD
• Average age of onset 12-17 years
• Migraine during or after motor aura
• Presence of other manifestations incl visual, sensory, and/or speech impairment
• Triggered by stress, anxiety, light, and/or heat
• Frequency from a few per week to one per month
• Duration can be prolonged >72 hours
• Average age of onset 12-17 years
• Migraine during or after motor aura
• Presence of other manifestations incl visual, sensory, and/or speech impairment
• Triggered by stress, anxiety, light, and/or heat
• Frequency from a few per week to one per month
• Duration can be prolonged >72 hours
•
• Normal neurologic exam between attacks
• Normal brain MRI
• Normal neurologic exam between attacks
• Normal brain MRI
• Average age of onset 12-17 years
• Migraine during or after motor aura
• Presence of other manifestations incl visual, sensory, and/or speech impairment
• Triggered by stress, anxiety, light, and/or heat
• Frequency from a few per week to one per month
• Duration can be prolonged >72 hours
• Normal neurologic exam between attacks
• Normal brain MRI
## Self-Limited (Familial) Infantile Epilepsy (SeLIE)
SeLIE is characterized by the following clinical and supportive findings [
Onset in first year of life (usually age 4-7 months)
Spontaneous or in context of fever
Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
Excellent response to anti-seizure medications
Resolution by age two years
Normal development & developmental outcome
Normal neurologic exam
Normal interictal EEG (with sporadic focal epileptiform activity)
Normal brain MRI
• Onset in first year of life (usually age 4-7 months)
• Spontaneous or in context of fever
• Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
• Excellent response to anti-seizure medications
• Resolution by age two years
• Onset in first year of life (usually age 4-7 months)
• Spontaneous or in context of fever
• Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
• Excellent response to anti-seizure medications
• Resolution by age two years
•
• Normal development & developmental outcome
• Normal neurologic exam
• Normal interictal EEG (with sporadic focal epileptiform activity)
• Normal brain MRI
• Normal development & developmental outcome
• Normal neurologic exam
• Normal interictal EEG (with sporadic focal epileptiform activity)
• Normal brain MRI
• Onset in first year of life (usually age 4-7 months)
• Spontaneous or in context of fever
• Occurring in clusters of multiple brief seizures per day: on average up to eight to ten seizures per day every two to three hours
• Excellent response to anti-seizure medications
• Resolution by age two years
• Normal development & developmental outcome
• Normal neurologic exam
• Normal interictal EEG (with sporadic focal epileptiform activity)
• Normal brain MRI
## Paroxysmal Kinesigenic Dyskinesia (PKD)
PKD is characterized by the following clinical and supportive findings [
Onset between ages 1-18 years
A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
An aura preceding attacks (10% of persons)
Short duration (typically <1 min)
High frequency (can be as many as 100 times per day)
No loss of consciousness or pain
Prevention or control w/carbamazepine
Normal neurologic exam between attacks
Normal brain MRI
No EEG changes during attacks
• Onset between ages 1-18 years
• A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
• An aura preceding attacks (10% of persons)
• Short duration (typically <1 min)
• High frequency (can be as many as 100 times per day)
• No loss of consciousness or pain
• Prevention or control w/carbamazepine
• Onset between ages 1-18 years
• A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
• An aura preceding attacks (10% of persons)
• Short duration (typically <1 min)
• High frequency (can be as many as 100 times per day)
• No loss of consciousness or pain
• Prevention or control w/carbamazepine
•
• Normal neurologic exam between attacks
• Normal brain MRI
• No EEG changes during attacks
• Normal neurologic exam between attacks
• Normal brain MRI
• No EEG changes during attacks
• Onset between ages 1-18 years
• A kinesigenic trigger (e.g., sudden voluntary movements, intention to move, or acceleration of movement)
• An aura preceding attacks (10% of persons)
• Short duration (typically <1 min)
• High frequency (can be as many as 100 times per day)
• No loss of consciousness or pain
• Prevention or control w/carbamazepine
• Normal neurologic exam between attacks
• Normal brain MRI
• No EEG changes during attacks
## Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (PKD/IC)
PKD/IC is characterized by symptoms fulfilling the below criteria:
In first year of life: seizures meeting criteria for SeLIE
In childhood or adolescence: paroxysmal movements meeting criteria for PKD
• In first year of life: seizures meeting criteria for SeLIE
• In childhood or adolescence: paroxysmal movements meeting criteria for PKD
## Hemiplegic Migraine (HM)
HM, as defined by the International Classification of Headache Disorders, 3rd edition [
Average age of onset 12-17 years
Migraine during or after motor aura
Presence of other manifestations incl visual, sensory, and/or speech impairment
Triggered by stress, anxiety, light, and/or heat
Frequency from a few per week to one per month
Duration can be prolonged >72 hours
Normal neurologic exam between attacks
Normal brain MRI
• Average age of onset 12-17 years
• Migraine during or after motor aura
• Presence of other manifestations incl visual, sensory, and/or speech impairment
• Triggered by stress, anxiety, light, and/or heat
• Frequency from a few per week to one per month
• Duration can be prolonged >72 hours
• Average age of onset 12-17 years
• Migraine during or after motor aura
• Presence of other manifestations incl visual, sensory, and/or speech impairment
• Triggered by stress, anxiety, light, and/or heat
• Frequency from a few per week to one per month
• Duration can be prolonged >72 hours
•
• Normal neurologic exam between attacks
• Normal brain MRI
• Normal neurologic exam between attacks
• Normal brain MRI
• Average age of onset 12-17 years
• Migraine during or after motor aura
• Presence of other manifestations incl visual, sensory, and/or speech impairment
• Triggered by stress, anxiety, light, and/or heat
• Frequency from a few per week to one per month
• Duration can be prolonged >72 hours
• Normal neurologic exam between attacks
• Normal brain MRI
## 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
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
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.
## 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
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
To date, more than 1,500 individuals have been identified with a heterozygous
+ = rare; ++ = infrequent; +++ = frequent
The core phenotypes of self-limited (familial) infantile epilepsy, paroxysmal kinesigenic dyskinesia (PKD), PKD with infantile convulsions, and hemiplegic migraine (which are more commonly seen in
Less common seizure semiologies include motor arrest, decreased responsiveness, and automatisms [
Seizures rarely progress to status epilepticus. While respiratory depression can occur either during seizures or from medications such as benzodiazepines, sudden unexpected death in epilepsy (SUDEP) and long-term sequelae have not been reported.
The interictal EEG for most individuals is unremarkable. Nevertheless, in rare instances interictal focal epileptiform discharges may be detected, including bilateral centrotemporal spikes [
Prognosis is favorable. Seizures generally show a complete response to first-line anti-seizure medications (ASMs). In most children seizures remit by age two years and developmental outcomes are normal.
Onset of
Dyskinesias in
In about 10% of affected individuals, PKD attacks are preceded by a nonspecific aura including a crawling sensation in the affected limb, paresthesias, or nonspecific epigastric discomfort.
Attacks are usually brief – in the range of a few seconds – but can last five or more minutes in some individuals. Episodes often respond well to ASMs, most commonly carbamazepine (see Management,
The frequency of attacks, which can range from 100 per day to one per week, tends to decrease with age and may resolve completely in mid- or late adulthood [
Visual symptoms or disturbance (e.g., scotoma, photopsia, or diplopia)
Sensory loss (e.g., numbness or paresthesia)
Speech symptoms (e.g., dysarthria)
Less commonly, pathogenic
Considerable variability in phenotype is seen both within and between families with the same
No genotype-phenotype correlations have been identified in
The penetrance of
Among the core phenotypes, penetrance is estimated to be 75%-95% for
Self-limited (familial) infantile epilepsy (SeLIE) was formerly known as benign familial infantile epilepsy (BFIE) or benign familial infantile seizures (BFIS). In the 2017 International League Against Epilepsy (ILAE) classification, the term "benign" was updated to "self-limited", emphasizing the notion that seizures typically resolved during early infancy and were associated with favorable developmental outcome [
Paroxysmal kinesigenic dyskinesia (PKD) was formerly known as paroxysmal kinesigenic choreoathetosis (PKC).
Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) was formerly known as infantile convulsions and choreoathetosis (ICCA).
In the International Parkinson and Movement Disorder Society Task Force Recommendations for Nomenclature of Genetic Movement Disorders, paroxysmal (Px) movement disorders (MD) associated with
Prevalence for PKD, the most common of the paroxysmal movement disorders (including both
To date, more than 600 individuals with
• Visual symptoms or disturbance (e.g., scotoma, photopsia, or diplopia)
• Sensory loss (e.g., numbness or paresthesia)
• Speech symptoms (e.g., dysarthria)
## Clinical Description
To date, more than 1,500 individuals have been identified with a heterozygous
+ = rare; ++ = infrequent; +++ = frequent
The core phenotypes of self-limited (familial) infantile epilepsy, paroxysmal kinesigenic dyskinesia (PKD), PKD with infantile convulsions, and hemiplegic migraine (which are more commonly seen in
Less common seizure semiologies include motor arrest, decreased responsiveness, and automatisms [
Seizures rarely progress to status epilepticus. While respiratory depression can occur either during seizures or from medications such as benzodiazepines, sudden unexpected death in epilepsy (SUDEP) and long-term sequelae have not been reported.
The interictal EEG for most individuals is unremarkable. Nevertheless, in rare instances interictal focal epileptiform discharges may be detected, including bilateral centrotemporal spikes [
Prognosis is favorable. Seizures generally show a complete response to first-line anti-seizure medications (ASMs). In most children seizures remit by age two years and developmental outcomes are normal.
Onset of
Dyskinesias in
In about 10% of affected individuals, PKD attacks are preceded by a nonspecific aura including a crawling sensation in the affected limb, paresthesias, or nonspecific epigastric discomfort.
Attacks are usually brief – in the range of a few seconds – but can last five or more minutes in some individuals. Episodes often respond well to ASMs, most commonly carbamazepine (see Management,
The frequency of attacks, which can range from 100 per day to one per week, tends to decrease with age and may resolve completely in mid- or late adulthood [
Visual symptoms or disturbance (e.g., scotoma, photopsia, or diplopia)
Sensory loss (e.g., numbness or paresthesia)
Speech symptoms (e.g., dysarthria)
Less commonly, pathogenic
Considerable variability in phenotype is seen both within and between families with the same
• Visual symptoms or disturbance (e.g., scotoma, photopsia, or diplopia)
• Sensory loss (e.g., numbness or paresthesia)
• Speech symptoms (e.g., dysarthria)
## Epilepsy
Less common seizure semiologies include motor arrest, decreased responsiveness, and automatisms [
Seizures rarely progress to status epilepticus. While respiratory depression can occur either during seizures or from medications such as benzodiazepines, sudden unexpected death in epilepsy (SUDEP) and long-term sequelae have not been reported.
The interictal EEG for most individuals is unremarkable. Nevertheless, in rare instances interictal focal epileptiform discharges may be detected, including bilateral centrotemporal spikes [
Prognosis is favorable. Seizures generally show a complete response to first-line anti-seizure medications (ASMs). In most children seizures remit by age two years and developmental outcomes are normal.
## Movement Disorders
Onset of
Dyskinesias in
In about 10% of affected individuals, PKD attacks are preceded by a nonspecific aura including a crawling sensation in the affected limb, paresthesias, or nonspecific epigastric discomfort.
Attacks are usually brief – in the range of a few seconds – but can last five or more minutes in some individuals. Episodes often respond well to ASMs, most commonly carbamazepine (see Management,
The frequency of attacks, which can range from 100 per day to one per week, tends to decrease with age and may resolve completely in mid- or late adulthood [
## Migraine
Visual symptoms or disturbance (e.g., scotoma, photopsia, or diplopia)
Sensory loss (e.g., numbness or paresthesia)
Speech symptoms (e.g., dysarthria)
Less commonly, pathogenic
• Visual symptoms or disturbance (e.g., scotoma, photopsia, or diplopia)
• Sensory loss (e.g., numbness or paresthesia)
• Speech symptoms (e.g., dysarthria)
## Intrafamilial and Interfamilial Variability
Considerable variability in phenotype is seen both within and between families with the same
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified in
## Penetrance
The penetrance of
Among the core phenotypes, penetrance is estimated to be 75%-95% for
## Nomenclature
Self-limited (familial) infantile epilepsy (SeLIE) was formerly known as benign familial infantile epilepsy (BFIE) or benign familial infantile seizures (BFIS). In the 2017 International League Against Epilepsy (ILAE) classification, the term "benign" was updated to "self-limited", emphasizing the notion that seizures typically resolved during early infancy and were associated with favorable developmental outcome [
Paroxysmal kinesigenic dyskinesia (PKD) was formerly known as paroxysmal kinesigenic choreoathetosis (PKC).
Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) was formerly known as infantile convulsions and choreoathetosis (ICCA).
In the International Parkinson and Movement Disorder Society Task Force Recommendations for Nomenclature of Genetic Movement Disorders, paroxysmal (Px) movement disorders (MD) associated with
## Prevalence
Prevalence for PKD, the most common of the paroxysmal movement disorders (including both
To date, more than 600 individuals with
## Genetically Related (Allelic) Disorders
The
## Differential Diagnosis
Other genes known to be associated with these phenotypes are listed in
Genes of Interest in the Differential Diagnosis of
Involve limbs, neck, &/or face
Often w/perioral dyskinesia ("facial twitches")
Dyskinesias often persist during sleep (nocturnal dyskinesias)
Attacks last longer
Recurrent hemiplegia
Onset age <18 mos
Variable other transient neurologic findings
Progressive cognitive deficits
Attacks last longer
Recurrent hemiplegia
Onset age <18 mos
Variable other transient neurologic findings
Progressive cognitive deficits
Brief intermittent episodes of ataxia of variable duration
Paroxysmal tonic upgaze or nystagmus may be present.
Onset of attacks before age 10 yrs
Attacks triggered by high metabolic demand
Most individuals have associated DD & acute episodes of encephalopathy.
Isolated presentations of paroxysmal exercise-induced dyskinesias are rare.
Initially dystonia may be paroxysmal before becoming permanent.
Exhibit diurnal variation (dystonia worse in evening)
Characterized by focal dystonia w/ascending pattern of progression
Favorable response to levodopa
Onset before age 20 yrs
Brief intermittent episodes of ataxia, myokymia, & dysarthria of variable duration
Can be assoc w/comorbidities such as hyperthermia & seizures
Triggered by alcohol, fatigue, or stress
Assoc w/DD & generalized epilepsy
Occur at rest, in absence of kinesigenic trigger
Are often precipitated by caffeine or alcohol
Last longer (usually mins to hrs) & tend to occur less frequently (a few per day)
Seizures in setting of fever
Often later onset of seizures
Can be assoc w/ID, comorbid ASD or ADHD, ataxia, hypotonia, or history of seizures
Attacks are characterized by orobuccolingual dyskinesia, choreiform movements, tremors, or action-induced myoclonus.
Triggered by prolonged exertion or exercise for usually 5-15 min
Duration often in range of mins (often up to 30 min)
Attacks are assoc w/gait abnormalities, incl ataxia, spastic, ataxic-spastic, & dystonic gait, also known as "criss-cross gait."
Includes a spectrum of manifestations, e.g., paroxysmal exercise-induced dyskinesia, classic phenotype w/infantile-onset epileptic encephalopathy, & atypical phenotypes w/o epilepsy incl mixed movement disorders & ID or adult onset w/minimal manifestations
Of note, the ketogenic diet is highly effective in controlling seizures & improving gait disturbance.
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; SeLNE = self-limited (familial) neonatal epilepsy; SeLIE = self-limited (familial) infantile epilepsy
Glucose transporter type 1 deficiency syndrome is most commonly inherited in an autosomal dominant manner; two families have demonstrated autosomal recessive inheritance (one of the families was consanguineous).
• Involve limbs, neck, &/or face
• Often w/perioral dyskinesia ("facial twitches")
• Dyskinesias often persist during sleep (nocturnal dyskinesias)
• Attacks last longer
• Recurrent hemiplegia
• Onset age <18 mos
• Variable other transient neurologic findings
• Progressive cognitive deficits
• Attacks last longer
• Recurrent hemiplegia
• Onset age <18 mos
• Variable other transient neurologic findings
• Progressive cognitive deficits
• Brief intermittent episodes of ataxia of variable duration
• Paroxysmal tonic upgaze or nystagmus may be present.
• Onset of attacks before age 10 yrs
• Attacks triggered by high metabolic demand
• Most individuals have associated DD & acute episodes of encephalopathy.
• Isolated presentations of paroxysmal exercise-induced dyskinesias are rare.
• Initially dystonia may be paroxysmal before becoming permanent.
• Exhibit diurnal variation (dystonia worse in evening)
• Characterized by focal dystonia w/ascending pattern of progression
• Favorable response to levodopa
• Onset before age 20 yrs
• Brief intermittent episodes of ataxia, myokymia, & dysarthria of variable duration
• Can be assoc w/comorbidities such as hyperthermia & seizures
• Triggered by alcohol, fatigue, or stress
• Assoc w/DD & generalized epilepsy
• Occur at rest, in absence of kinesigenic trigger
• Are often precipitated by caffeine or alcohol
• Last longer (usually mins to hrs) & tend to occur less frequently (a few per day)
• Seizures in setting of fever
• Often later onset of seizures
• Can be assoc w/ID, comorbid ASD or ADHD, ataxia, hypotonia, or history of seizures
• Attacks are characterized by orobuccolingual dyskinesia, choreiform movements, tremors, or action-induced myoclonus.
• Triggered by prolonged exertion or exercise for usually 5-15 min
• Duration often in range of mins (often up to 30 min)
• Attacks are assoc w/gait abnormalities, incl ataxia, spastic, ataxic-spastic, & dystonic gait, also known as "criss-cross gait."
• Includes a spectrum of manifestations, e.g., paroxysmal exercise-induced dyskinesia, classic phenotype w/infantile-onset epileptic encephalopathy, & atypical phenotypes w/o epilepsy incl mixed movement disorders & ID or adult onset w/minimal manifestations
• Of note, the ketogenic diet is highly effective in controlling seizures & improving gait disturbance.
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Leading phenomenology of movement disorder (e.g., dystonia, chorea). Obtain videos of episodes where possible.
Time course & fluctuations in manifestations
Triggers for episodic manifestations
Baseline assessment of tone (e.g., hypotonia, spasticity, rigidity)
Functional impairment incl speech & swallowing
EEG if concern for seizures
Brain MRI if atypical exam findings
Treatment trial w/carbamazepine
Community or
Social work involvement for parental support
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Seizures in SeLIE most often also respond to other first-line ASMs (incl levetiracetam). ASMs should be chosen based on best risk vs benefit profile.
A seizure rescue plan for prolonged seizures is recommended.
Anecdotal evidence only
Acetazolamide or medications for typical migraine w/aura can be considered.
ASMs = anti-seizure medications; PKD = paroxysmal kinesigenic dyskinesia; SeLIE = self-limited (familial) infantile epilepsy
Rescue medications (commonly benzodiazepines including lorazepam, diazepam, or midazolam) are crucial during seizures that last more than five minutes or seizure clusters.
Currently, no proven interventions reduce the risk of individuals with SeLIE to develop PKD later in life. Management strategies primarily focus on seizure control and monitoring developmental progress.
Sodium channel blockers including carbamazepine or oxcarbazepine remain the first-line treatment, unless contraindicated. Notably, the required doses are generally lower than those used to treat epilepsy, with reported control at doses around 100 mg/day in most individuals.
Other ASMs including levetiracetam, lacosamide, phenytoin, valproate, lamotrigine, or topiramate may also be effective and offer alternatives when first-line options are unsuitable.
Lifestyle modifications, including avoiding known triggers such as stress, sleep deprivation, or anxiety, can reduce the frequency of PKD episodes.
No other pharmacotherapies or non-pharmacologic treatments have been investigated systematically.
Monitoring existing manifestations, the individual's response to supportive care, and the emergence of new manifestations requires regularly scheduled follow up with the treating neurologist as well as educators and social services. The evaluations summarized in
Neurologic exam & baseline EEG
Imaging & further workup per treating neurologist
Neurologic exam
Imaging & further workup per treating neurologist
The response to ASMs can inform decisions on medication weaning. Notably, seizures in SeLIE typically subside by age two years, thus reducing the need for prolonged ASM use beyond this age.
Although heterozygous
See
Prenatal exposure to anti-seizure medications (ASMs) may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Because of the fetal risk related to use of ASMs, women with mild manifestations of
See
Search
• Leading phenomenology of movement disorder (e.g., dystonia, chorea). Obtain videos of episodes where possible.
• Time course & fluctuations in manifestations
• Triggers for episodic manifestations
• Baseline assessment of tone (e.g., hypotonia, spasticity, rigidity)
• Functional impairment incl speech & swallowing
• EEG if concern for seizures
• Brain MRI if atypical exam findings
• Treatment trial w/carbamazepine
• Community or
• Social work involvement for parental support
• Seizures in SeLIE most often also respond to other first-line ASMs (incl levetiracetam). ASMs should be chosen based on best risk vs benefit profile.
• A seizure rescue plan for prolonged seizures is recommended.
• Anecdotal evidence only
• Acetazolamide or medications for typical migraine w/aura can be considered.
• Neurologic exam & baseline EEG
• Imaging & further workup per treating neurologist
• Neurologic exam
• Imaging & further workup per treating neurologist
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Leading phenomenology of movement disorder (e.g., dystonia, chorea). Obtain videos of episodes where possible.
Time course & fluctuations in manifestations
Triggers for episodic manifestations
Baseline assessment of tone (e.g., hypotonia, spasticity, rigidity)
Functional impairment incl speech & swallowing
EEG if concern for seizures
Brain MRI if atypical exam findings
Treatment trial w/carbamazepine
Community or
Social work involvement for parental support
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Leading phenomenology of movement disorder (e.g., dystonia, chorea). Obtain videos of episodes where possible.
• Time course & fluctuations in manifestations
• Triggers for episodic manifestations
• Baseline assessment of tone (e.g., hypotonia, spasticity, rigidity)
• Functional impairment incl speech & swallowing
• EEG if concern for seizures
• Brain MRI if atypical exam findings
• Treatment trial w/carbamazepine
• Community or
• Social work involvement for parental support
## Treatment of Manifestations
There is no cure for
Seizures in SeLIE most often also respond to other first-line ASMs (incl levetiracetam). ASMs should be chosen based on best risk vs benefit profile.
A seizure rescue plan for prolonged seizures is recommended.
Anecdotal evidence only
Acetazolamide or medications for typical migraine w/aura can be considered.
ASMs = anti-seizure medications; PKD = paroxysmal kinesigenic dyskinesia; SeLIE = self-limited (familial) infantile epilepsy
Rescue medications (commonly benzodiazepines including lorazepam, diazepam, or midazolam) are crucial during seizures that last more than five minutes or seizure clusters.
Currently, no proven interventions reduce the risk of individuals with SeLIE to develop PKD later in life. Management strategies primarily focus on seizure control and monitoring developmental progress.
Sodium channel blockers including carbamazepine or oxcarbazepine remain the first-line treatment, unless contraindicated. Notably, the required doses are generally lower than those used to treat epilepsy, with reported control at doses around 100 mg/day in most individuals.
Other ASMs including levetiracetam, lacosamide, phenytoin, valproate, lamotrigine, or topiramate may also be effective and offer alternatives when first-line options are unsuitable.
Lifestyle modifications, including avoiding known triggers such as stress, sleep deprivation, or anxiety, can reduce the frequency of PKD episodes.
No other pharmacotherapies or non-pharmacologic treatments have been investigated systematically.
• Seizures in SeLIE most often also respond to other first-line ASMs (incl levetiracetam). ASMs should be chosen based on best risk vs benefit profile.
• A seizure rescue plan for prolonged seizures is recommended.
• Anecdotal evidence only
• Acetazolamide or medications for typical migraine w/aura can be considered.
## Surveillance
Monitoring existing manifestations, the individual's response to supportive care, and the emergence of new manifestations requires regularly scheduled follow up with the treating neurologist as well as educators and social services. The evaluations summarized in
Neurologic exam & baseline EEG
Imaging & further workup per treating neurologist
Neurologic exam
Imaging & further workup per treating neurologist
The response to ASMs can inform decisions on medication weaning. Notably, seizures in SeLIE typically subside by age two years, thus reducing the need for prolonged ASM use beyond this age.
Although heterozygous
• Neurologic exam & baseline EEG
• Imaging & further workup per treating neurologist
• Neurologic exam
• Imaging & further workup per treating neurologist
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Prenatal exposure to anti-seizure medications (ASMs) may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Because of the fetal risk related to use of ASMs, women with mild manifestations of
See
## Therapies Under Investigation
Search
## Genetic Counseling
Note: Biallelic
About 90% of individuals diagnosed with
About 10% of individuals diagnosed with
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 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 a
If a parent of the proband is affected and/or is known to be heterozygous for 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.
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 centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• About 90% of individuals diagnosed with
• About 10% of individuals diagnosed with
• 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 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 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 is known to be heterozygous for 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: Biallelic
## Risk to Family Members
About 90% of individuals diagnosed with
About 10% of individuals diagnosed with
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 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 a
If a parent of the proband is affected and/or is known to be heterozygous for the
If the
If the parents have not been tested for the
• About 90% of individuals diagnosed with
• About 10% of individuals diagnosed with
• 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 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 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 is known to be heterozygous for the
• 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 and preimplantation genetic 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 and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
•
•
•
•
•
•
## Molecular Genetics
PRRT2-Related Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for PRRT2-Related Disorder (
Studies have demonstrated that PRRT2 deficiency sensitizes the cerebellar cortex to spreading depolarization, thereby increasing the excitability of cerebellar neurons. This heightened excitability can disrupt normal neuronal firing patterns in deep cerebellar nuclei crucial for motor control. In mice lacking
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Studies have demonstrated that PRRT2 deficiency sensitizes the cerebellar cortex to spreading depolarization, thereby increasing the excitability of cerebellar neurons. This heightened excitability can disrupt normal neuronal firing patterns in deep cerebellar nuclei crucial for motor control. In mice lacking
Variants listed in the table have been provided by the authors.
## Chapter Notes
The Movement Disorder Society Genetic mutation database (
Recommendations on the Nomenclature of Genetic Movement Disorders are provided by the Task Force on the Nomenclature of Genetic Movement Disorders from the International Parkinson and Movement Disorders Society. Current recommendations are provided in
The authors are grateful to the many patients and families who support research on
Darius Ebrahimi-Fakhari, MD, PhD (2018-present)Christine Klein, MD; University of Lübeck (2018-2024)Christelle Moufawad El Achkar, MD; Harvard Medical School (2018-2024)Vincente Quiroz, MD (2024-present)Kathryn Yang, MD, FRCPC (2024-present)
4 July 2024 (bp) Comprehensive update posted live
11 January 2018 (bp) Review posted live
16 August 2017 (def) Original submission
• 4 July 2024 (bp) Comprehensive update posted live
• 11 January 2018 (bp) Review posted live
• 16 August 2017 (def) Original submission
## Author Notes
The Movement Disorder Society Genetic mutation database (
Recommendations on the Nomenclature of Genetic Movement Disorders are provided by the Task Force on the Nomenclature of Genetic Movement Disorders from the International Parkinson and Movement Disorders Society. Current recommendations are provided in
## Acknowledgments
The authors are grateful to the many patients and families who support research on
## Author History
Darius Ebrahimi-Fakhari, MD, PhD (2018-present)Christine Klein, MD; University of Lübeck (2018-2024)Christelle Moufawad El Achkar, MD; Harvard Medical School (2018-2024)Vincente Quiroz, MD (2024-present)Kathryn Yang, MD, FRCPC (2024-present)
## Revision History
4 July 2024 (bp) Comprehensive update posted live
11 January 2018 (bp) Review posted live
16 August 2017 (def) Original submission
• 4 July 2024 (bp) Comprehensive update posted live
• 11 January 2018 (bp) Review posted live
• 16 August 2017 (def) Original submission
## References
Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol. 1995;38:571-9.
Kato N, Sadamatsu M, Kikuchi T, Niikawa N, Fukuyama Y. Paroxysmal kinesigenic choreoathetosis: from first discovery in 1892 to genetic linkage with benign familial infantile convulsions. Epilepsy Res. 2006;70:S174-84.
Kertesz A. Paroxysmal kinesigenic choreoathetosis. An entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including 1 autopsied. Neurology. 1967;17:680-90.
Mount LA, Reback S. Familial paroxysmal choreoathetosis. Arch Neurol Psychiatry. 1940;44:841-7.
• Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol. 1995;38:571-9.
• Kato N, Sadamatsu M, Kikuchi T, Niikawa N, Fukuyama Y. Paroxysmal kinesigenic choreoathetosis: from first discovery in 1892 to genetic linkage with benign familial infantile convulsions. Epilepsy Res. 2006;70:S174-84.
• Kertesz A. Paroxysmal kinesigenic choreoathetosis. An entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including 1 autopsied. Neurology. 1967;17:680-90.
• Mount LA, Reback S. Familial paroxysmal choreoathetosis. Arch Neurol Psychiatry. 1940;44:841-7.
## Literature Cited
## Suggested Reading (Historical References)
Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol. 1995;38:571-9.
Kato N, Sadamatsu M, Kikuchi T, Niikawa N, Fukuyama Y. Paroxysmal kinesigenic choreoathetosis: from first discovery in 1892 to genetic linkage with benign familial infantile convulsions. Epilepsy Res. 2006;70:S174-84.
Kertesz A. Paroxysmal kinesigenic choreoathetosis. An entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including 1 autopsied. Neurology. 1967;17:680-90.
Mount LA, Reback S. Familial paroxysmal choreoathetosis. Arch Neurol Psychiatry. 1940;44:841-7.
• Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol. 1995;38:571-9.
• Kato N, Sadamatsu M, Kikuchi T, Niikawa N, Fukuyama Y. Paroxysmal kinesigenic choreoathetosis: from first discovery in 1892 to genetic linkage with benign familial infantile convulsions. Epilepsy Res. 2006;70:S174-84.
• Kertesz A. Paroxysmal kinesigenic choreoathetosis. An entity within the paroxysmal choreoathetosis syndrome. Description of 10 cases, including 1 autopsied. Neurology. 1967;17:680-90.
• Mount LA, Reback S. Familial paroxysmal choreoathetosis. Arch Neurol Psychiatry. 1940;44:841-7.
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
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|
[
"PRS Superactivity",
"Ribose-phosphate pyrophosphokinase 1",
"PRPS1",
"Phosphoribosylpyrophosphate Synthetase Superactivity"
] |
Phosphoribosylpyrophosphate Synthetase Superactivity
|
Arjan PM de Brouwer, John Christodoulou
|
Summary Phosphoribosylpyrophosphate synthetase (PRS) superactivity comprises two phenotypes, both characterized by hyperuricemia and hyperuricosuria. The mild phenotype (~75% of affected males) with onset in the second or third decade of life is typically limited to these biochemical findings, whereas the severe phenotype (~25% of affected males) with onset in the first decade of life has in addition to these biochemical findings variable combinations of developmental delay (DD) / intellectual disability (ID), sensorineural hearing loss, hypotonia, and ataxia. In the mild phenotype, uric acid crystalluria or a urinary stone is commonly the first clinical finding, followed later by gouty arthritis if serum urate concentration is not controlled. In male probands with the mild phenotype, detection of high activity or lack of allosteric regulation of the PRS-I enzyme (PRS-I enzyme assay) establishes the diagnosis. Molecular genetic testing of In male probands with the severe phenotype, molecular genetic testing establishes the diagnosis by identification of a hemizygous PRPS1 pathogenic variant in males and a heterozygous In symptomatic female probands, PRS-I enzyme assay and/or In individuals with the severe phenotype, DD/ID, sensorineural hearing loss, hypotonia, and ataxia are managed per standard care. In the severe phenotype: monitor development / educational needs, neurologic manifestations, and hearing. In male and female relatives: molecular genetic testing if a In male relatives at risk: measurement of serum urate concentration and 24-hour urinary uric acid excretion or spot urinary urate-to-creatinine ratio. Note: Biochemical testing is unlikely to be informative in asymptomatic females. PRS superactivity caused by a pathogenic variant in PRS superactivity caused by elevated
|
Phosphoribosylpyrophosphate Synthetase (PRS) Superactivity: Phenotypes in Males and Females
In all males with mild PRS superactivity evaluated to date, the sequence of the
Biochemical testing is unlikely to be informative in asymptomatic females.
## Diagnosis
No consensus clinical diagnostic criteria for phosphoribosylpyrophosphate synthetase (PRS) superactivity have been published.
Phosphoribosylpyrophosphate synthetase (PRS) superactivity
The
Gouty arthritis
Note: Absence of gout does not exclude consideration of PRS superactivity.
Significant hyperuricemia and significantly elevated daily urinary uric acid excretion
The ratio of urinary urate to creatinine concentration may be more helpful for screening purposes. PRS superactivity values are typically greater than twofold the upper limit of normal.
Male and female adult serum urate ranges differ.
"Normal" serum urate concentrations and 24-hour urinary urate excretion vary by age and weight. If tested for serum urate concentrations, the individual should be on a standard diet with no medications influencing serum urate levels.
Uric acid urolithiasis
The
Intellectual disability
Sensorineural hearing impairment
Hypotonia
Ataxia
The diagnosis of the
PRS-I enzyme activity can be analyzed in fibroblasts, lymphoblasts, and erythrocytes [
Phosphoribosylpyrophosphate Synthetase (PRS) Enzyme Activity and Nucleotide Levels in PRS Superactivity
Adenylates (AMP, ADP, ATP) and guanylates (GMP, GDP, GTP)
Note: Molecular genetic testing by
The diagnosis of the
Note:
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 Phosphoribosylpyrophosphate Synthetase (PRS) Superactivity
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
Six males with metabolic and neurodevelopmental abnormalities in infancy or early childhood; one male with onset of metabolic (but not neurodevelopmental) features in the teen years; three women with late childhood-onset gout who were heterozygous for a
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.
• Gouty arthritis
• Note: Absence of gout does not exclude consideration of PRS superactivity.
• Significant hyperuricemia and significantly elevated daily urinary uric acid excretion
• The ratio of urinary urate to creatinine concentration may be more helpful for screening purposes. PRS superactivity values are typically greater than twofold the upper limit of normal.
• Male and female adult serum urate ranges differ.
• "Normal" serum urate concentrations and 24-hour urinary urate excretion vary by age and weight. If tested for serum urate concentrations, the individual should be on a standard diet with no medications influencing serum urate levels.
• The ratio of urinary urate to creatinine concentration may be more helpful for screening purposes. PRS superactivity values are typically greater than twofold the upper limit of normal.
• Male and female adult serum urate ranges differ.
• "Normal" serum urate concentrations and 24-hour urinary urate excretion vary by age and weight. If tested for serum urate concentrations, the individual should be on a standard diet with no medications influencing serum urate levels.
• Uric acid urolithiasis
• The ratio of urinary urate to creatinine concentration may be more helpful for screening purposes. PRS superactivity values are typically greater than twofold the upper limit of normal.
• Male and female adult serum urate ranges differ.
• "Normal" serum urate concentrations and 24-hour urinary urate excretion vary by age and weight. If tested for serum urate concentrations, the individual should be on a standard diet with no medications influencing serum urate levels.
• Intellectual disability
• Sensorineural hearing impairment
• Hypotonia
• Ataxia
## Suggestive Findings
Phosphoribosylpyrophosphate synthetase (PRS) superactivity
The
Gouty arthritis
Note: Absence of gout does not exclude consideration of PRS superactivity.
Significant hyperuricemia and significantly elevated daily urinary uric acid excretion
The ratio of urinary urate to creatinine concentration may be more helpful for screening purposes. PRS superactivity values are typically greater than twofold the upper limit of normal.
Male and female adult serum urate ranges differ.
"Normal" serum urate concentrations and 24-hour urinary urate excretion vary by age and weight. If tested for serum urate concentrations, the individual should be on a standard diet with no medications influencing serum urate levels.
Uric acid urolithiasis
The
Intellectual disability
Sensorineural hearing impairment
Hypotonia
Ataxia
• Gouty arthritis
• Note: Absence of gout does not exclude consideration of PRS superactivity.
• Significant hyperuricemia and significantly elevated daily urinary uric acid excretion
• The ratio of urinary urate to creatinine concentration may be more helpful for screening purposes. PRS superactivity values are typically greater than twofold the upper limit of normal.
• Male and female adult serum urate ranges differ.
• "Normal" serum urate concentrations and 24-hour urinary urate excretion vary by age and weight. If tested for serum urate concentrations, the individual should be on a standard diet with no medications influencing serum urate levels.
• The ratio of urinary urate to creatinine concentration may be more helpful for screening purposes. PRS superactivity values are typically greater than twofold the upper limit of normal.
• Male and female adult serum urate ranges differ.
• "Normal" serum urate concentrations and 24-hour urinary urate excretion vary by age and weight. If tested for serum urate concentrations, the individual should be on a standard diet with no medications influencing serum urate levels.
• Uric acid urolithiasis
• The ratio of urinary urate to creatinine concentration may be more helpful for screening purposes. PRS superactivity values are typically greater than twofold the upper limit of normal.
• Male and female adult serum urate ranges differ.
• "Normal" serum urate concentrations and 24-hour urinary urate excretion vary by age and weight. If tested for serum urate concentrations, the individual should be on a standard diet with no medications influencing serum urate levels.
• Intellectual disability
• Sensorineural hearing impairment
• Hypotonia
• Ataxia
## Establishing the Diagnosis
The diagnosis of the
PRS-I enzyme activity can be analyzed in fibroblasts, lymphoblasts, and erythrocytes [
Phosphoribosylpyrophosphate Synthetase (PRS) Enzyme Activity and Nucleotide Levels in PRS Superactivity
Adenylates (AMP, ADP, ATP) and guanylates (GMP, GDP, GTP)
Note: Molecular genetic testing by
The diagnosis of the
Note:
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 Phosphoribosylpyrophosphate Synthetase (PRS) Superactivity
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
Six males with metabolic and neurodevelopmental abnormalities in infancy or early childhood; one male with onset of metabolic (but not neurodevelopmental) features in the teen years; three women with late childhood-onset gout who were heterozygous for a
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.
## Enzyme Analysis
The diagnosis of the
PRS-I enzyme activity can be analyzed in fibroblasts, lymphoblasts, and erythrocytes [
Phosphoribosylpyrophosphate Synthetase (PRS) Enzyme Activity and Nucleotide Levels in PRS Superactivity
Adenylates (AMP, ADP, ATP) and guanylates (GMP, GDP, GTP)
Note: Molecular genetic testing by
## Molecular Genetic Testing
The diagnosis of the
Note:
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 Phosphoribosylpyrophosphate Synthetase (PRS) Superactivity
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
Six males with metabolic and neurodevelopmental abnormalities in infancy or early childhood; one male with onset of metabolic (but not neurodevelopmental) features in the teen years; three women with late childhood-onset gout who were heterozygous for a
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
The two phosphoribosylpyrophosphate synthetase (PRS) superactivity phenotypes are mild (onset in 2nd or 3rd decade of life) and severe (onset in 1st decade of life).
Renal impairment can potentially result from uric acid crystal deposition in the renal collecting system or from urate crystal deposition in the renal interstitium.
Kidney stones and acute kidney failure as a result of obstructive uropathy from uric acid crystal deposition (stones or gravel) were described in the first family identified [
Heterozygous females in families with the mild PRS superactivity phenotype can show the metabolic features of the disease.
Heterozygous females in families with the severe PRS superactivity phenotype can also show the metabolic and/or neurodevelopmental features of the disease [
No genotype-phenotype correlations have been identified.
"PRPP synthetase (PRS) superactivity" is the name originally applied to the overall disorder. With the increasing recognition of two varieties of defects – that is, single-nucleotide variants (SNVs) in
No prevalence has been estimated. To date, 33 individuals with PRS superactivity have been described worldwide.
## Clinical Description
The two phosphoribosylpyrophosphate synthetase (PRS) superactivity phenotypes are mild (onset in 2nd or 3rd decade of life) and severe (onset in 1st decade of life).
Renal impairment can potentially result from uric acid crystal deposition in the renal collecting system or from urate crystal deposition in the renal interstitium.
Kidney stones and acute kidney failure as a result of obstructive uropathy from uric acid crystal deposition (stones or gravel) were described in the first family identified [
Heterozygous females in families with the mild PRS superactivity phenotype can show the metabolic features of the disease.
Heterozygous females in families with the severe PRS superactivity phenotype can also show the metabolic and/or neurodevelopmental features of the disease [
## Males
Renal impairment can potentially result from uric acid crystal deposition in the renal collecting system or from urate crystal deposition in the renal interstitium.
Kidney stones and acute kidney failure as a result of obstructive uropathy from uric acid crystal deposition (stones or gravel) were described in the first family identified [
## Heterozygous Females
Heterozygous females in families with the mild PRS superactivity phenotype can show the metabolic features of the disease.
Heterozygous females in families with the severe PRS superactivity phenotype can also show the metabolic and/or neurodevelopmental features of the disease [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
"PRPP synthetase (PRS) superactivity" is the name originally applied to the overall disorder. With the increasing recognition of two varieties of defects – that is, single-nucleotide variants (SNVs) in
## Prevalence
No prevalence has been estimated. To date, 33 individuals with PRS superactivity have been described worldwide.
## Genetically Related (Allelic) Disorders
Germline pathogenic variants in
## Differential Diagnosis
Disorders of purine and pyrimidine metabolism to consider in the differential diagnosis of phosphoribosylpyrophosphate synthetase (PRS) superactivity are:
Hypoxanthine-guanine phosphoribosyltransferase deficiency, an X-linked disorder caused by pathogenic variants in
Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, an autosomal recessive disorder caused by pathogenic variants in
Disorders of Purine and Pyrimidine Metabolism that Overlap with Phosphoribosylpyrophosphate Synthetase (PRS) Superactivity
AHCY deficiency = hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase; HPRT = hypoxanthine-guanine phosphoribosyltransferase
• Hypoxanthine-guanine phosphoribosyltransferase deficiency, an X-linked disorder caused by pathogenic variants in
• Hypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase, an autosomal recessive disorder caused by pathogenic variants in
## Management
To establish the extent of disease and needs in a male or female diagnosed with phosphoribosylpyrophosphate synthetase (PRS) superactivity, the following evaluations are recommended.
Serum urate concentration
Joint examination for evidence of gout – generally, evaluation of joint integrity only, except during an acute flare of arthritis or in an individual with chronic deformity or tophus formation following multiple attacks
Assessment of kidney function and structural integrity (e.g., kidney ultrasound examination)
Neurologic evaluation for hypotonia, ataxia, presence/absence of tendon reflexes
Audiometry for evidence of hearing loss
Developmental assessment, including motor, adaptive, cognitive, & speech-language evaluation
Evaluation for early intervention / special education
Dietary changes:
Reduced intake of red and organ meats, poultry, and shellfish [
Avoidance of high-fructose corn syrup-containing foods and drinks
Increased low-fat dairy intake
Allopurinol, a xanthine oxidase inhibitor, prescribed in doses with the ultimate aim of achieving serum urate concentrations lower than 6.0 mg/dL (360 μmol/L). The starting dose should be 100 mg once a day (in adults) with titration every three to four weeks according to the serum urate concentration. However, because of the uric acid overproduction and excessive uric acid excretion, allopurinol should be prescribed conservatively, as there is a high risk for xanthinuria and xanthine renal lithiasis; see
Febuxostat, a newer urate-lowering xanthine oxidase inhibitor. Febuxostat has not been tested in individuals with PRS superactivity, but there is no reason a priori to doubt that it will be effective in the treatment of this disorder. Febuxostat should also be prescribed conservatively, because of a high risk for xanthinuria causing renal lithiasis. Note: Excretion of >1.1 g uric acid per day in an adult is associated with a greater than 50% risk for kidney stones.
High daily fluid intake (i.e., ≥2 L/day in an adult)
Potassium citrate (usually administered 4x/day to alkalinize the urine) when urate urinary tract stones are present or uric acid gravel is in the urine [
Note: The interventions described only prevent/treat gout and the other metabolic complications of hyperuricemia; they have no known beneficial effect on hearing loss or neurodevelopmental impairment.
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.
Consider evaluation for alternative means of communication (e.g.,
Monthly measurement of 24-hour uric acid excretion in the urine is particularly helpful in the assessment of the response to treatment. Alternatively, a spot urinary urate-to-creatinine ratio can be informative if accessibility to 24-hour urine samples is restricted.
Once a normal serum urate concentration is achieved and maintained, serum urate concentration should be monitored at a minimum annually to assure that the targeted concentration is maintained.
A 24-hour urine should also be monitored at a minimum annually for urate and xanthine concentrations particularly to ensure that urinary xanthine does not exceed solubility (<1 mmol/L); plasma xanthine is cleared efficiently and does not accumulate.
Note: Under usual circumstances, renal functional consequences are avoided if serum urate concentration and urinary excretion of urate are normalized and urinary xanthine does not routinely exceed its solubility (~1 mmol/L).
Audiometry should be repeated as deemed appropriate by the treating audiologist/otolaryngologist.
Neurologic evaluation should be performed annually or more frequently as recommended by the treating neurologist.
Monitor developmental progress and educational needs at each visit.
The following should be avoided in all individuals:
Red and organ meats, shellfish, or oily fish (e.g., anchovies, sardines) in excess; beer; high-fructose corn syrup-enriched foods and drinks [
Dehydration
If possible, urate-retaining medications: low-dose aspirin, thiazide diuretics
It is appropriate to screen apparently asymptomatic older and younger at-risk relatives of an individual with PRS superactivity in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures for hyperuricemia and hyperuricosuria.
Evaluations include:
In male and female relatives at risk for the severe phenotype: molecular genetic testing if a
In male relatives at risk for the mild phenotype: measurement of serum urate concentration, and 24-hour urinary uric acid excretion or spot urinary urate-to-creatinine ratio. Biochemical testing is unlikely to be informative in asymptomatic females.
Note: (1) Because collection of 24-hour urine in an infant or young child is very difficult, measurement of urinary urate-to-creatinine ratio in a spot urine sample may be helpful. (2) Sometimes the serum urate concentrations are not extremely elevated in children with PRS superactivity, probably as a result of higher renal clearance of urate; however, the urine urate excretion is abnormally high for age in all individuals.
See
Dietary
Search
• Serum urate concentration
• Joint examination for evidence of gout – generally, evaluation of joint integrity only, except during an acute flare of arthritis or in an individual with chronic deformity or tophus formation following multiple attacks
• Assessment of kidney function and structural integrity (e.g., kidney ultrasound examination)
• Neurologic evaluation for hypotonia, ataxia, presence/absence of tendon reflexes
• Audiometry for evidence of hearing loss
• Developmental assessment, including motor, adaptive, cognitive, & speech-language evaluation
• Evaluation for early intervention / special education
• Dietary changes:
• Reduced intake of red and organ meats, poultry, and shellfish [
• Avoidance of high-fructose corn syrup-containing foods and drinks
• Increased low-fat dairy intake
• Reduced intake of red and organ meats, poultry, and shellfish [
• Avoidance of high-fructose corn syrup-containing foods and drinks
• Increased low-fat dairy intake
• Allopurinol, a xanthine oxidase inhibitor, prescribed in doses with the ultimate aim of achieving serum urate concentrations lower than 6.0 mg/dL (360 μmol/L). The starting dose should be 100 mg once a day (in adults) with titration every three to four weeks according to the serum urate concentration. However, because of the uric acid overproduction and excessive uric acid excretion, allopurinol should be prescribed conservatively, as there is a high risk for xanthinuria and xanthine renal lithiasis; see
• Febuxostat, a newer urate-lowering xanthine oxidase inhibitor. Febuxostat has not been tested in individuals with PRS superactivity, but there is no reason a priori to doubt that it will be effective in the treatment of this disorder. Febuxostat should also be prescribed conservatively, because of a high risk for xanthinuria causing renal lithiasis. Note: Excretion of >1.1 g uric acid per day in an adult is associated with a greater than 50% risk for kidney stones.
• High daily fluid intake (i.e., ≥2 L/day in an adult)
• Potassium citrate (usually administered 4x/day to alkalinize the urine) when urate urinary tract stones are present or uric acid gravel is in the urine [
• Reduced intake of red and organ meats, poultry, and shellfish [
• Avoidance of high-fructose corn syrup-containing foods and drinks
• Increased low-fat dairy intake
• 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.
• Red and organ meats, shellfish, or oily fish (e.g., anchovies, sardines) in excess; beer; high-fructose corn syrup-enriched foods and drinks [
• Dehydration
• If possible, urate-retaining medications: low-dose aspirin, thiazide diuretics
• In male and female relatives at risk for the severe phenotype: molecular genetic testing if a
• In male relatives at risk for the mild phenotype: measurement of serum urate concentration, and 24-hour urinary uric acid excretion or spot urinary urate-to-creatinine ratio. Biochemical testing is unlikely to be informative in asymptomatic females.
• Note: (1) Because collection of 24-hour urine in an infant or young child is very difficult, measurement of urinary urate-to-creatinine ratio in a spot urine sample may be helpful. (2) Sometimes the serum urate concentrations are not extremely elevated in children with PRS superactivity, probably as a result of higher renal clearance of urate; however, the urine urate excretion is abnormally high for age in all individuals.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in a male or female diagnosed with phosphoribosylpyrophosphate synthetase (PRS) superactivity, the following evaluations are recommended.
Serum urate concentration
Joint examination for evidence of gout – generally, evaluation of joint integrity only, except during an acute flare of arthritis or in an individual with chronic deformity or tophus formation following multiple attacks
Assessment of kidney function and structural integrity (e.g., kidney ultrasound examination)
Neurologic evaluation for hypotonia, ataxia, presence/absence of tendon reflexes
Audiometry for evidence of hearing loss
Developmental assessment, including motor, adaptive, cognitive, & speech-language evaluation
Evaluation for early intervention / special education
• Serum urate concentration
• Joint examination for evidence of gout – generally, evaluation of joint integrity only, except during an acute flare of arthritis or in an individual with chronic deformity or tophus formation following multiple attacks
• Assessment of kidney function and structural integrity (e.g., kidney ultrasound examination)
• Neurologic evaluation for hypotonia, ataxia, presence/absence of tendon reflexes
• Audiometry for evidence of hearing loss
• Developmental assessment, including motor, adaptive, cognitive, & speech-language evaluation
• Evaluation for early intervention / special education
## Treatment of Manifestations ‒ All PRS Superactivity
Dietary changes:
Reduced intake of red and organ meats, poultry, and shellfish [
Avoidance of high-fructose corn syrup-containing foods and drinks
Increased low-fat dairy intake
Allopurinol, a xanthine oxidase inhibitor, prescribed in doses with the ultimate aim of achieving serum urate concentrations lower than 6.0 mg/dL (360 μmol/L). The starting dose should be 100 mg once a day (in adults) with titration every three to four weeks according to the serum urate concentration. However, because of the uric acid overproduction and excessive uric acid excretion, allopurinol should be prescribed conservatively, as there is a high risk for xanthinuria and xanthine renal lithiasis; see
Febuxostat, a newer urate-lowering xanthine oxidase inhibitor. Febuxostat has not been tested in individuals with PRS superactivity, but there is no reason a priori to doubt that it will be effective in the treatment of this disorder. Febuxostat should also be prescribed conservatively, because of a high risk for xanthinuria causing renal lithiasis. Note: Excretion of >1.1 g uric acid per day in an adult is associated with a greater than 50% risk for kidney stones.
High daily fluid intake (i.e., ≥2 L/day in an adult)
Potassium citrate (usually administered 4x/day to alkalinize the urine) when urate urinary tract stones are present or uric acid gravel is in the urine [
Note: The interventions described only prevent/treat gout and the other metabolic complications of hyperuricemia; they have no known beneficial effect on hearing loss or neurodevelopmental impairment.
• Dietary changes:
• Reduced intake of red and organ meats, poultry, and shellfish [
• Avoidance of high-fructose corn syrup-containing foods and drinks
• Increased low-fat dairy intake
• Reduced intake of red and organ meats, poultry, and shellfish [
• Avoidance of high-fructose corn syrup-containing foods and drinks
• Increased low-fat dairy intake
• Allopurinol, a xanthine oxidase inhibitor, prescribed in doses with the ultimate aim of achieving serum urate concentrations lower than 6.0 mg/dL (360 μmol/L). The starting dose should be 100 mg once a day (in adults) with titration every three to four weeks according to the serum urate concentration. However, because of the uric acid overproduction and excessive uric acid excretion, allopurinol should be prescribed conservatively, as there is a high risk for xanthinuria and xanthine renal lithiasis; see
• Febuxostat, a newer urate-lowering xanthine oxidase inhibitor. Febuxostat has not been tested in individuals with PRS superactivity, but there is no reason a priori to doubt that it will be effective in the treatment of this disorder. Febuxostat should also be prescribed conservatively, because of a high risk for xanthinuria causing renal lithiasis. Note: Excretion of >1.1 g uric acid per day in an adult is associated with a greater than 50% risk for kidney stones.
• High daily fluid intake (i.e., ≥2 L/day in an adult)
• Potassium citrate (usually administered 4x/day to alkalinize the urine) when urate urinary tract stones are present or uric acid gravel is in the urine [
• Reduced intake of red and organ meats, poultry, and shellfish [
• Avoidance of high-fructose corn syrup-containing foods and drinks
• Increased low-fat dairy intake
## Treatment of Manifestations ‒ Severe PRS Superactivity Phenotype
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.
Consider evaluation for alternative means of communication (e.g.,
• 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.
## 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.
## Communication Issues
Consider evaluation for alternative means of communication (e.g.,
## Surveillance
Monthly measurement of 24-hour uric acid excretion in the urine is particularly helpful in the assessment of the response to treatment. Alternatively, a spot urinary urate-to-creatinine ratio can be informative if accessibility to 24-hour urine samples is restricted.
Once a normal serum urate concentration is achieved and maintained, serum urate concentration should be monitored at a minimum annually to assure that the targeted concentration is maintained.
A 24-hour urine should also be monitored at a minimum annually for urate and xanthine concentrations particularly to ensure that urinary xanthine does not exceed solubility (<1 mmol/L); plasma xanthine is cleared efficiently and does not accumulate.
Note: Under usual circumstances, renal functional consequences are avoided if serum urate concentration and urinary excretion of urate are normalized and urinary xanthine does not routinely exceed its solubility (~1 mmol/L).
Audiometry should be repeated as deemed appropriate by the treating audiologist/otolaryngologist.
Neurologic evaluation should be performed annually or more frequently as recommended by the treating neurologist.
Monitor developmental progress and educational needs at each visit.
## All Individuals
Monthly measurement of 24-hour uric acid excretion in the urine is particularly helpful in the assessment of the response to treatment. Alternatively, a spot urinary urate-to-creatinine ratio can be informative if accessibility to 24-hour urine samples is restricted.
Once a normal serum urate concentration is achieved and maintained, serum urate concentration should be monitored at a minimum annually to assure that the targeted concentration is maintained.
A 24-hour urine should also be monitored at a minimum annually for urate and xanthine concentrations particularly to ensure that urinary xanthine does not exceed solubility (<1 mmol/L); plasma xanthine is cleared efficiently and does not accumulate.
Note: Under usual circumstances, renal functional consequences are avoided if serum urate concentration and urinary excretion of urate are normalized and urinary xanthine does not routinely exceed its solubility (~1 mmol/L).
## Individuals with the Severe PRS Superactivity Phenotype
Audiometry should be repeated as deemed appropriate by the treating audiologist/otolaryngologist.
Neurologic evaluation should be performed annually or more frequently as recommended by the treating neurologist.
Monitor developmental progress and educational needs at each visit.
## Agents/Circumstances to Avoid
The following should be avoided in all individuals:
Red and organ meats, shellfish, or oily fish (e.g., anchovies, sardines) in excess; beer; high-fructose corn syrup-enriched foods and drinks [
Dehydration
If possible, urate-retaining medications: low-dose aspirin, thiazide diuretics
• Red and organ meats, shellfish, or oily fish (e.g., anchovies, sardines) in excess; beer; high-fructose corn syrup-enriched foods and drinks [
• Dehydration
• If possible, urate-retaining medications: low-dose aspirin, thiazide diuretics
## Evaluation of Relatives at Risk
It is appropriate to screen apparently asymptomatic older and younger at-risk relatives of an individual with PRS superactivity in order to identify as early as possible those who would benefit from initiation of treatment and preventive measures for hyperuricemia and hyperuricosuria.
Evaluations include:
In male and female relatives at risk for the severe phenotype: molecular genetic testing if a
In male relatives at risk for the mild phenotype: measurement of serum urate concentration, and 24-hour urinary uric acid excretion or spot urinary urate-to-creatinine ratio. Biochemical testing is unlikely to be informative in asymptomatic females.
Note: (1) Because collection of 24-hour urine in an infant or young child is very difficult, measurement of urinary urate-to-creatinine ratio in a spot urine sample may be helpful. (2) Sometimes the serum urate concentrations are not extremely elevated in children with PRS superactivity, probably as a result of higher renal clearance of urate; however, the urine urate excretion is abnormally high for age in all individuals.
See
• In male and female relatives at risk for the severe phenotype: molecular genetic testing if a
• In male relatives at risk for the mild phenotype: measurement of serum urate concentration, and 24-hour urinary uric acid excretion or spot urinary urate-to-creatinine ratio. Biochemical testing is unlikely to be informative in asymptomatic females.
• Note: (1) Because collection of 24-hour urine in an infant or young child is very difficult, measurement of urinary urate-to-creatinine ratio in a spot urine sample may be helpful. (2) Sometimes the serum urate concentrations are not extremely elevated in children with PRS superactivity, probably as a result of higher renal clearance of urate; however, the urine urate excretion is abnormally high for age in all individuals.
## Therapies Under Investigation
Dietary
Search
## Genetic Counseling
Phosphoribosylpyrophosphate synthetase (PRS) superactivity caused by a pathogenic variant in
PRS superactivity caused by elevated
The father of an affected male will not have PRS superactivity 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 familial
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 allow reliable recurrence risk assessment and to determine her need for clinical management (see
If the mother of the proband has a
Males who inherit the pathogenic variant will be severely affected.
Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have variable manifestations including hyperuricemia, nephrolithiasis, gout, and (rarely) neurodevelopmental features [
If the proband represents a simplex case and the
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
If the mother of the proband has a
If the father of the proband has a
If the proband represents a simplex case and if the
Affected males transmit the
All of their daughters, who will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
None of their sons.
Women with a
Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
Males who inherit the pathogenic variant will be affected.
Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the
Of note, biochemical testing is unlikely to be informative in asymptomatic females.
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 and/or are at risk of having PRS superactivity.
If a
Note: The identification of 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.
• The father of an affected male will not have PRS superactivity 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 familial
• 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 allow reliable recurrence risk assessment and to determine her need for clinical management (see
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be severely affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have variable manifestations including hyperuricemia, nephrolithiasis, gout, and (rarely) neurodevelopmental features [
• Males who inherit the pathogenic variant will be severely affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have variable manifestations including hyperuricemia, nephrolithiasis, gout, and (rarely) neurodevelopmental features [
• If the proband represents a simplex case and the
• Males who inherit the pathogenic variant will be severely affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have variable manifestations including hyperuricemia, nephrolithiasis, gout, and (rarely) neurodevelopmental features [
• 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
• If the mother of the proband has a
• If the father of the proband has a
• If the proband represents a simplex case and if the
• Affected males transmit the
• All of their daughters, who will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• None of their sons.
• All of their daughters, who will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• None of their sons.
• Women with a
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• Males who inherit the pathogenic variant will be affected.
• All of their daughters, who will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• None of their sons.
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• Males who inherit the pathogenic variant will be 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 and/or are at risk of having PRS superactivity.
## Mode of Inheritance
Phosphoribosylpyrophosphate synthetase (PRS) superactivity caused by a pathogenic variant in
PRS superactivity caused by elevated
## Risk to Family Members of a Proband with a
The father of an affected male will not have PRS superactivity 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 familial
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 allow reliable recurrence risk assessment and to determine her need for clinical management (see
If the mother of the proband has a
Males who inherit the pathogenic variant will be severely affected.
Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have variable manifestations including hyperuricemia, nephrolithiasis, gout, and (rarely) neurodevelopmental features [
If the proband represents a simplex case and the
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
If the mother of the proband has a
If the father of the proband has a
If the proband represents a simplex case and if the
Affected males transmit the
All of their daughters, who will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
None of their sons.
Women with a
Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
Males who inherit the pathogenic variant will be affected.
• The father of an affected male will not have PRS superactivity 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 familial
• 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 allow reliable recurrence risk assessment and to determine her need for clinical management (see
• If the mother of the proband has a
• Males who inherit the pathogenic variant will be severely affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have variable manifestations including hyperuricemia, nephrolithiasis, gout, and (rarely) neurodevelopmental features [
• Males who inherit the pathogenic variant will be severely affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have variable manifestations including hyperuricemia, nephrolithiasis, gout, and (rarely) neurodevelopmental features [
• If the proband represents a simplex case and the
• Males who inherit the pathogenic variant will be severely affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have variable manifestations including hyperuricemia, nephrolithiasis, gout, and (rarely) neurodevelopmental features [
• 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
• If the mother of the proband has a
• If the father of the proband has a
• If the proband represents a simplex case and if the
• Affected males transmit the
• All of their daughters, who will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• None of their sons.
• All of their daughters, who will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• None of their sons.
• Women with a
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• Males who inherit the pathogenic variant will be affected.
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• Males who inherit the pathogenic variant will be affected.
• All of their daughters, who will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• None of their sons.
• Females who inherit the pathogenic variant will be heterozygotes and may be asymptomatic or have a range of features (see Clinical Description,
• Males who inherit the pathogenic variant will be affected.
## Heterozygote Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status requires prior identification of the
Of note, biochemical testing is unlikely to be informative in asymptomatic females.
## 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 and/or are at risk of having PRS superactivity.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected and/or are at risk of having PRS superactivity.
## Prenatal Testing and Preimplantation Genetic Testing
If a
Note: The identification of 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
Phosphoribosylpyrophosphate Synthetase Superactivity: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Phosphoribosylpyrophosphate Synthetase Superactivity (
PRS superactivity is an inborn error of purine metabolism. Phosphoribosylpyrophosphate synthetase 1 (also known as ribose-phosphate pyrophosphokinase 1) catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for the
Establish the diagnosis in individuals with the mild PRS superactivity phenotype;
Evaluate novel
Analysis of PRS-1 enzyme activity is available at:
• Establish the diagnosis in individuals with the mild PRS superactivity phenotype;
• Evaluate novel
## Molecular Pathogenesis
PRS superactivity is an inborn error of purine metabolism. Phosphoribosylpyrophosphate synthetase 1 (also known as ribose-phosphate pyrophosphokinase 1) catalyzes the phosphoribosylation of ribose 5-phosphate to 5-phosphoribosyl-1-pyrophosphate, which is necessary for the
Establish the diagnosis in individuals with the mild PRS superactivity phenotype;
Evaluate novel
Analysis of PRS-1 enzyme activity is available at:
• Establish the diagnosis in individuals with the mild PRS superactivity phenotype;
• Evaluate novel
## Chapter Notes
The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to Dr John Christodoulou is generously supported by the Royal Children's Hospital Foundation.
Michael A Becker, MD; University of Chicago Pritzker School of Medicine (2008-2013)John Christodoulou, MBBS, PhD (2013-present)Arjan PM de Brouwer, PhD (2013-present)John A Duley, PhD; University of Queensland (2013-2022)
17 February 2022 (bp) Comprehensive update posted live
17 December 2015 (me) Comprehensive update posted live
8 August 2013 (me) Comprehensive update posted live
11 January 2011 (cd) Revision: additions to therapies under investigation
2 November 2010 (me) Comprehensive update posted live
23 September 2008 (me) Review posted live
17 July 2008 (mb) Initial submission
• 17 February 2022 (bp) Comprehensive update posted live
• 17 December 2015 (me) Comprehensive update posted live
• 8 August 2013 (me) Comprehensive update posted live
• 11 January 2011 (cd) Revision: additions to therapies under investigation
• 2 November 2010 (me) Comprehensive update posted live
• 23 September 2008 (me) Review posted live
• 17 July 2008 (mb) Initial submission
## Acknowledgments
The research conducted at the Murdoch Children's Research Institute was supported by the Victorian Government's Operational Infrastructure Support Program. The Chair in Genomic Medicine awarded to Dr John Christodoulou is generously supported by the Royal Children's Hospital Foundation.
## Author History
Michael A Becker, MD; University of Chicago Pritzker School of Medicine (2008-2013)John Christodoulou, MBBS, PhD (2013-present)Arjan PM de Brouwer, PhD (2013-present)John A Duley, PhD; University of Queensland (2013-2022)
## Revision History
17 February 2022 (bp) Comprehensive update posted live
17 December 2015 (me) Comprehensive update posted live
8 August 2013 (me) Comprehensive update posted live
11 January 2011 (cd) Revision: additions to therapies under investigation
2 November 2010 (me) Comprehensive update posted live
23 September 2008 (me) Review posted live
17 July 2008 (mb) Initial submission
• 17 February 2022 (bp) Comprehensive update posted live
• 17 December 2015 (me) Comprehensive update posted live
• 8 August 2013 (me) Comprehensive update posted live
• 11 January 2011 (cd) Revision: additions to therapies under investigation
• 2 November 2010 (me) Comprehensive update posted live
• 23 September 2008 (me) Review posted live
• 17 July 2008 (mb) Initial submission
## References
## Literature Cited
|
[
"MA Becker, M Kim, K Husain, T Kang. Regulation of purine nucleotide synthesis in human B lymphoblasts with both hypoxanthine-guanine phosphoribosyltransferase and phosphoribosylpyrophosphate synthetase superactivity.. J Biol Chem 1992;267:4317-21",
"MA Becker, MJ Losman, M Kim. Mechanisms of accelerated purine nucleotide synthesis in human fibroblasts with superactive phosphoribosylpyrophosphate synthetases.. J Biol Chem 1987;262:5596-602",
"MA Becker, MJ Losman, J Wilson, HA Simmonds. Superactivity of human phosphoribosyl pyrophosphate synthetase due to altered regulation by nucleotide inhibitors and inorganic phosphate.. Biochim Biophys Acta 1986;882:168-76",
"MA Becker, JG Puig, FA Mateos, ML Jimenez, M Kim, HA Simmonds. Inherited superactivity of phosphoribosylpyrophosphate synthetase: association of uric acid overproduction and sensorineural deafness.. Am J Med 1988;85:383-90",
"HK Choi, K Atkinson, EW Karlson, W Willett, G Curhan. Purine-rich foods, dairy and protein intake, and the risk of gout in men.. N Engl J Med 2004;350:1093-103",
"P García-Pavía, RJ Torres, M Rivero, M Ahmed, J García-Puig, MA Becker. Phosphoribosylpyrophosphate synthetase overactivity as a cause of uric acid overproduction in a young woman.. Arthritis Rheum. 2003;48:2036-41",
"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",
"MJ Losman, S Hecker, S Woo, MA Becker. Diagnostic evaluation of phosphoribosylpyrophosphate synthetase activities in hemolysates.. J Lab Clin Med 1984;103:932-43",
"O Sperling, P Boer, S Persky-Brosh, E Kanarek, VA De. Altered kinetic property of erythrocyte phosphoribosylpsyrophosphate synthetase in excessive purine production.. Rev Eur Etud Clin Biol 1972;17:703-6",
"RJ Torres, FA Mateos, JG Puig, MA Becker. Determination of phosphoribosylpyrophosphate synthetase activity in human cells by a non-isotopic, one step method.. Clin Chim Acta 1996;245:105-12",
"M Zikánová, D Wahezi, A Hay, B Stiburková, C Pitts, D Mušálková, V Škopová, V Barešová, O Soucková, K Hodanová, M Živná, V Stránecký, H Hartmannová, A Hnízda, AJ Bleyer, S Kmoch. Clinical manifestations and molecular aspects of phosphoribosylpyrophosphate synthetase superactivity in females.. Rheumatology (Oxford) 2018;57:1180-5"
] |
23/9/2008
|
17/2/2022
|
11/1/2011
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
prss1-hp
|
prss1-hp
|
[
"Serine protease 1",
"PRSS1",
"PRSS1-Related Hereditary Pancreatitis"
] |
David C Whitcomb
|
Summary The diagnosis of High-penetrance HP caused by gain-of-function
|
## Diagnosis
The clinical features of
Acute pancreatitis occurring in childhood
Recurrent acute attacks of pancreatitis of unknown cause
Chronic pancreatitis of unknown cause, particularly with onset before age 25 years
A family history of recurrent acute pancreatitis, chronic pancreatitis, and/or childhood pancreatitis consistent with autosomal dominant inheritance
A family history of pancreatitis, diabetes mellitus, or pancreatic cancer
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
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, pathogenic, chronic pancreatitis (CP) causing, and CP predisposing. 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
One of two pathogenic variants (
The presence of a cytosine at two
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.
• Acute pancreatitis occurring in childhood
• Recurrent acute attacks of pancreatitis of unknown cause
• Chronic pancreatitis of unknown cause, particularly with onset before age 25 years
• A family history of recurrent acute pancreatitis, chronic pancreatitis, and/or childhood pancreatitis consistent with autosomal dominant inheritance
• A family history of pancreatitis, diabetes mellitus, or pancreatic cancer
• For an introduction to multigene panels click
## Suggestive Findings
Acute pancreatitis occurring in childhood
Recurrent acute attacks of pancreatitis of unknown cause
Chronic pancreatitis of unknown cause, particularly with onset before age 25 years
A family history of recurrent acute pancreatitis, chronic pancreatitis, and/or childhood pancreatitis consistent with autosomal dominant inheritance
A family history of pancreatitis, diabetes mellitus, or pancreatic cancer
• Acute pancreatitis occurring in childhood
• Recurrent acute attacks of pancreatitis of unknown cause
• Chronic pancreatitis of unknown cause, particularly with onset before age 25 years
• A family history of recurrent acute pancreatitis, chronic pancreatitis, and/or childhood pancreatitis consistent with autosomal dominant inheritance
• A family history of pancreatitis, diabetes mellitus, or pancreatic cancer
## 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
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, pathogenic, chronic pancreatitis (CP) causing, and CP predisposing. 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
One of two pathogenic variants (
The presence of a cytosine at two
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 multigene panels click
## Clinical Characteristics
In
Persons with
Long-standing inflammation results in complications that can include the following:
Episodic or continuous mild-to-severe abdominal pain. Pain is usually sharp and stabbing in initial attacks, becoming deep and burning as the syndrome progresses. The most psychologically distressing pain is constant chronic pain, regardless of intensity [
Exocrine pancreatic insufficiency leading to maldigestion with symptoms of gas and bloating and the appearance of diarrhea, oil in the stool (steatorrhea), and/or floating stools. Other signs of maldigestion include weight loss, fat-soluble-vitamin deficiency, and protein deficiency with low albumin, prealbumin, or retinol-binding protein detected on blood testing.
Diabetes mellitus (DM) (pancreatic endocrine insufficiency) manifesting initially as inappropriately elevated levels of blood glucose (glucose intolerance). Up to 48% of persons with
Pain is often the most common and stressful complication of pancreatitis, although the severity of the pain experience is highly variable. An exploratory genome-wide association study suggested that much of the heterogeneity in pain severity and chronicity is related to genetic variants affecting proteins expressed in the pancreas, sensory nerves, spinal cord, and brain, and/or associated with psychiatric stress disorders [
Other common symptoms with chronic pancreatitis include nighttime sweats, bloating, or cramping, greasy or oily stools, feeling cold, and gastroesophageal reflux disease [
Note: Other
The reported penetrance of
Spain. Forty percent for p.Arg122Cys [
France. Ninety-three percent for p.Asn29Ile and p.Arg122His [
England. Eighty percent [
Europe. Forty-three percent for p.Ala16Val [
United States. Eighty percent for p.Asn29Ile and p.Arg122His [
In some instances, hereditary pancreatitis has been referred to as chronic calcific pancreatitis, familial pancreatitis, or recurrent or relapsing acute or chronic pancreatitis; however, these are nonspecific clinical diagnoses and do not describe the etiology of the disorder.
"Hereditary pancreatitis" is generally reserved for individuals and families with germline highly penetrant heterozygous gain-of-function variants in
"Familial pancreatitis" is used to describe kindreds with two or more closely related individuals (up to second-degree relatives) with pancreatitis. Other causes of pancreatitis must be excluded, including
A report from France estimated a population prevalence of 0.3:100,000 persons with
In Germany, 5% of individuals with CP had
In Denmark, of 12.4% of persons initially classified as having idiopathic acute and chronic pancreatitis, 9% were found to have a
In Spain, 7.7% of individuals with CP had
In the North American Pancreatitis Study II, about 5% of individuals had
Among children with pancreatitis, the incidence of
In the INSPPIRE cohort of 301 children primarily from the United States, 17% of individuals with recurrent AP and 46% of children with CP had a
In the ExAC database, the
• Episodic or continuous mild-to-severe abdominal pain. Pain is usually sharp and stabbing in initial attacks, becoming deep and burning as the syndrome progresses. The most psychologically distressing pain is constant chronic pain, regardless of intensity [
• Exocrine pancreatic insufficiency leading to maldigestion with symptoms of gas and bloating and the appearance of diarrhea, oil in the stool (steatorrhea), and/or floating stools. Other signs of maldigestion include weight loss, fat-soluble-vitamin deficiency, and protein deficiency with low albumin, prealbumin, or retinol-binding protein detected on blood testing.
• Diabetes mellitus (DM) (pancreatic endocrine insufficiency) manifesting initially as inappropriately elevated levels of blood glucose (glucose intolerance). Up to 48% of persons with
• Pain is often the most common and stressful complication of pancreatitis, although the severity of the pain experience is highly variable. An exploratory genome-wide association study suggested that much of the heterogeneity in pain severity and chronicity is related to genetic variants affecting proteins expressed in the pancreas, sensory nerves, spinal cord, and brain, and/or associated with psychiatric stress disorders [
• Other common symptoms with chronic pancreatitis include nighttime sweats, bloating, or cramping, greasy or oily stools, feeling cold, and gastroesophageal reflux disease [
• Spain. Forty percent for p.Arg122Cys [
• France. Ninety-three percent for p.Asn29Ile and p.Arg122His [
• England. Eighty percent [
• Europe. Forty-three percent for p.Ala16Val [
• United States. Eighty percent for p.Asn29Ile and p.Arg122His [
• In Germany, 5% of individuals with CP had
• In Denmark, of 12.4% of persons initially classified as having idiopathic acute and chronic pancreatitis, 9% were found to have a
• In Spain, 7.7% of individuals with CP had
• In the North American Pancreatitis Study II, about 5% of individuals had
• Among children with pancreatitis, the incidence of
• In the INSPPIRE cohort of 301 children primarily from the United States, 17% of individuals with recurrent AP and 46% of children with CP had a
## Clinical Description
In
Persons with
Long-standing inflammation results in complications that can include the following:
Episodic or continuous mild-to-severe abdominal pain. Pain is usually sharp and stabbing in initial attacks, becoming deep and burning as the syndrome progresses. The most psychologically distressing pain is constant chronic pain, regardless of intensity [
Exocrine pancreatic insufficiency leading to maldigestion with symptoms of gas and bloating and the appearance of diarrhea, oil in the stool (steatorrhea), and/or floating stools. Other signs of maldigestion include weight loss, fat-soluble-vitamin deficiency, and protein deficiency with low albumin, prealbumin, or retinol-binding protein detected on blood testing.
Diabetes mellitus (DM) (pancreatic endocrine insufficiency) manifesting initially as inappropriately elevated levels of blood glucose (glucose intolerance). Up to 48% of persons with
Pain is often the most common and stressful complication of pancreatitis, although the severity of the pain experience is highly variable. An exploratory genome-wide association study suggested that much of the heterogeneity in pain severity and chronicity is related to genetic variants affecting proteins expressed in the pancreas, sensory nerves, spinal cord, and brain, and/or associated with psychiatric stress disorders [
Other common symptoms with chronic pancreatitis include nighttime sweats, bloating, or cramping, greasy or oily stools, feeling cold, and gastroesophageal reflux disease [
• Episodic or continuous mild-to-severe abdominal pain. Pain is usually sharp and stabbing in initial attacks, becoming deep and burning as the syndrome progresses. The most psychologically distressing pain is constant chronic pain, regardless of intensity [
• Exocrine pancreatic insufficiency leading to maldigestion with symptoms of gas and bloating and the appearance of diarrhea, oil in the stool (steatorrhea), and/or floating stools. Other signs of maldigestion include weight loss, fat-soluble-vitamin deficiency, and protein deficiency with low albumin, prealbumin, or retinol-binding protein detected on blood testing.
• Diabetes mellitus (DM) (pancreatic endocrine insufficiency) manifesting initially as inappropriately elevated levels of blood glucose (glucose intolerance). Up to 48% of persons with
• Pain is often the most common and stressful complication of pancreatitis, although the severity of the pain experience is highly variable. An exploratory genome-wide association study suggested that much of the heterogeneity in pain severity and chronicity is related to genetic variants affecting proteins expressed in the pancreas, sensory nerves, spinal cord, and brain, and/or associated with psychiatric stress disorders [
• Other common symptoms with chronic pancreatitis include nighttime sweats, bloating, or cramping, greasy or oily stools, feeling cold, and gastroesophageal reflux disease [
## Genotype-Phenotype Correlations
Note: Other
## Penetrance
The reported penetrance of
Spain. Forty percent for p.Arg122Cys [
France. Ninety-three percent for p.Asn29Ile and p.Arg122His [
England. Eighty percent [
Europe. Forty-three percent for p.Ala16Val [
United States. Eighty percent for p.Asn29Ile and p.Arg122His [
• Spain. Forty percent for p.Arg122Cys [
• France. Ninety-three percent for p.Asn29Ile and p.Arg122His [
• England. Eighty percent [
• Europe. Forty-three percent for p.Ala16Val [
• United States. Eighty percent for p.Asn29Ile and p.Arg122His [
## Nomenclature
In some instances, hereditary pancreatitis has been referred to as chronic calcific pancreatitis, familial pancreatitis, or recurrent or relapsing acute or chronic pancreatitis; however, these are nonspecific clinical diagnoses and do not describe the etiology of the disorder.
"Hereditary pancreatitis" is generally reserved for individuals and families with germline highly penetrant heterozygous gain-of-function variants in
"Familial pancreatitis" is used to describe kindreds with two or more closely related individuals (up to second-degree relatives) with pancreatitis. Other causes of pancreatitis must be excluded, including
## Prevalence
A report from France estimated a population prevalence of 0.3:100,000 persons with
In Germany, 5% of individuals with CP had
In Denmark, of 12.4% of persons initially classified as having idiopathic acute and chronic pancreatitis, 9% were found to have a
In Spain, 7.7% of individuals with CP had
In the North American Pancreatitis Study II, about 5% of individuals had
Among children with pancreatitis, the incidence of
In the INSPPIRE cohort of 301 children primarily from the United States, 17% of individuals with recurrent AP and 46% of children with CP had a
In the ExAC database, the
• In Germany, 5% of individuals with CP had
• In Denmark, of 12.4% of persons initially classified as having idiopathic acute and chronic pancreatitis, 9% were found to have a
• In Spain, 7.7% of individuals with CP had
• In the North American Pancreatitis Study II, about 5% of individuals had
• Among children with pancreatitis, the incidence of
• In the INSPPIRE cohort of 301 children primarily from the United States, 17% of individuals with recurrent AP and 46% of children with CP had a
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The morphologic features and laboratory findings of
See Pancreatitis Overview,
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Referral to a gastroenterologist for evaluation of pancreatic exocrine function using invasive or noninvasive testing
Fecal elastase-1 analysis can be falsely positive with diarrhea but can be used while an individual is taking pancreatic enzyme replacement therapy. This test is insensitive for mild pancreatic exocrine insufficiency [
Secretin-stimulated pancreatic bicarbonate secretion testing requires intubation of the duodenum and careful measure of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive but only assesses duct function.
An American Gastroenterological Association Clinical Practice Update on the epidemiology, evaluation, and management of exocrine pancreatic insufficiency has been published [
Abdominal imaging is an important tool for determining the stage and complications of pancreatic disease. Standards for reporting and reviewing abdominal images have been published [
Referral to an endocrinologist for evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance). Diabetes mellitus (DM) can occur in nearly half of all individuals with pancreatitis, and early evaluation and management remains important, since many risk factors that overlap with type 2 DM are manageable.
Referral to a pancreatic cancer surveillance program in persons with chronic pancreatitis (CP) and/or risk factors for pancreatic cancer (e.g., age >40 years, family history of pancreatic cancer, history of smoking)
Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, and/or genetics advanced practice provider (nurse practitioner or physician assistant)
Medical treatment and management for
Treatment of acute pancreatitis (AP) usually focuses on acute fluid and pain management. Discontinuation of smoking and alcohol use reduces the frequency of recurrent attacks, slows the rate of progression, and decreases the likelihood of complications, including DM and pancreatic cancer [
Analgesics are offered when pancreatic enzyme replacement therapy is not sufficient to control pain.
Antioxidants have been reported to improve pain control in a few individuals with HP. In India, antioxidant treatment was associated with better pain control and outcomes [
Endoscopic or surgical interventions may be useful for treating obstructive pain [
Total pancreatectomy with islet autotransplantation (TPIAT) may be considered in individuals with severe pain and/or inflammation that cannot be controlled by other approaches. Efficacy increases when this is done approximately two years before chronic pain develops [
In addition to severe pain, endoscopic and surgical interventions are reserved for complications such as pseudocysts, bile duct or duodenal obstruction, infected pancreatic necrosis, and malignancy.
Although a variety of surgical approaches are used for non-cancerous pancreatic disorders that cause pain or obstruction from multiple strictures, pancreatic drainage surgeries in those with HP are unlikely to stop the underlying inflammatory process. Furthermore, pancreatic surgery often reduces the number of islet cells, which are essential in pancreatic endocrine function [
Treatment of CP focuses on improving quality of life by managing pancreatic pain, maldigestion, and DM.
One small study from Italy suggested that vitamins and antioxidants reduced pain in
Pain from maldigestion is improved with pancreatic digestive enzymes [
If the main pancreatic duct is obstructed, a trial of endoscopic treatment is often used for diagnostic, therapeutic, and prognostic reasons in determining longer-term therapy.
Surgery has been reported to be helpful by many individuals; however, surgical approaches should be postponed if islet autotransplantation is being considered.
Several expert groups are offering TPIAT in an effort to both control severe pain and delay the development of DM [
Psychiatric stress disorders are being recognized as a major driver of severe pain experiences [
Pancreatic enzyme replacement therapy improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea (fat in the stool), and/or diarrhea [
The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU, and 1 IU = 3 USP units.) Since a minimum of 10% of normal pancreatic enzyme output is needed to digest a meal, about 70,000-80,000 USP units of lipase are required for an average-sized adult (70 kg) with total pancreatic insufficiency. The amount can be reduced for smaller persons and those with residual pancreatic exocrine function while monitoring symptoms and nutritional parameters [
Monitor for glucose intolerance.
Optimize nutrient digestion with pancreatic enzyme replacement therapy to stimulate foregut hormone release and minimize hindgut hormone release. Metformin is recommended as an oral antidiabetic agent [
Synchronize the digestion and absorption of nutrients with insulin therapy delivery, with special attention to hypoglycemia resulting from loss of glucagon cells [
The ability to prevent the primary manifestations of
Surveillance for pancreatic cancer may benefit individuals with
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing for the
It is of key importance to teach young individuals who are heterozygous for a
See
A recognition of the need for new treatments and the challenges in developing classic pharmaceutical trials for rare diseases led to an NIH workshop during PancreasFest 2018 [
Search
• Referral to a gastroenterologist for evaluation of pancreatic exocrine function using invasive or noninvasive testing
• Fecal elastase-1 analysis can be falsely positive with diarrhea but can be used while an individual is taking pancreatic enzyme replacement therapy. This test is insensitive for mild pancreatic exocrine insufficiency [
• Secretin-stimulated pancreatic bicarbonate secretion testing requires intubation of the duodenum and careful measure of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive but only assesses duct function.
• An American Gastroenterological Association Clinical Practice Update on the epidemiology, evaluation, and management of exocrine pancreatic insufficiency has been published [
• Abdominal imaging is an important tool for determining the stage and complications of pancreatic disease. Standards for reporting and reviewing abdominal images have been published [
• Referral to an endocrinologist for evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance). Diabetes mellitus (DM) can occur in nearly half of all individuals with pancreatitis, and early evaluation and management remains important, since many risk factors that overlap with type 2 DM are manageable.
• Referral to a pancreatic cancer surveillance program in persons with chronic pancreatitis (CP) and/or risk factors for pancreatic cancer (e.g., age >40 years, family history of pancreatic cancer, history of smoking)
• Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, and/or genetics advanced practice provider (nurse practitioner or physician assistant)
• Analgesics are offered when pancreatic enzyme replacement therapy is not sufficient to control pain.
• Antioxidants have been reported to improve pain control in a few individuals with HP. In India, antioxidant treatment was associated with better pain control and outcomes [
• Endoscopic or surgical interventions may be useful for treating obstructive pain [
• Total pancreatectomy with islet autotransplantation (TPIAT) may be considered in individuals with severe pain and/or inflammation that cannot be controlled by other approaches. Efficacy increases when this is done approximately two years before chronic pain develops [
• One small study from Italy suggested that vitamins and antioxidants reduced pain in
• Pain from maldigestion is improved with pancreatic digestive enzymes [
• If the main pancreatic duct is obstructed, a trial of endoscopic treatment is often used for diagnostic, therapeutic, and prognostic reasons in determining longer-term therapy.
• Surgery has been reported to be helpful by many individuals; however, surgical approaches should be postponed if islet autotransplantation is being considered.
• Several expert groups are offering TPIAT in an effort to both control severe pain and delay the development of DM [
• Psychiatric stress disorders are being recognized as a major driver of severe pain experiences [
• Pancreatic enzyme replacement therapy improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea (fat in the stool), and/or diarrhea [
• The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU, and 1 IU = 3 USP units.) Since a minimum of 10% of normal pancreatic enzyme output is needed to digest a meal, about 70,000-80,000 USP units of lipase are required for an average-sized adult (70 kg) with total pancreatic insufficiency. The amount can be reduced for smaller persons and those with residual pancreatic exocrine function while monitoring symptoms and nutritional parameters [
• Monitor for glucose intolerance.
• Optimize nutrient digestion with pancreatic enzyme replacement therapy to stimulate foregut hormone release and minimize hindgut hormone release. Metformin is recommended as an oral antidiabetic agent [
• Synchronize the digestion and absorption of nutrients with insulin therapy delivery, with special attention to hypoglycemia resulting from loss of glucagon cells [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Referral to a gastroenterologist for evaluation of pancreatic exocrine function using invasive or noninvasive testing
Fecal elastase-1 analysis can be falsely positive with diarrhea but can be used while an individual is taking pancreatic enzyme replacement therapy. This test is insensitive for mild pancreatic exocrine insufficiency [
Secretin-stimulated pancreatic bicarbonate secretion testing requires intubation of the duodenum and careful measure of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive but only assesses duct function.
An American Gastroenterological Association Clinical Practice Update on the epidemiology, evaluation, and management of exocrine pancreatic insufficiency has been published [
Abdominal imaging is an important tool for determining the stage and complications of pancreatic disease. Standards for reporting and reviewing abdominal images have been published [
Referral to an endocrinologist for evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance). Diabetes mellitus (DM) can occur in nearly half of all individuals with pancreatitis, and early evaluation and management remains important, since many risk factors that overlap with type 2 DM are manageable.
Referral to a pancreatic cancer surveillance program in persons with chronic pancreatitis (CP) and/or risk factors for pancreatic cancer (e.g., age >40 years, family history of pancreatic cancer, history of smoking)
Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, and/or genetics advanced practice provider (nurse practitioner or physician assistant)
• Referral to a gastroenterologist for evaluation of pancreatic exocrine function using invasive or noninvasive testing
• Fecal elastase-1 analysis can be falsely positive with diarrhea but can be used while an individual is taking pancreatic enzyme replacement therapy. This test is insensitive for mild pancreatic exocrine insufficiency [
• Secretin-stimulated pancreatic bicarbonate secretion testing requires intubation of the duodenum and careful measure of pancreatic bicarbonate secretion over about an hour (depending on the method). It is considered very sensitive but only assesses duct function.
• An American Gastroenterological Association Clinical Practice Update on the epidemiology, evaluation, and management of exocrine pancreatic insufficiency has been published [
• Abdominal imaging is an important tool for determining the stage and complications of pancreatic disease. Standards for reporting and reviewing abdominal images have been published [
• Referral to an endocrinologist for evaluation of pancreatic endocrine function (i.e., assessment of glucose tolerance). Diabetes mellitus (DM) can occur in nearly half of all individuals with pancreatitis, and early evaluation and management remains important, since many risk factors that overlap with type 2 DM are manageable.
• Referral to a pancreatic cancer surveillance program in persons with chronic pancreatitis (CP) and/or risk factors for pancreatic cancer (e.g., age >40 years, family history of pancreatic cancer, history of smoking)
• Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, and/or genetics advanced practice provider (nurse practitioner or physician assistant)
## Treatment of Manifestations
Medical treatment and management for
Treatment of acute pancreatitis (AP) usually focuses on acute fluid and pain management. Discontinuation of smoking and alcohol use reduces the frequency of recurrent attacks, slows the rate of progression, and decreases the likelihood of complications, including DM and pancreatic cancer [
Analgesics are offered when pancreatic enzyme replacement therapy is not sufficient to control pain.
Antioxidants have been reported to improve pain control in a few individuals with HP. In India, antioxidant treatment was associated with better pain control and outcomes [
Endoscopic or surgical interventions may be useful for treating obstructive pain [
Total pancreatectomy with islet autotransplantation (TPIAT) may be considered in individuals with severe pain and/or inflammation that cannot be controlled by other approaches. Efficacy increases when this is done approximately two years before chronic pain develops [
In addition to severe pain, endoscopic and surgical interventions are reserved for complications such as pseudocysts, bile duct or duodenal obstruction, infected pancreatic necrosis, and malignancy.
Although a variety of surgical approaches are used for non-cancerous pancreatic disorders that cause pain or obstruction from multiple strictures, pancreatic drainage surgeries in those with HP are unlikely to stop the underlying inflammatory process. Furthermore, pancreatic surgery often reduces the number of islet cells, which are essential in pancreatic endocrine function [
Treatment of CP focuses on improving quality of life by managing pancreatic pain, maldigestion, and DM.
One small study from Italy suggested that vitamins and antioxidants reduced pain in
Pain from maldigestion is improved with pancreatic digestive enzymes [
If the main pancreatic duct is obstructed, a trial of endoscopic treatment is often used for diagnostic, therapeutic, and prognostic reasons in determining longer-term therapy.
Surgery has been reported to be helpful by many individuals; however, surgical approaches should be postponed if islet autotransplantation is being considered.
Several expert groups are offering TPIAT in an effort to both control severe pain and delay the development of DM [
Psychiatric stress disorders are being recognized as a major driver of severe pain experiences [
Pancreatic enzyme replacement therapy improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea (fat in the stool), and/or diarrhea [
The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU, and 1 IU = 3 USP units.) Since a minimum of 10% of normal pancreatic enzyme output is needed to digest a meal, about 70,000-80,000 USP units of lipase are required for an average-sized adult (70 kg) with total pancreatic insufficiency. The amount can be reduced for smaller persons and those with residual pancreatic exocrine function while monitoring symptoms and nutritional parameters [
Monitor for glucose intolerance.
Optimize nutrient digestion with pancreatic enzyme replacement therapy to stimulate foregut hormone release and minimize hindgut hormone release. Metformin is recommended as an oral antidiabetic agent [
Synchronize the digestion and absorption of nutrients with insulin therapy delivery, with special attention to hypoglycemia resulting from loss of glucagon cells [
• Analgesics are offered when pancreatic enzyme replacement therapy is not sufficient to control pain.
• Antioxidants have been reported to improve pain control in a few individuals with HP. In India, antioxidant treatment was associated with better pain control and outcomes [
• Endoscopic or surgical interventions may be useful for treating obstructive pain [
• Total pancreatectomy with islet autotransplantation (TPIAT) may be considered in individuals with severe pain and/or inflammation that cannot be controlled by other approaches. Efficacy increases when this is done approximately two years before chronic pain develops [
• One small study from Italy suggested that vitamins and antioxidants reduced pain in
• Pain from maldigestion is improved with pancreatic digestive enzymes [
• If the main pancreatic duct is obstructed, a trial of endoscopic treatment is often used for diagnostic, therapeutic, and prognostic reasons in determining longer-term therapy.
• Surgery has been reported to be helpful by many individuals; however, surgical approaches should be postponed if islet autotransplantation is being considered.
• Several expert groups are offering TPIAT in an effort to both control severe pain and delay the development of DM [
• Psychiatric stress disorders are being recognized as a major driver of severe pain experiences [
• Pancreatic enzyme replacement therapy improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea (fat in the stool), and/or diarrhea [
• The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU, and 1 IU = 3 USP units.) Since a minimum of 10% of normal pancreatic enzyme output is needed to digest a meal, about 70,000-80,000 USP units of lipase are required for an average-sized adult (70 kg) with total pancreatic insufficiency. The amount can be reduced for smaller persons and those with residual pancreatic exocrine function while monitoring symptoms and nutritional parameters [
• Monitor for glucose intolerance.
• Optimize nutrient digestion with pancreatic enzyme replacement therapy to stimulate foregut hormone release and minimize hindgut hormone release. Metformin is recommended as an oral antidiabetic agent [
• Synchronize the digestion and absorption of nutrients with insulin therapy delivery, with special attention to hypoglycemia resulting from loss of glucagon cells [
## Acute Pancreatitis
Treatment of acute pancreatitis (AP) usually focuses on acute fluid and pain management. Discontinuation of smoking and alcohol use reduces the frequency of recurrent attacks, slows the rate of progression, and decreases the likelihood of complications, including DM and pancreatic cancer [
Analgesics are offered when pancreatic enzyme replacement therapy is not sufficient to control pain.
Antioxidants have been reported to improve pain control in a few individuals with HP. In India, antioxidant treatment was associated with better pain control and outcomes [
Endoscopic or surgical interventions may be useful for treating obstructive pain [
Total pancreatectomy with islet autotransplantation (TPIAT) may be considered in individuals with severe pain and/or inflammation that cannot be controlled by other approaches. Efficacy increases when this is done approximately two years before chronic pain develops [
In addition to severe pain, endoscopic and surgical interventions are reserved for complications such as pseudocysts, bile duct or duodenal obstruction, infected pancreatic necrosis, and malignancy.
Although a variety of surgical approaches are used for non-cancerous pancreatic disorders that cause pain or obstruction from multiple strictures, pancreatic drainage surgeries in those with HP are unlikely to stop the underlying inflammatory process. Furthermore, pancreatic surgery often reduces the number of islet cells, which are essential in pancreatic endocrine function [
• Analgesics are offered when pancreatic enzyme replacement therapy is not sufficient to control pain.
• Antioxidants have been reported to improve pain control in a few individuals with HP. In India, antioxidant treatment was associated with better pain control and outcomes [
• Endoscopic or surgical interventions may be useful for treating obstructive pain [
• Total pancreatectomy with islet autotransplantation (TPIAT) may be considered in individuals with severe pain and/or inflammation that cannot be controlled by other approaches. Efficacy increases when this is done approximately two years before chronic pain develops [
## Chronic Pancreatitis
Treatment of CP focuses on improving quality of life by managing pancreatic pain, maldigestion, and DM.
One small study from Italy suggested that vitamins and antioxidants reduced pain in
Pain from maldigestion is improved with pancreatic digestive enzymes [
If the main pancreatic duct is obstructed, a trial of endoscopic treatment is often used for diagnostic, therapeutic, and prognostic reasons in determining longer-term therapy.
Surgery has been reported to be helpful by many individuals; however, surgical approaches should be postponed if islet autotransplantation is being considered.
Several expert groups are offering TPIAT in an effort to both control severe pain and delay the development of DM [
Psychiatric stress disorders are being recognized as a major driver of severe pain experiences [
Pancreatic enzyme replacement therapy improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea (fat in the stool), and/or diarrhea [
The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU, and 1 IU = 3 USP units.) Since a minimum of 10% of normal pancreatic enzyme output is needed to digest a meal, about 70,000-80,000 USP units of lipase are required for an average-sized adult (70 kg) with total pancreatic insufficiency. The amount can be reduced for smaller persons and those with residual pancreatic exocrine function while monitoring symptoms and nutritional parameters [
Monitor for glucose intolerance.
Optimize nutrient digestion with pancreatic enzyme replacement therapy to stimulate foregut hormone release and minimize hindgut hormone release. Metformin is recommended as an oral antidiabetic agent [
Synchronize the digestion and absorption of nutrients with insulin therapy delivery, with special attention to hypoglycemia resulting from loss of glucagon cells [
• One small study from Italy suggested that vitamins and antioxidants reduced pain in
• Pain from maldigestion is improved with pancreatic digestive enzymes [
• If the main pancreatic duct is obstructed, a trial of endoscopic treatment is often used for diagnostic, therapeutic, and prognostic reasons in determining longer-term therapy.
• Surgery has been reported to be helpful by many individuals; however, surgical approaches should be postponed if islet autotransplantation is being considered.
• Several expert groups are offering TPIAT in an effort to both control severe pain and delay the development of DM [
• Psychiatric stress disorders are being recognized as a major driver of severe pain experiences [
• Pancreatic enzyme replacement therapy improves digestion in those with pancreatic insufficiency who have pain with eating, steatorrhea (fat in the stool), and/or diarrhea [
• The amount of pancreatic enzyme replacement necessary depends on the diet and on the amount of residual pancreatic function (which diminishes over time). The normal amount of lipase secreted is about 750,000-1,000,000 units (USP) per meal. (Note that earlier papers used IU, and 1 IU = 3 USP units.) Since a minimum of 10% of normal pancreatic enzyme output is needed to digest a meal, about 70,000-80,000 USP units of lipase are required for an average-sized adult (70 kg) with total pancreatic insufficiency. The amount can be reduced for smaller persons and those with residual pancreatic exocrine function while monitoring symptoms and nutritional parameters [
• Monitor for glucose intolerance.
• Optimize nutrient digestion with pancreatic enzyme replacement therapy to stimulate foregut hormone release and minimize hindgut hormone release. Metformin is recommended as an oral antidiabetic agent [
• Synchronize the digestion and absorption of nutrients with insulin therapy delivery, with special attention to hypoglycemia resulting from loss of glucagon cells [
## Prevention of Primary Manifestations
The ability to prevent the primary manifestations of
## Surveillance
Surveillance for pancreatic cancer may benefit individuals with
## Agents/Circumstances to Avoid
## 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 by molecular genetic testing for the
It is of key importance to teach young individuals who are heterozygous for a
See
## Therapies Under Investigation
A recognition of the need for new treatments and the challenges in developing classic pharmaceutical trials for rare diseases led to an NIH workshop during PancreasFest 2018 [
Search
## Genetic Counseling
Hereditary pancreatitis (HP) caused by gain-of-function
Note: A number of other variants in the coding and noncoding regions of the
Many individuals diagnosed with
Some individuals diagnosed with
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, inform recurrence risk assessment, and determine their need for pancreatic cancer
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 has a
If the 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 1% because of the possibility of parental gonadal mosaicism [
If the parents have not been tested for the
See Management,
The impact of
Counseling must address the full age-related spectrum associated with
All family members at risk must be counseled about the known hypersensitivity of the pancreas to alcohol, the marked increased risk of pancreatic cancer with cigarette smoking, and the benefits of exercise and eating a healthy diet supplemented with vitamins and antioxidants.
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.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
• Some individuals diagnosed with
• 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, inform recurrence risk assessment, and determine their need for pancreatic cancer
• 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 has a
• If the 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 1% because of the possibility of parental gonadal mosaicism [
• If the parents have not been tested for the
• The impact of
• Counseling must address the full age-related spectrum associated with
• All family members at risk must be counseled about the known hypersensitivity of the pancreas to alcohol, the marked increased risk of pancreatic cancer with cigarette smoking, and the benefits of exercise and eating a healthy diet supplemented with vitamins and antioxidants.
• 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 pancreatitis (HP) caused by gain-of-function
Note: A number of other variants in the coding and noncoding regions of the
## Risk to Family Members
Many individuals diagnosed with
Some individuals diagnosed with
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, inform recurrence risk assessment, and determine their need for pancreatic cancer
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 has a
If the 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 1% because of the possibility of parental gonadal mosaicism [
If the parents have not been tested for the
• Many individuals diagnosed with
• Some individuals diagnosed with
• 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, inform recurrence risk assessment, and determine their need for pancreatic cancer
• 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 has a
• If the 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 1% because of the possibility of parental gonadal mosaicism [
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
The impact of
Counseling must address the full age-related spectrum associated with
All family members at risk must be counseled about the known hypersensitivity of the pancreas to alcohol, the marked increased risk of pancreatic cancer with cigarette smoking, and the benefits of exercise and eating a healthy diet supplemented with vitamins and antioxidants.
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.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 impact of
• Counseling must address the full age-related spectrum associated with
• All family members at risk must be counseled about the known hypersensitivity of the pancreas to alcohol, the marked increased risk of pancreatic cancer with cigarette smoking, and the benefits of exercise and eating a healthy diet supplemented with vitamins and antioxidants.
• 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
The National Pancreas Foundation
•
•
•
•
•
• The National Pancreas Foundation
•
•
•
•
•
## Molecular Genetics
PRSS1-Related Hereditary Pancreatitis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for PRSS1-Related Hereditary Pancreatitis (
Three trypsinogens are synthesized by the pancreas as digestive enzymes [
Cationic trypsinogen (two thirds of trypsinogens), encoded by
Anionic trypsinogen (one third of trypsinogens), encoded by
Mesotrypsinogen (<5% of trypsinogens), encoded by
Trypsinogens are expressed as a pre-propeptide that is processed to trypsinogen by cleavage of a signal peptide. Trypsinogen is activated to trypsin by cleavage of an eight-amino-acid trypsinogen activation peptide (TAP), which is typically initiated in the intestine by the action of enterokinase. The TAP can also be cleaved by trypsin in the presence of calcium and association with a binding site formed in the activation region. Trypsin is an endopeptidase that cleaves peptide chains following an arginine or lysine residue that also serves as the master activator of pancreatic zymogens by cleaving the activation peptide of most major digestive enzymes made by the pancreas.
Trypsinogen has a second calcium-binding site that persists in trypsin which, when occupied by calcium, prevents trypsin autolysis at p.Arg122 and degradation by chymotrypsin C (CTRC) binding at p.Leu81 [
Gain-of-function variants increase conversion of trypsinogen to active trypsin, or reduce the degradation of active trypsin; thus, the amount of active, intrapancreatic trypsin is increased. Active intrapancreatic trypsin may activate other zymogens (preactivated digestive enzymes), cross-activate the immune system, and/or cause direct injury [
The effect of premature trypsin activation may be accentuated by loss of function in modifier genes, including the genes encoding the following proteins [
Pancreatic secretory trypsin inhibitor (encoded by
Chymotrypsin C (
Calcium-sensing receptor (
Cystic fibrosis transmembrane conductance regulator (
This suggestion is based on the observation that the non-
Copy number variants, including duplication of
High-penetrance pathogenic variants
Together these variants account for ~90% of persons w/molecularly confirmed
CP = chronic pancreatitis; HP = hereditary pancreatitis; SNPs = single nucleotide polymorphisms
Variants listed in the table have been provided by the author.
• Cationic trypsinogen (two thirds of trypsinogens), encoded by
• Anionic trypsinogen (one third of trypsinogens), encoded by
• Mesotrypsinogen (<5% of trypsinogens), encoded by
• Pancreatic secretory trypsin inhibitor (encoded by
• Chymotrypsin C (
• Calcium-sensing receptor (
• Cystic fibrosis transmembrane conductance regulator (
• High-penetrance pathogenic variants
• Together these variants account for ~90% of persons w/molecularly confirmed
## Molecular Pathogenesis
Three trypsinogens are synthesized by the pancreas as digestive enzymes [
Cationic trypsinogen (two thirds of trypsinogens), encoded by
Anionic trypsinogen (one third of trypsinogens), encoded by
Mesotrypsinogen (<5% of trypsinogens), encoded by
Trypsinogens are expressed as a pre-propeptide that is processed to trypsinogen by cleavage of a signal peptide. Trypsinogen is activated to trypsin by cleavage of an eight-amino-acid trypsinogen activation peptide (TAP), which is typically initiated in the intestine by the action of enterokinase. The TAP can also be cleaved by trypsin in the presence of calcium and association with a binding site formed in the activation region. Trypsin is an endopeptidase that cleaves peptide chains following an arginine or lysine residue that also serves as the master activator of pancreatic zymogens by cleaving the activation peptide of most major digestive enzymes made by the pancreas.
Trypsinogen has a second calcium-binding site that persists in trypsin which, when occupied by calcium, prevents trypsin autolysis at p.Arg122 and degradation by chymotrypsin C (CTRC) binding at p.Leu81 [
Gain-of-function variants increase conversion of trypsinogen to active trypsin, or reduce the degradation of active trypsin; thus, the amount of active, intrapancreatic trypsin is increased. Active intrapancreatic trypsin may activate other zymogens (preactivated digestive enzymes), cross-activate the immune system, and/or cause direct injury [
The effect of premature trypsin activation may be accentuated by loss of function in modifier genes, including the genes encoding the following proteins [
Pancreatic secretory trypsin inhibitor (encoded by
Chymotrypsin C (
Calcium-sensing receptor (
Cystic fibrosis transmembrane conductance regulator (
This suggestion is based on the observation that the non-
Copy number variants, including duplication of
High-penetrance pathogenic variants
Together these variants account for ~90% of persons w/molecularly confirmed
CP = chronic pancreatitis; HP = hereditary pancreatitis; SNPs = single nucleotide polymorphisms
Variants listed in the table have been provided by the author.
• Cationic trypsinogen (two thirds of trypsinogens), encoded by
• Anionic trypsinogen (one third of trypsinogens), encoded by
• Mesotrypsinogen (<5% of trypsinogens), encoded by
• Pancreatic secretory trypsin inhibitor (encoded by
• Chymotrypsin C (
• Calcium-sensing receptor (
• Cystic fibrosis transmembrane conductance regulator (
• High-penetrance pathogenic variants
• Together these variants account for ~90% of persons w/molecularly confirmed
## Chapter Notes
David Whitcomb recently retired from the University of Pittsburgh (he is emeritus professor and still involved with the program). Dr Whitcomb also started Ariel Precision Medicine, which does genetic testing for hereditary pancreatitis and other forms of pancreatitis and their complications (including pancreatic cancer risks). Finally, Dr Whitcomb started SMART-MD Journal of Precision Medicine (
Jessica LaRusch, PhD; Ariel Precision Medicine (2012-2025)Celeste Shelton, MS, CGC, PhD; Ariel Precision Medicine (2019-2025)Sheila Solomon, MS, CGC; GeneDx (2012-2025)David C Whitcomb, MD, PhD (2012-present)
27 March 2025 (sw) Comprehensive update posted live
25 April 2019 (sw) Comprehensive update posted live
1 March 2012 (me) Review posted live
5 August 2011 (ss) Initial submission
• 27 March 2025 (sw) Comprehensive update posted live
• 25 April 2019 (sw) Comprehensive update posted live
• 1 March 2012 (me) Review posted live
• 5 August 2011 (ss) Initial submission
## Author Notes
David Whitcomb recently retired from the University of Pittsburgh (he is emeritus professor and still involved with the program). Dr Whitcomb also started Ariel Precision Medicine, which does genetic testing for hereditary pancreatitis and other forms of pancreatitis and their complications (including pancreatic cancer risks). Finally, Dr Whitcomb started SMART-MD Journal of Precision Medicine (
## Author History
Jessica LaRusch, PhD; Ariel Precision Medicine (2012-2025)Celeste Shelton, MS, CGC, PhD; Ariel Precision Medicine (2019-2025)Sheila Solomon, MS, CGC; GeneDx (2012-2025)David C Whitcomb, MD, PhD (2012-present)
## Revision History
27 March 2025 (sw) Comprehensive update posted live
25 April 2019 (sw) Comprehensive update posted live
1 March 2012 (me) Review posted live
5 August 2011 (ss) Initial submission
• 27 March 2025 (sw) Comprehensive update posted live
• 25 April 2019 (sw) Comprehensive update posted live
• 1 March 2012 (me) Review posted live
• 5 August 2011 (ss) Initial submission
## References
Ellis I, Lerch MM, Whitcomb DC; Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology. Genetic testing for hereditary pancreatitis: guidelines for indications, counseling, consent and privacy issues. Pancreatology. 2001;1:405-15. [
Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am. 2007;36:325-33. [
• Ellis I, Lerch MM, Whitcomb DC; Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology. Genetic testing for hereditary pancreatitis: guidelines for indications, counseling, consent and privacy issues. Pancreatology. 2001;1:405-15. [
• Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am. 2007;36:325-33. [
## Published Guidelines / Consensus Statements
Ellis I, Lerch MM, Whitcomb DC; Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology. Genetic testing for hereditary pancreatitis: guidelines for indications, counseling, consent and privacy issues. Pancreatology. 2001;1:405-15. [
Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am. 2007;36:325-33. [
• Ellis I, Lerch MM, Whitcomb DC; Consensus Committees of the European Registry of Hereditary Pancreatic Diseases, Midwest Multi-Center Pancreatic Study Group, International Association of Pancreatology. Genetic testing for hereditary pancreatitis: guidelines for indications, counseling, consent and privacy issues. Pancreatology. 2001;1:405-15. [
• Fink EN, Kant JA, Whitcomb DC. Genetic counseling for nonsyndromic pancreatitis. Gastroenterol Clin North Am. 2007;36:325-33. [
## Literature Cited
|
[] |
1/3/2012
|
27/3/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
psach
|
psach
|
[
"Pseudoachondroplasia (PSACH)",
"Pseudoachondroplasia (PSACH)",
"Cartilage oligomeric matrix protein",
"COMP",
"COMP-Related Pseudoachondroplasia"
] |
Michael D Briggs, Michael J Wright
|
Summary The diagnosis of
|
## Diagnosis
Normal length at birth
Normal facies
Waddling gait, recognized at the onset of walking
Decline in growth rate to below the standard growth curve by approximately age two years, leading to moderately severe disproportionate short-limb short stature
Moderate brachydactyly
Ligamentous laxity and joint hyperextensibility, particularly in the hands, knees, and ankles
Mild myopathy reported for some individuals
Restricted extension at the elbows and hips
Valgus, varus, or windswept deformity of the lower limbs
Mild scoliosis
Lumbar lordosis (~50% of affected individuals)
Joint pain during childhood, particularly in the large joints of the lower extremities; may be the presenting symptom in mildly affected individuals
Delayed epiphyseal ossification with irregular epiphyses and metaphyses of the long bones (consistent)
Small capital femoral epiphyses, short femoral necks, and irregular, flared metaphyseal borders; small pelvis and poorly modeled acetabulae with irregular margins that may be sclerotic, especially in older individuals
Significant brachydactyly; short metacarpals and phalanges that show small or cone-shaped epiphyses and irregular metaphyses; small, irregular carpal bones
Anterior beaking or tonguing of the vertebral bodies on lateral view. This distinctive appearance of the vertebrae normalizes with age, emphasizing the importance of obtaining in childhood the radiographs to be used in diagnosis (see
The diagnosis of
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
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.
• Normal length at birth
• Normal facies
• Waddling gait, recognized at the onset of walking
• Decline in growth rate to below the standard growth curve by approximately age two years, leading to moderately severe disproportionate short-limb short stature
• Moderate brachydactyly
• Ligamentous laxity and joint hyperextensibility, particularly in the hands, knees, and ankles
• Mild myopathy reported for some individuals
• Restricted extension at the elbows and hips
• Valgus, varus, or windswept deformity of the lower limbs
• Mild scoliosis
• Lumbar lordosis (~50% of affected individuals)
• Joint pain during childhood, particularly in the large joints of the lower extremities; may be the presenting symptom in mildly affected individuals
• Delayed epiphyseal ossification with irregular epiphyses and metaphyses of the long bones (consistent)
• Small capital femoral epiphyses, short femoral necks, and irregular, flared metaphyseal borders; small pelvis and poorly modeled acetabulae with irregular margins that may be sclerotic, especially in older individuals
• Significant brachydactyly; short metacarpals and phalanges that show small or cone-shaped epiphyses and irregular metaphyses; small, irregular carpal bones
• Anterior beaking or tonguing of the vertebral bodies on lateral view. This distinctive appearance of the vertebrae normalizes with age, emphasizing the importance of obtaining in childhood the radiographs to be used in diagnosis (see
• For an introduction to multigene panels click
## Suggestive Findings
Normal length at birth
Normal facies
Waddling gait, recognized at the onset of walking
Decline in growth rate to below the standard growth curve by approximately age two years, leading to moderately severe disproportionate short-limb short stature
Moderate brachydactyly
Ligamentous laxity and joint hyperextensibility, particularly in the hands, knees, and ankles
Mild myopathy reported for some individuals
Restricted extension at the elbows and hips
Valgus, varus, or windswept deformity of the lower limbs
Mild scoliosis
Lumbar lordosis (~50% of affected individuals)
Joint pain during childhood, particularly in the large joints of the lower extremities; may be the presenting symptom in mildly affected individuals
Delayed epiphyseal ossification with irregular epiphyses and metaphyses of the long bones (consistent)
Small capital femoral epiphyses, short femoral necks, and irregular, flared metaphyseal borders; small pelvis and poorly modeled acetabulae with irregular margins that may be sclerotic, especially in older individuals
Significant brachydactyly; short metacarpals and phalanges that show small or cone-shaped epiphyses and irregular metaphyses; small, irregular carpal bones
Anterior beaking or tonguing of the vertebral bodies on lateral view. This distinctive appearance of the vertebrae normalizes with age, emphasizing the importance of obtaining in childhood the radiographs to be used in diagnosis (see
• Normal length at birth
• Normal facies
• Waddling gait, recognized at the onset of walking
• Decline in growth rate to below the standard growth curve by approximately age two years, leading to moderately severe disproportionate short-limb short stature
• Moderate brachydactyly
• Ligamentous laxity and joint hyperextensibility, particularly in the hands, knees, and ankles
• Mild myopathy reported for some individuals
• Restricted extension at the elbows and hips
• Valgus, varus, or windswept deformity of the lower limbs
• Mild scoliosis
• Lumbar lordosis (~50% of affected individuals)
• Joint pain during childhood, particularly in the large joints of the lower extremities; may be the presenting symptom in mildly affected individuals
• Delayed epiphyseal ossification with irregular epiphyses and metaphyses of the long bones (consistent)
• Small capital femoral epiphyses, short femoral necks, and irregular, flared metaphyseal borders; small pelvis and poorly modeled acetabulae with irregular margins that may be sclerotic, especially in older individuals
• Significant brachydactyly; short metacarpals and phalanges that show small or cone-shaped epiphyses and irregular metaphyses; small, irregular carpal bones
• Anterior beaking or tonguing of the vertebral bodies on lateral view. This distinctive appearance of the vertebrae normalizes with age, emphasizing the importance of obtaining in childhood the radiographs to be used in diagnosis (see
## Establishing the Diagnosis
The diagnosis of
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
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.
• For an introduction to multigene panels click
## Clinical Characteristics
Some individuals have mild myopathy.
A systematic analysis of the relationship between genotype and phenotype has been performed on 300 reported
Pathogenic missense variants of nucleotides encoding either the N- or C-type motifs within each of the type III calcium-binding domains showed no significant association with either the MED or the PSACH phenotype.
Pathogenic missense variants in nucleotides encoding the fourth and fifth (of 8 total) type III calcium-binding repeats (i.e., T3
Pathogenic missense variants in nucleotides encoding the sixth through eighth type III calcium-binding repeats (i.e., T3
The majority of pathogenic in-frame deletions, insertions, or indels were associated with PSACH (n=74; 82%), whereas a smaller proportion were associated with MED (n=16; 18%); however, in several instances, the same pathogenic variant was reported to cause both PSACH and MED [
Correlations from prior studies:
Individuals with a pathogenic variant in the seventh type III calcium-binding repeat are reported to have more severe short stature than those with pathogenic variants in the other type III repeats [
Individuals heterozygous for the common
Most type III calcium-binding repeats have both an N- and C-type motif (see
Penetrance is 100%.
In the past, four subtypes of pseudoachondroplasia, including dominant and recessive forms, were recognized under the term pseudoachondroplasia. The current classification recognizes a single, dominantly inherited phenotype referred to as
No firm data on the prevalence of
• Pathogenic missense variants of nucleotides encoding either the N- or C-type motifs within each of the type III calcium-binding domains showed no significant association with either the MED or the PSACH phenotype.
• Pathogenic missense variants in nucleotides encoding the fourth and fifth (of 8 total) type III calcium-binding repeats (i.e., T3
• Pathogenic missense variants in nucleotides encoding the sixth through eighth type III calcium-binding repeats (i.e., T3
• The majority of pathogenic in-frame deletions, insertions, or indels were associated with PSACH (n=74; 82%), whereas a smaller proportion were associated with MED (n=16; 18%); however, in several instances, the same pathogenic variant was reported to cause both PSACH and MED [
• Individuals with a pathogenic variant in the seventh type III calcium-binding repeat are reported to have more severe short stature than those with pathogenic variants in the other type III repeats [
• Individuals heterozygous for the common
• Most type III calcium-binding repeats have both an N- and C-type motif (see
## Clinical Description
Some individuals have mild myopathy.
## Genotype-Phenotype Correlations
A systematic analysis of the relationship between genotype and phenotype has been performed on 300 reported
Pathogenic missense variants of nucleotides encoding either the N- or C-type motifs within each of the type III calcium-binding domains showed no significant association with either the MED or the PSACH phenotype.
Pathogenic missense variants in nucleotides encoding the fourth and fifth (of 8 total) type III calcium-binding repeats (i.e., T3
Pathogenic missense variants in nucleotides encoding the sixth through eighth type III calcium-binding repeats (i.e., T3
The majority of pathogenic in-frame deletions, insertions, or indels were associated with PSACH (n=74; 82%), whereas a smaller proportion were associated with MED (n=16; 18%); however, in several instances, the same pathogenic variant was reported to cause both PSACH and MED [
Correlations from prior studies:
Individuals with a pathogenic variant in the seventh type III calcium-binding repeat are reported to have more severe short stature than those with pathogenic variants in the other type III repeats [
Individuals heterozygous for the common
Most type III calcium-binding repeats have both an N- and C-type motif (see
• Pathogenic missense variants of nucleotides encoding either the N- or C-type motifs within each of the type III calcium-binding domains showed no significant association with either the MED or the PSACH phenotype.
• Pathogenic missense variants in nucleotides encoding the fourth and fifth (of 8 total) type III calcium-binding repeats (i.e., T3
• Pathogenic missense variants in nucleotides encoding the sixth through eighth type III calcium-binding repeats (i.e., T3
• The majority of pathogenic in-frame deletions, insertions, or indels were associated with PSACH (n=74; 82%), whereas a smaller proportion were associated with MED (n=16; 18%); however, in several instances, the same pathogenic variant was reported to cause both PSACH and MED [
• Individuals with a pathogenic variant in the seventh type III calcium-binding repeat are reported to have more severe short stature than those with pathogenic variants in the other type III repeats [
• Individuals heterozygous for the common
• Most type III calcium-binding repeats have both an N- and C-type motif (see
## Penetrance
Penetrance is 100%.
## Nomenclature
In the past, four subtypes of pseudoachondroplasia, including dominant and recessive forms, were recognized under the term pseudoachondroplasia. The current classification recognizes a single, dominantly inherited phenotype referred to as
## Prevalence
No firm data on the prevalence of
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
Onset in early childhood of hip &/or knee pain after exercise; children may have fatigue w/extended walking
Waddling gait (less consistent than in
Adult height in low range of normal or mildly short
Relatively short limbs in comparison to trunk
Progressive joint deformity w/early-onset osteoarthritis, particularly of large weight-bearing joints
Delayed ossification of the epiphyses of the long tubular bones
Epiphyseal ossification centers are initially small w/irregular contours, usually most pronounced in the hips &/or knees.
Tubular bones may be mildly shortened.
Spine is by definition normal, although Schmorl bodies & irregular vertebral end plates may be observed.
Arthritis is later in onset & less severe in AD MED than
Stature is typically greater in AD MED.
Joint pain (usually hips, knees) w/onset usually in late childhood
Malformations of hands, feet, & knees
Scoliosis
Stature w/in normal range prior to puberty; in adulthood, stature is slightly diminished, ranging from 150 to 180 cm.
Functional disability is mild or absent.
~50% have some abnormal finding at birth (e.g., clubfoot, clinodactyly, or, rarely, cystic ear swelling) not seen in
Taller stature in those w/AR MED
AR MED has later-onset & less severe joint pain.
AD = autosomal dominant; AR = autosomal recessive;
Pathogenic variants remain undetected in approximately 20% of individuals with MED.
Homozygous
Another resource to help diagnose skeletal dysplasias using radiographic images, dREAMS, is available
• Onset in early childhood of hip &/or knee pain after exercise; children may have fatigue w/extended walking
• Waddling gait (less consistent than in
• Adult height in low range of normal or mildly short
• Relatively short limbs in comparison to trunk
• Progressive joint deformity w/early-onset osteoarthritis, particularly of large weight-bearing joints
• Delayed ossification of the epiphyses of the long tubular bones
• Epiphyseal ossification centers are initially small w/irregular contours, usually most pronounced in the hips &/or knees.
• Tubular bones may be mildly shortened.
• Spine is by definition normal, although Schmorl bodies & irregular vertebral end plates may be observed.
• Arthritis is later in onset & less severe in AD MED than
• Stature is typically greater in AD MED.
• Joint pain (usually hips, knees) w/onset usually in late childhood
• Malformations of hands, feet, & knees
• Scoliosis
• Stature w/in normal range prior to puberty; in adulthood, stature is slightly diminished, ranging from 150 to 180 cm.
• Functional disability is mild or absent.
• ~50% have some abnormal finding at birth (e.g., clubfoot, clinodactyly, or, rarely, cystic ear swelling) not seen in
• Taller stature in those w/AR MED
• AR MED has later-onset & less severe joint pain.
## Management
To establish the extent of disease and needs in an individual diagnosed with
Eval for skeletal manifestations, ligamentous laxity, & arthritis
Skeletal survey incl AP views of hips, knees, & hands & lateral views of knees & spine
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Common during childhood
Subsequent revision commonly needed (most likely due to severe joint instability that can be present in some affected persons).
Very few examples of extended limb lengthening have been reported in persons w/
Outcome of the procedure in persons w/
Awareness is important in caring for the affected person.
Social support organizations incl the Little People of America & similar organizations in other countries (see
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Symptoms related to joint hypermobility
Symptomatic lower limb malalignment
Evidence of kyphoscoliosis
Evidence of degenerative joint disease manifesting as joint pain
In the small fraction of individuals with odontoid hypoplasia, extreme neck flexion and extension should be avoided.
See
For females with
Search
Growth hormone treatment is ineffective in
• Eval for skeletal manifestations, ligamentous laxity, & arthritis
• Skeletal survey incl AP views of hips, knees, & hands & lateral views of knees & spine
• Common during childhood
• Subsequent revision commonly needed (most likely due to severe joint instability that can be present in some affected persons).
• Very few examples of extended limb lengthening have been reported in persons w/
• Outcome of the procedure in persons w/
• Awareness is important in caring for the affected person.
• Social support organizations incl the Little People of America & similar organizations in other countries (see
• Symptoms related to joint hypermobility
• Symptomatic lower limb malalignment
• Evidence of kyphoscoliosis
• Evidence of degenerative joint disease manifesting as joint pain
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Eval for skeletal manifestations, ligamentous laxity, & arthritis
Skeletal survey incl AP views of hips, knees, & hands & lateral views of knees & spine
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Eval for skeletal manifestations, ligamentous laxity, & arthritis
• Skeletal survey incl AP views of hips, knees, & hands & lateral views of knees & spine
## Treatment of Manifestations
There is no cure for
Common during childhood
Subsequent revision commonly needed (most likely due to severe joint instability that can be present in some affected persons).
Very few examples of extended limb lengthening have been reported in persons w/
Outcome of the procedure in persons w/
Awareness is important in caring for the affected person.
Social support organizations incl the Little People of America & similar organizations in other countries (see
• Common during childhood
• Subsequent revision commonly needed (most likely due to severe joint instability that can be present in some affected persons).
• Very few examples of extended limb lengthening have been reported in persons w/
• Outcome of the procedure in persons w/
• Awareness is important in caring for the affected person.
• Social support organizations incl the Little People of America & similar organizations in other countries (see
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Symptoms related to joint hypermobility
Symptomatic lower limb malalignment
Evidence of kyphoscoliosis
Evidence of degenerative joint disease manifesting as joint pain
• Symptoms related to joint hypermobility
• Symptomatic lower limb malalignment
• Evidence of kyphoscoliosis
• Evidence of degenerative joint disease manifesting as joint pain
## Agents/Circumstances to Avoid
In the small fraction of individuals with odontoid hypoplasia, extreme neck flexion and extension should be avoided.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
For females with
## Therapies Under Investigation
Search
## Other
Growth hormone treatment is ineffective in
## Genetic Counseling
Some individuals diagnosed with
A proband diagnosed with
If the proband appears to be the only affected family member (i.e., a simplex case), evaluation of the parents of the proband is recommended in order to evaluate their genetic status and inform recurrence risk assessment; recommended evaluations include physical examination, radiographs, and molecular genetic testing. (Molecular genetic testing may detect parental somatic mosaicism 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.* 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. Germline mosaicism for a
* A parent with somatic and germline mosaicism for a
If one parent of the proband has
If both parents have
If the parents are clinically unaffected, the recurrence 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
Each child of an individual with
Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with
If both partners have a dominantly inherited bone growth disorder, offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having average stature and bone growth, and a 25% chance of having double heterozygosity for the two disorders.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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
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
• A proband diagnosed with
• If the proband appears to be the only affected family member (i.e., a simplex case), evaluation of the parents of the proband is recommended in order to evaluate their genetic status and inform recurrence risk assessment; recommended evaluations include physical examination, radiographs, and molecular genetic testing. (Molecular genetic testing may detect parental somatic mosaicism 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.* 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. Germline mosaicism for a
• * 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. Germline mosaicism for a
• * 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. Germline mosaicism for a
• * A parent with somatic and germline mosaicism for a
• If one parent of the proband has
• If both parents have
• If the parents are clinically unaffected, the recurrence 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
• Each child of an individual with
• Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with
• If both partners have a dominantly inherited bone growth disorder, offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having average stature and bone growth, and a 25% chance of having double heterozygosity for the two disorders.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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
## Mode of Inheritance
## Risk to Family Members
Some individuals diagnosed with
A proband diagnosed with
If the proband appears to be the only affected family member (i.e., a simplex case), evaluation of the parents of the proband is recommended in order to evaluate their genetic status and inform recurrence risk assessment; recommended evaluations include physical examination, radiographs, and molecular genetic testing. (Molecular genetic testing may detect parental somatic mosaicism 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.* 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. Germline mosaicism for a
* A parent with somatic and germline mosaicism for a
If one parent of the proband has
If both parents have
If the parents are clinically unaffected, the recurrence 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
Each child of an individual with
Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with
If both partners have a dominantly inherited bone growth disorder, offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having average stature and bone growth, and a 25% chance of having double heterozygosity for the two disorders.
• Some individuals diagnosed with
• A proband diagnosed with
• If the proband appears to be the only affected family member (i.e., a simplex case), evaluation of the parents of the proband is recommended in order to evaluate their genetic status and inform recurrence risk assessment; recommended evaluations include physical examination, radiographs, and molecular genetic testing. (Molecular genetic testing may detect parental somatic mosaicism 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.* 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. Germline mosaicism for a
• * 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. Germline mosaicism for a
• * 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. Germline mosaicism for a
• * A parent with somatic and germline mosaicism for a
• If one parent of the proband has
• If both parents have
• If the parents are clinically unaffected, the recurrence 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
• Each child of an individual with
• Because many individuals with short stature select reproductive partners with short stature, offspring of individuals with
• If both partners have a dominantly inherited bone growth disorder, offspring have a 25% chance of having the maternal bone growth disorder, a 25% chance of having the paternal bone growth disorder, a 25% chance of having average stature and bone growth, and a 25% chance of having double heterozygosity for the two disorders.
## 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
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic 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
## 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
European Reference Network on Rare Bone Diseases
United Kingdom
United Kingdom
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•
•
•
•
• United Kingdom
•
•
• European Reference Network on Rare Bone Diseases
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
## Molecular Genetics
COMP-Related Pseudoachondroplasia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for COMP-Related Pseudoachondroplasia (
Cartilage oligomeric matrix protein (COMP) is composed of an amino-terminal coiled-coil domain, four type II (EGF-like) repeats, eight consecutive type III (calmodulin-like calcium-binding) repeats, and a carboxyl-terminal globular domain. The type III motifs typically are composed of both an N- and a C-type motif, although the third and fifth type III repeats lack the N-type motif. COMP is a homopentameric adhesive glycoprotein found predominantly in the cartilage extracellular matrix [
Pathogenic variants in the exons encoding the type III repeats of COMP result in the misfolding of the mutated protein and its retention in the rough endoplasmic reticulum (rER) of chondrocytes. This protein retention results in ER stress that ultimately causes increased cell death in vitro [
The effect of pathogenic variants in the exons encoding the C-terminal globular domain of COMP is not fully resolved, but these pathogenic variants are not thought to prevent the secretion of mutated COMP in vitro [
All individuals with pseudoachondroplasia appear to have
Approximately 30% of individuals have the same pathogenic variant: deletion of a single aspartic acid codon
Evidence suggests that pathogenic variants in exons 7 and 8 encoding the type II repeats may be an uncommon cause of
A single in-frame exon deletion and a single pathogenic variant predicting synthesis of a truncated protein have also been characterized but not analyzed in depth [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
The reference sequence
## Molecular Pathogenesis
Cartilage oligomeric matrix protein (COMP) is composed of an amino-terminal coiled-coil domain, four type II (EGF-like) repeats, eight consecutive type III (calmodulin-like calcium-binding) repeats, and a carboxyl-terminal globular domain. The type III motifs typically are composed of both an N- and a C-type motif, although the third and fifth type III repeats lack the N-type motif. COMP is a homopentameric adhesive glycoprotein found predominantly in the cartilage extracellular matrix [
Pathogenic variants in the exons encoding the type III repeats of COMP result in the misfolding of the mutated protein and its retention in the rough endoplasmic reticulum (rER) of chondrocytes. This protein retention results in ER stress that ultimately causes increased cell death in vitro [
The effect of pathogenic variants in the exons encoding the C-terminal globular domain of COMP is not fully resolved, but these pathogenic variants are not thought to prevent the secretion of mutated COMP in vitro [
All individuals with pseudoachondroplasia appear to have
Approximately 30% of individuals have the same pathogenic variant: deletion of a single aspartic acid codon
Evidence suggests that pathogenic variants in exons 7 and 8 encoding the type II repeats may be an uncommon cause of
A single in-frame exon deletion and a single pathogenic variant predicting synthesis of a truncated protein have also been characterized but not analyzed in depth [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
The reference sequence
## Chapter Notes
Michael D Briggs, PhD (2013-present)Daniel H Cohn, PhD; University of California, Los Angeles (2004-2013)Michael J Wright, MB, ChB, MSc, FRCP (2013-present)
30 November 2023 (sw) Comprehensive update posted live
16 August 2018 (sw) Comprehensive update posted live
16 July 2015 (me) Comprehensive update posted live
28 February 2013 (me) Comprehensive update posted live
13 April 2010 (me) Comprehensive update posted live
11 December 2006 (me) Comprehensive update posted live
20 August 2004 (ca) Review posted live
6 April 2004 (dc) Original submission
• 30 November 2023 (sw) Comprehensive update posted live
• 16 August 2018 (sw) Comprehensive update posted live
• 16 July 2015 (me) Comprehensive update posted live
• 28 February 2013 (me) Comprehensive update posted live
• 13 April 2010 (me) Comprehensive update posted live
• 11 December 2006 (me) Comprehensive update posted live
• 20 August 2004 (ca) Review posted live
• 6 April 2004 (dc) Original submission
## Author History
Michael D Briggs, PhD (2013-present)Daniel H Cohn, PhD; University of California, Los Angeles (2004-2013)Michael J Wright, MB, ChB, MSc, FRCP (2013-present)
## Revision History
30 November 2023 (sw) Comprehensive update posted live
16 August 2018 (sw) Comprehensive update posted live
16 July 2015 (me) Comprehensive update posted live
28 February 2013 (me) Comprehensive update posted live
13 April 2010 (me) Comprehensive update posted live
11 December 2006 (me) Comprehensive update posted live
20 August 2004 (ca) Review posted live
6 April 2004 (dc) Original submission
• 30 November 2023 (sw) Comprehensive update posted live
• 16 August 2018 (sw) Comprehensive update posted live
• 16 July 2015 (me) Comprehensive update posted live
• 28 February 2013 (me) Comprehensive update posted live
• 13 April 2010 (me) Comprehensive update posted live
• 11 December 2006 (me) Comprehensive update posted live
• 20 August 2004 (ca) Review posted live
• 6 April 2004 (dc) Original submission
## References
## Literature Cited
Radiographs of a prepubertal child showing the changes typical of pseudoachondroplasia
|
[] |
20/8/2004
|
30/11/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
ptps-def
|
ptps-def
|
[
"6-Pyruvoyl-Tetrahydropterin Synthase Deficiency",
"PTS Deficiency",
"6-Pyruvoyl-Tetrahydropterin Synthase Deficiency",
"PTS Deficiency",
"6-pyruvoyl tetrahydrobiopterin synthase",
"PTS",
"PTS-Related Tetrahydrobiopterin Deficiency"
] |
Thomas Opladen, Nicola Longo, Nenad Blau
|
Summary In the mild (peripheral) form, affected individuals are usually asymptomatic apart from an increase in phenylalanine (Phe) levels. Some remain asymptomatic. However, with time, some have mild developmental delays and can develop deficiency of neurotransmitter production, such that treatment of some asymptomatic individuals may be required. The biochemical diagnosis of PTPSD is established in a proband with confirmed hyperphenylalaninemia, elevated neopterin levels, reduced biopterin levels, and a decreased biopterin-to-neopterin ratio in urine or dried blood spots (DBS) and normal dihydropteridine reductase (DHPR) activity in DBS. The molecular diagnosis of PTPSD is established in a proband by identification of biallelic pathogenic (or likely pathogenic) variants in PTPSD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
Deficiency of tetrahydrobiopterin (BH4), a cofactor for the enzyme phenylalanine hydroxylase (PAH), can lead to accumulation of phenylalanine (Phe) in the blood (hyperphenylalaninemia). In addition, it impairs activity of tyrosine (Tyr) and tryptophan hydroxylase, leading to defective synthesis of neurotransmitters; this, together with hyperphenylalaninemia, can cause central nervous system (CNS) dysfunction. BH4 can be synthesized directly from guanosine triphosphate (GTP) by GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase (PTPS), and sepiapterin reductase, or it can be produced through a salvage pathway by sepiapterin reductase and dihyropteridine reductase. This chapter focuses on deficiency of BH4 due to reduced or absent PTPS (PTPSD).
A diagnosis of PTPSD may be suspected due to an
NBS for PTPSD is primarily based on use of dried blood spots (DBS) collected between 24 hours and 72 hours after birth to quantify Phe and Tyr concentrations by tandem mass spectrometry (MS/MS). In the United States (US) and European Union (EU) most NBS laboratories determine their own levels for results that are considered out of range. For information on NBS by state in the US, see
Immediately on receipt of out-of-range NBS results (i.e., elevated Phe levels and/or elevated Phe:Tyr ratio), further evaluation to
Recommended types of diagnostic testing for infants with elevated Phe levels on NBS are reviewed in
For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
If a metabolic specialist is not available, the treatments suggested in
A symptomatic individual can have either typical findings associated with later-diagnosed PTPSD or untreated PTPSD resulting from any of the following: NBS not performed, false negative NBS result, symptom onset prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Supportive – but nonspecific – clinical findings, brain MRI findings, and preliminary laboratory findings are listed here.
Microcephaly
Intellectual disability
Seizures or epilepsy
Disturbance of muscle tone and posture
Drowsiness
Irritability
Oculogyric crises
Abnormal movements
Temperature instability
Hypersalivation
Swallowing difficulties
Brain atrophy
Isolated central tegmental tract hyperintensity
White matter abnormalities
The biochemical diagnosis of PTPSD is established in a proband with confirmed hyperphenylalaninemia (see
Testing Recommended at Time of Detection of Hyperphenylalaninemia
Adapted from
ACMG = American College of Medical Genetics and Genomics; BH4 = tetrahydrobiopterin; DBS = dried blood spots; DPHR = dihydropterine reductase; EU = European Union; NBS = newborn screening; PAH = phenylalanine hydroxylase; Phe = phenylalanine; Try = tyrosine
Note: If multiple amino acids are elevated on plasma amino acid analysis, other causes can include liver disease and/or the use of total parenteral nutrition.
Deficiency of 6-pyruvoyl-tetrahydropterin synthase (PTPS) is characterized by elevated neopterin levels, reduced biopterin levels, and a decreased biopterin-to-neopterin ratio.
If there is reduced biopterin and elevated neopterin, it is important to determine if this abnormality is sufficient to impact the production of brain neurotransmitters. Therefore, a lumbar puncture is often performed to measure neopterin, biopterin, and neurotransmitter metabolites such as homovanillic acid (HVA) and 5-hydroxyindole acetic acid (HIAA).
Low levels of neurotransmitter metabolites indicate the need to initiate therapy with neurotransmitter precursors (see
Note: A sapropterin dihydrochloride (BH4) loading test, in which an individual is given 20 mg/kg of sapropterin with subsequent serial measurements of serum Phe levels at baseline (prior to the sapropterin load), four hours, eight hours, 24 hours, 32 hours, and 48 hours after the loading dose is positive in people with PTPSD; however, with the availability of pterin analysis and genetic testing, this loading test is rather outdated.
The molecular diagnosis of PTPSD
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 PTPSD, molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in PTPSD
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. 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 recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
• If a metabolic specialist is not available, the treatments suggested in
• Microcephaly
• Intellectual disability
• Seizures or epilepsy
• Disturbance of muscle tone and posture
• Drowsiness
• Irritability
• Oculogyric crises
• Abnormal movements
• Temperature instability
• Hypersalivation
• Swallowing difficulties
• Brain atrophy
• Isolated central tegmental tract hyperintensity
• White matter abnormalities
• For an introduction to multigene panels click
## Suggestive Findings
A diagnosis of PTPSD may be suspected due to an
NBS for PTPSD is primarily based on use of dried blood spots (DBS) collected between 24 hours and 72 hours after birth to quantify Phe and Tyr concentrations by tandem mass spectrometry (MS/MS). In the United States (US) and European Union (EU) most NBS laboratories determine their own levels for results that are considered out of range. For information on NBS by state in the US, see
Immediately on receipt of out-of-range NBS results (i.e., elevated Phe levels and/or elevated Phe:Tyr ratio), further evaluation to
Recommended types of diagnostic testing for infants with elevated Phe levels on NBS are reviewed in
For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
If a metabolic specialist is not available, the treatments suggested in
A symptomatic individual can have either typical findings associated with later-diagnosed PTPSD or untreated PTPSD resulting from any of the following: NBS not performed, false negative NBS result, symptom onset prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Supportive – but nonspecific – clinical findings, brain MRI findings, and preliminary laboratory findings are listed here.
Microcephaly
Intellectual disability
Seizures or epilepsy
Disturbance of muscle tone and posture
Drowsiness
Irritability
Oculogyric crises
Abnormal movements
Temperature instability
Hypersalivation
Swallowing difficulties
Brain atrophy
Isolated central tegmental tract hyperintensity
White matter abnormalities
• For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
• If a metabolic specialist is not available, the treatments suggested in
• Microcephaly
• Intellectual disability
• Seizures or epilepsy
• Disturbance of muscle tone and posture
• Drowsiness
• Irritability
• Oculogyric crises
• Abnormal movements
• Temperature instability
• Hypersalivation
• Swallowing difficulties
• Brain atrophy
• Isolated central tegmental tract hyperintensity
• White matter abnormalities
## Abnormal NBS Result
NBS for PTPSD is primarily based on use of dried blood spots (DBS) collected between 24 hours and 72 hours after birth to quantify Phe and Tyr concentrations by tandem mass spectrometry (MS/MS). In the United States (US) and European Union (EU) most NBS laboratories determine their own levels for results that are considered out of range. For information on NBS by state in the US, see
Immediately on receipt of out-of-range NBS results (i.e., elevated Phe levels and/or elevated Phe:Tyr ratio), further evaluation to
Recommended types of diagnostic testing for infants with elevated Phe levels on NBS are reviewed in
For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
If a metabolic specialist is not available, the treatments suggested in
• For recommendations on presumptive treatment while awaiting diagnostic confirmation, consult a metabolic specialist to discuss immediate care needs.
• If a metabolic specialist is not available, the treatments suggested in
## Symptomatic Individual
A symptomatic individual can have either typical findings associated with later-diagnosed PTPSD or untreated PTPSD resulting from any of the following: NBS not performed, false negative NBS result, symptom onset prior to receiving NBS result, or caregivers not adherent to recommended treatment after a positive NBS result. Supportive – but nonspecific – clinical findings, brain MRI findings, and preliminary laboratory findings are listed here.
Microcephaly
Intellectual disability
Seizures or epilepsy
Disturbance of muscle tone and posture
Drowsiness
Irritability
Oculogyric crises
Abnormal movements
Temperature instability
Hypersalivation
Swallowing difficulties
Brain atrophy
Isolated central tegmental tract hyperintensity
White matter abnormalities
• Microcephaly
• Intellectual disability
• Seizures or epilepsy
• Disturbance of muscle tone and posture
• Drowsiness
• Irritability
• Oculogyric crises
• Abnormal movements
• Temperature instability
• Hypersalivation
• Swallowing difficulties
• Brain atrophy
• Isolated central tegmental tract hyperintensity
• White matter abnormalities
## Establishing the Diagnosis
The biochemical diagnosis of PTPSD is established in a proband with confirmed hyperphenylalaninemia (see
Testing Recommended at Time of Detection of Hyperphenylalaninemia
Adapted from
ACMG = American College of Medical Genetics and Genomics; BH4 = tetrahydrobiopterin; DBS = dried blood spots; DPHR = dihydropterine reductase; EU = European Union; NBS = newborn screening; PAH = phenylalanine hydroxylase; Phe = phenylalanine; Try = tyrosine
Note: If multiple amino acids are elevated on plasma amino acid analysis, other causes can include liver disease and/or the use of total parenteral nutrition.
Deficiency of 6-pyruvoyl-tetrahydropterin synthase (PTPS) is characterized by elevated neopterin levels, reduced biopterin levels, and a decreased biopterin-to-neopterin ratio.
If there is reduced biopterin and elevated neopterin, it is important to determine if this abnormality is sufficient to impact the production of brain neurotransmitters. Therefore, a lumbar puncture is often performed to measure neopterin, biopterin, and neurotransmitter metabolites such as homovanillic acid (HVA) and 5-hydroxyindole acetic acid (HIAA).
Low levels of neurotransmitter metabolites indicate the need to initiate therapy with neurotransmitter precursors (see
Note: A sapropterin dihydrochloride (BH4) loading test, in which an individual is given 20 mg/kg of sapropterin with subsequent serial measurements of serum Phe levels at baseline (prior to the sapropterin load), four hours, eight hours, 24 hours, 32 hours, and 48 hours after the loading dose is positive in people with PTPSD; however, with the availability of pterin analysis and genetic testing, this loading test is rather outdated.
The molecular diagnosis of PTPSD
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 PTPSD, molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in PTPSD
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. 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
## Analyte Diagnosis
The biochemical diagnosis of PTPSD is established in a proband with confirmed hyperphenylalaninemia (see
Testing Recommended at Time of Detection of Hyperphenylalaninemia
Adapted from
ACMG = American College of Medical Genetics and Genomics; BH4 = tetrahydrobiopterin; DBS = dried blood spots; DPHR = dihydropterine reductase; EU = European Union; NBS = newborn screening; PAH = phenylalanine hydroxylase; Phe = phenylalanine; Try = tyrosine
Note: If multiple amino acids are elevated on plasma amino acid analysis, other causes can include liver disease and/or the use of total parenteral nutrition.
Deficiency of 6-pyruvoyl-tetrahydropterin synthase (PTPS) is characterized by elevated neopterin levels, reduced biopterin levels, and a decreased biopterin-to-neopterin ratio.
If there is reduced biopterin and elevated neopterin, it is important to determine if this abnormality is sufficient to impact the production of brain neurotransmitters. Therefore, a lumbar puncture is often performed to measure neopterin, biopterin, and neurotransmitter metabolites such as homovanillic acid (HVA) and 5-hydroxyindole acetic acid (HIAA).
Low levels of neurotransmitter metabolites indicate the need to initiate therapy with neurotransmitter precursors (see
Note: A sapropterin dihydrochloride (BH4) loading test, in which an individual is given 20 mg/kg of sapropterin with subsequent serial measurements of serum Phe levels at baseline (prior to the sapropterin load), four hours, eight hours, 24 hours, 32 hours, and 48 hours after the loading dose is positive in people with PTPSD; however, with the availability of pterin analysis and genetic testing, this loading test is rather outdated.
## Molecular Diagnosis
The molecular diagnosis of PTPSD
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 PTPSD, molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in PTPSD
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. 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
##
When the phenotypic and laboratory findings suggest the diagnosis of PTPSD, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
##
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in PTPSD
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. 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
The clinical spectrum of PTPSD is broad and differs according to age of onset, severity of disease, and whether preventative therapies were initiated and maintained from an early age. In general, this condition can be divided into two forms [
Affected individuals can experience symptoms as early as the neonatal period. Clinical signs can include hypotonia, movement disorders, abnormal eye movements, autonomic dysregulation, and impaired development. However, affected infants who are diagnosed through NBS are usually asymptomatic, although there is an increased risk of prematurity and low birth weight (even without prematurity).
Once results of confirmatory testing are available, these children are started on BH4 therapy and can revert to a totally normal diet without the need of Phe or protein restriction.
Select Features of Severe PTPSD
Based on
SD = standard deviation
After correcting for sex and gestational age
Developmental delays are usually noted around age one month.
Without treatment, developmental delays become more marked.
With treatment, affected individuals might still require additional help in school.
Speech is typically the most affected developmental parameter.
Development frequently improves during adolescence, with many adults having a normal IQ level [
Independent or partially independent living is often attainable, with some affected individuals attending college.
Axial hypotonia with limb hypertonia
Movement disorders, most frequently seen after age three months:
Dysarthria
Dystonia
Tremors
Abnormal gait
Parkinsonism, including bradykinesia or cogwheeling
Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
Motor tics
Attention-deficit/hyperactivity disorder (ADHD)
Anxiety
Depression
Aggression
Oppositional defiant disorder (ODD)
Emotional dysregulation
Irritability
Infant feeding difficulties can lead to growth failure early in life. This usually resolves with time and appropriate medical therapy. Supplementation with neurotransmitter precursors can improve feeding issues, such as swallowing problems and gastroesophageal reflux disease.
Weight and height often improve over time, such that they approach typical values [
Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
Some affected individuals have true growth hormone deficiency (see
Currently there is no evidence that individuals with PTPSD have issues with bone health; however, as there are recommendations for maintaining bone health in individuals with PAH deficiency, this has also been recommended for individuals with PTPSD (see
Periventricular hyperintensities
Delayed myelination
Brain calcifications
Brain atrophy
Pituitary gland hyperplasia or adenoma
In the mild (peripheral) form, affected individuals are usually asymptomatic apart from an increase in Phe levels. With time, they can have mild developmental delays and can develop deficiency of neurotransmitter production. Some remain asymptomatic.
No clinically relevant genotype-phenotype correlations have been identified.
BH4-deficient hyperphenylalaninemia is an umbrella term encompassing all types of hyperphenylalaninemia caused by BH4 deficiency, i.e., hyperphenylalaninemia associated with pathogenic variants in
Hyperphenylalaninemia type III is an outdated term previously used to denote PTPSD.
The exact global prevalence of PTPSD is still unknown. However, it is estimated that BH4 deficiencies (all forms) account for about 1%-2% of hyperphenylalaninemias, which have a prevalence of approximately one in 15,000 individuals. Additionally, PTPSD specifically accounts for around 54% of all BH4 deficiencies [
• Developmental delays are usually noted around age one month.
• Without treatment, developmental delays become more marked.
• With treatment, affected individuals might still require additional help in school.
• Speech is typically the most affected developmental parameter.
• Development frequently improves during adolescence, with many adults having a normal IQ level [
• Independent or partially independent living is often attainable, with some affected individuals attending college.
• Speech is typically the most affected developmental parameter.
• Development frequently improves during adolescence, with many adults having a normal IQ level [
• Independent or partially independent living is often attainable, with some affected individuals attending college.
• Speech is typically the most affected developmental parameter.
• Development frequently improves during adolescence, with many adults having a normal IQ level [
• Independent or partially independent living is often attainable, with some affected individuals attending college.
• Axial hypotonia with limb hypertonia
• Movement disorders, most frequently seen after age three months:
• Dysarthria
• Dystonia
• Tremors
• Abnormal gait
• Parkinsonism, including bradykinesia or cogwheeling
• Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
• Motor tics
• Dysarthria
• Dystonia
• Tremors
• Abnormal gait
• Parkinsonism, including bradykinesia or cogwheeling
• Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
• Motor tics
• Dysarthria
• Dystonia
• Tremors
• Abnormal gait
• Parkinsonism, including bradykinesia or cogwheeling
• Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
• Motor tics
• Attention-deficit/hyperactivity disorder (ADHD)
• Anxiety
• Depression
• Aggression
• Oppositional defiant disorder (ODD)
• Emotional dysregulation
• Irritability
• Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
• Some affected individuals have true growth hormone deficiency (see
• Currently there is no evidence that individuals with PTPSD have issues with bone health; however, as there are recommendations for maintaining bone health in individuals with PAH deficiency, this has also been recommended for individuals with PTPSD (see
• Periventricular hyperintensities
• Delayed myelination
• Brain calcifications
• Brain atrophy
• Pituitary gland hyperplasia or adenoma
• Periventricular hyperintensities
• Delayed myelination
• Brain calcifications
• Brain atrophy
• Pituitary gland hyperplasia or adenoma
• Periventricular hyperintensities
• Delayed myelination
• Brain calcifications
• Brain atrophy
• Pituitary gland hyperplasia or adenoma
## Clinical Description
The clinical spectrum of PTPSD is broad and differs according to age of onset, severity of disease, and whether preventative therapies were initiated and maintained from an early age. In general, this condition can be divided into two forms [
Affected individuals can experience symptoms as early as the neonatal period. Clinical signs can include hypotonia, movement disorders, abnormal eye movements, autonomic dysregulation, and impaired development. However, affected infants who are diagnosed through NBS are usually asymptomatic, although there is an increased risk of prematurity and low birth weight (even without prematurity).
Once results of confirmatory testing are available, these children are started on BH4 therapy and can revert to a totally normal diet without the need of Phe or protein restriction.
Select Features of Severe PTPSD
Based on
SD = standard deviation
After correcting for sex and gestational age
Developmental delays are usually noted around age one month.
Without treatment, developmental delays become more marked.
With treatment, affected individuals might still require additional help in school.
Speech is typically the most affected developmental parameter.
Development frequently improves during adolescence, with many adults having a normal IQ level [
Independent or partially independent living is often attainable, with some affected individuals attending college.
Axial hypotonia with limb hypertonia
Movement disorders, most frequently seen after age three months:
Dysarthria
Dystonia
Tremors
Abnormal gait
Parkinsonism, including bradykinesia or cogwheeling
Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
Motor tics
Attention-deficit/hyperactivity disorder (ADHD)
Anxiety
Depression
Aggression
Oppositional defiant disorder (ODD)
Emotional dysregulation
Irritability
Infant feeding difficulties can lead to growth failure early in life. This usually resolves with time and appropriate medical therapy. Supplementation with neurotransmitter precursors can improve feeding issues, such as swallowing problems and gastroesophageal reflux disease.
Weight and height often improve over time, such that they approach typical values [
Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
Some affected individuals have true growth hormone deficiency (see
Currently there is no evidence that individuals with PTPSD have issues with bone health; however, as there are recommendations for maintaining bone health in individuals with PAH deficiency, this has also been recommended for individuals with PTPSD (see
Periventricular hyperintensities
Delayed myelination
Brain calcifications
Brain atrophy
Pituitary gland hyperplasia or adenoma
In the mild (peripheral) form, affected individuals are usually asymptomatic apart from an increase in Phe levels. With time, they can have mild developmental delays and can develop deficiency of neurotransmitter production. Some remain asymptomatic.
• Developmental delays are usually noted around age one month.
• Without treatment, developmental delays become more marked.
• With treatment, affected individuals might still require additional help in school.
• Speech is typically the most affected developmental parameter.
• Development frequently improves during adolescence, with many adults having a normal IQ level [
• Independent or partially independent living is often attainable, with some affected individuals attending college.
• Speech is typically the most affected developmental parameter.
• Development frequently improves during adolescence, with many adults having a normal IQ level [
• Independent or partially independent living is often attainable, with some affected individuals attending college.
• Speech is typically the most affected developmental parameter.
• Development frequently improves during adolescence, with many adults having a normal IQ level [
• Independent or partially independent living is often attainable, with some affected individuals attending college.
• Axial hypotonia with limb hypertonia
• Movement disorders, most frequently seen after age three months:
• Dysarthria
• Dystonia
• Tremors
• Abnormal gait
• Parkinsonism, including bradykinesia or cogwheeling
• Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
• Motor tics
• Dysarthria
• Dystonia
• Tremors
• Abnormal gait
• Parkinsonism, including bradykinesia or cogwheeling
• Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
• Motor tics
• Dysarthria
• Dystonia
• Tremors
• Abnormal gait
• Parkinsonism, including bradykinesia or cogwheeling
• Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
• Motor tics
• Attention-deficit/hyperactivity disorder (ADHD)
• Anxiety
• Depression
• Aggression
• Oppositional defiant disorder (ODD)
• Emotional dysregulation
• Irritability
• Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
• Some affected individuals have true growth hormone deficiency (see
• Currently there is no evidence that individuals with PTPSD have issues with bone health; however, as there are recommendations for maintaining bone health in individuals with PAH deficiency, this has also been recommended for individuals with PTPSD (see
• Periventricular hyperintensities
• Delayed myelination
• Brain calcifications
• Brain atrophy
• Pituitary gland hyperplasia or adenoma
• Periventricular hyperintensities
• Delayed myelination
• Brain calcifications
• Brain atrophy
• Pituitary gland hyperplasia or adenoma
• Periventricular hyperintensities
• Delayed myelination
• Brain calcifications
• Brain atrophy
• Pituitary gland hyperplasia or adenoma
## Severe PTPSD
Affected individuals can experience symptoms as early as the neonatal period. Clinical signs can include hypotonia, movement disorders, abnormal eye movements, autonomic dysregulation, and impaired development. However, affected infants who are diagnosed through NBS are usually asymptomatic, although there is an increased risk of prematurity and low birth weight (even without prematurity).
Once results of confirmatory testing are available, these children are started on BH4 therapy and can revert to a totally normal diet without the need of Phe or protein restriction.
Select Features of Severe PTPSD
Based on
SD = standard deviation
After correcting for sex and gestational age
Developmental delays are usually noted around age one month.
Without treatment, developmental delays become more marked.
With treatment, affected individuals might still require additional help in school.
Speech is typically the most affected developmental parameter.
Development frequently improves during adolescence, with many adults having a normal IQ level [
Independent or partially independent living is often attainable, with some affected individuals attending college.
Axial hypotonia with limb hypertonia
Movement disorders, most frequently seen after age three months:
Dysarthria
Dystonia
Tremors
Abnormal gait
Parkinsonism, including bradykinesia or cogwheeling
Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
Motor tics
Attention-deficit/hyperactivity disorder (ADHD)
Anxiety
Depression
Aggression
Oppositional defiant disorder (ODD)
Emotional dysregulation
Irritability
Infant feeding difficulties can lead to growth failure early in life. This usually resolves with time and appropriate medical therapy. Supplementation with neurotransmitter precursors can improve feeding issues, such as swallowing problems and gastroesophageal reflux disease.
Weight and height often improve over time, such that they approach typical values [
Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
Some affected individuals have true growth hormone deficiency (see
Currently there is no evidence that individuals with PTPSD have issues with bone health; however, as there are recommendations for maintaining bone health in individuals with PAH deficiency, this has also been recommended for individuals with PTPSD (see
Periventricular hyperintensities
Delayed myelination
Brain calcifications
Brain atrophy
Pituitary gland hyperplasia or adenoma
• Developmental delays are usually noted around age one month.
• Without treatment, developmental delays become more marked.
• With treatment, affected individuals might still require additional help in school.
• Speech is typically the most affected developmental parameter.
• Development frequently improves during adolescence, with many adults having a normal IQ level [
• Independent or partially independent living is often attainable, with some affected individuals attending college.
• Speech is typically the most affected developmental parameter.
• Development frequently improves during adolescence, with many adults having a normal IQ level [
• Independent or partially independent living is often attainable, with some affected individuals attending college.
• Speech is typically the most affected developmental parameter.
• Development frequently improves during adolescence, with many adults having a normal IQ level [
• Independent or partially independent living is often attainable, with some affected individuals attending college.
• Axial hypotonia with limb hypertonia
• Movement disorders, most frequently seen after age three months:
• Dysarthria
• Dystonia
• Tremors
• Abnormal gait
• Parkinsonism, including bradykinesia or cogwheeling
• Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
• Motor tics
• Dysarthria
• Dystonia
• Tremors
• Abnormal gait
• Parkinsonism, including bradykinesia or cogwheeling
• Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
• Motor tics
• Dysarthria
• Dystonia
• Tremors
• Abnormal gait
• Parkinsonism, including bradykinesia or cogwheeling
• Oculogyric crises, manifesting as sudden, involuntary, sustained dystonic upward deviation of the eyes
• Motor tics
• Attention-deficit/hyperactivity disorder (ADHD)
• Anxiety
• Depression
• Aggression
• Oppositional defiant disorder (ODD)
• Emotional dysregulation
• Irritability
• Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
• Some affected individuals have true growth hormone deficiency (see
• Currently there is no evidence that individuals with PTPSD have issues with bone health; however, as there are recommendations for maintaining bone health in individuals with PAH deficiency, this has also been recommended for individuals with PTPSD (see
• Periventricular hyperintensities
• Delayed myelination
• Brain calcifications
• Brain atrophy
• Pituitary gland hyperplasia or adenoma
• Periventricular hyperintensities
• Delayed myelination
• Brain calcifications
• Brain atrophy
• Pituitary gland hyperplasia or adenoma
• Periventricular hyperintensities
• Delayed myelination
• Brain calcifications
• Brain atrophy
• Pituitary gland hyperplasia or adenoma
## Mild (Peripheral) PTPSD
In the mild (peripheral) form, affected individuals are usually asymptomatic apart from an increase in Phe levels. With time, they can have mild developmental delays and can develop deficiency of neurotransmitter production. Some remain asymptomatic.
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been identified.
## Nomenclature
BH4-deficient hyperphenylalaninemia is an umbrella term encompassing all types of hyperphenylalaninemia caused by BH4 deficiency, i.e., hyperphenylalaninemia associated with pathogenic variants in
Hyperphenylalaninemia type III is an outdated term previously used to denote PTPSD.
## Prevalence
The exact global prevalence of PTPSD is still unknown. However, it is estimated that BH4 deficiencies (all forms) account for about 1%-2% of hyperphenylalaninemias, which have a prevalence of approximately one in 15,000 individuals. Additionally, PTPSD specifically accounts for around 54% of all BH4 deficiencies [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The most common genetic cause of hyperphenylalaninemia is
Inherited co-chaperone DNAJC12 deficiency has been identified as a potential differential diagnosis for primary hyperphenylalaninemia, alongside PAH deficiency and disorders of BH4 metabolism (see
Disorders Known to Cause Hyperphenylalaninemia
AR = autosomal recessive; BH4 = tetrahydrobiopterin; MOI = mode of inheritance
## Management
Consensus guidelines for the diagnosis and treatment of tetrahydrobiopterin (BH4) deficiencies have been published [
To establish the extent of disease and needs in an individual diagnosed with PTPSD, the evaluations summarized in
PTPSD: Recommended Evaluations Following Initial Diagnosis
Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended).
Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
CSF = cerebrospinal fluid; MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist; PTPSD =
After a new diagnosis of PTPSD in a child, the closest hospital and local pediatrician should also be informed.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
The general concepts of immediate care for children with confirmed PTPSD include supplementation of the missing neurotransmitter precursors (in those who have low neurotransmitter levels in cerebrospinal fluid [CSF]) and restoring deficient cofactors to normalize hyperphenylalaninemia.
In individuals with hyperphenylalaninemia, immediate therapy involving dietary phenylalanine (Phe) restriction is recommended to lower Phe levels, similar to the approach taken in
For infants, Phe-free metabolic infant formula in combination with breastmilk and/or infant formula may be used.
However, once a diagnosis of PTPSD is confirmed, treatment typically involves the administration of oral sapropterin, which is a synthetic form of BH4, or a Phe-reduced diet, if sapropterin is not available.
BH4 can easily reach the liver and enable the enzyme PAH to function properly.
Unlike in PAH deficiency, oral sapropterin has the ability to completely normalize Phe levels, eliminating the need for a long-term restricted diet.
Therefore, after initiating sapropterin therapy, the diet can be liberalized.
Sapropterin has limited access to the central nervous system (CNS), and this access is only achieved at high doses, typically around 40 mg/kg/day (although this would be considered an off-label dose for this medication).
Due to this limitation, therapy with sapropterin does not fully normalize the activity of tyrosine (Tyr) or tryptophan hydroxylase in people with PTPSD.
Additional treatment strategies are necessary for long-term management and may include the use of neurotransmitter precursors and/or dopamine and serotonin agonists, or other medications to address specific neurotransmitter deficiencies and maintain optimal neurologic function.
Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
PTPSD: Targeted Pharmacologic Therapy
Start at 0.1 mg/kg/day in 2-3 divided doses.
Increase every 2 weeks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day.
Dose at breakfast & lunch; avoid nighttime doses if insomnia is experienced.
Dose sublingual preparations much lower (see package insert).
Start w/2 µg/kg/day divided BID.
Increase by 1 µg/kg every 2 weeks, if tolerated, to max of 10 µg/kg/day
Start w/2 mg/day.
Increase weekly by 2 mg up to a max of 8 mg/day.
Do not cut patches.
Drug-induced dyskinesias require a lower dose &/or slower dose increase.
Skin reactions occur in about 30% of people.
BID = twice a day; CSF = cerebrospinal fluid; DCI = decarboxylase inhibitor; PAH = phenylalanine hydroxylase; PTPSD =
Levodopa treatment should be started at 0.5 to 1 mg/kg/day and be stepwise increased to a final dose of up to 10 mg/kg/day (or the individual maximally tolerated dosage) in at least four to five doses per day over a time period of five to 10 (or more) weeks.
The pace of dosage increase depends on individual levodopa sensitivity.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended (see
PTPSD: Supportive Care
Movement disorders can be confused w/epilepsy.
Education of parents/caregivers
Feeding therapy may be considered.
Gastrostomy tube placement is usually not required.
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; PTPSD =
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.
Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
As PTPSD is a lifelong disorder with varying implications according to age, smooth transition of care of affected individuals from a pediatric setting to an adult-centered multidisciplinary care setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Because standardized procedures for transitional care do not exist for PTPSD due to the absence of multidisciplinary outpatient departments and lack of adult-specific metabolic centers in most places, the following have been observed:
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PTPSD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
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.
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in
PTPSD: Recommended Biochemical Surveillance
Age 1-7 yrs: every 3-6 mos
Age 8-18 yrs: every 6-12 mos
Based on Tables 2 and
Phe = phenylalanine; PTPSD =
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
PTPSD: Recommended Surveillance for Clinical Manifestations
Measurement of growth parameters
Eval of nutritional status
Assess developmental milestones & overall developmental progress.
Assure that educational needs are being addressed.
Periodic parathormone level
DXA scan in adults
DXA = dual-energy x-ray absorptiometry; PTPSD =
Aspartame is an artificial sweetener in widespread use that is often added to soft drinks, foods, and some medications to improve their taste. It is metabolized in the gastrointestinal tract into Phe and other byproducts. Persons with PTPSD on a Phe-reduced diet should either avoid products containing aspartame or calculate total intake of Phe when using such products and adapt diet components accordingly [
Note: Some medications (such as antibiotics) contain aspartame; thus, short treatment courses might need to be given if no alternative antibiotics are readily available.
The initial newborn screening (NBS) Phe measurement (collected when the newborn is on a normal formula / breast milk diet) should determine if the Phe concentration is elevated. If the blood Phe concentration is elevated, a Phe-free formula should be provided as soon as possible to quickly reduce the infant's blood Phe concentration (see
In most circumstances, the NBS blood Phe measurement will be available before the results of molecular genetic testing, even if the familial pathogenic variants are known. Molecular genetic testing can be used to confirm the diagnosis in a newborn with a positive NBS (molecular genetic testing in this circumstance is most informative if the familial
Review of sib NBS results is recommended to confirm the disease status of at-risk sibs. If older sibs have not undergone NBS, it is important to measure blood Phe concentrations of at-risk sibs to clarify their disease status.
If the
See
Women with PTPSD who have received appropriate treatment throughout childhood and adolescence and during pregnancy may have offspring with normal intellectual and behavioral development, particularly if levels of Phe are kept in the normal range during pregnancy. Intensive clinical and biochemical supervision by a multidisciplinary team before, during, and after pregnancy in a woman with PTPSD is essential to control the symptoms of the disease, adjust the treatment if needed, and monitor the development of the fetus. If the affected woman has elevated blood Phe concentrations during pregnancy, the fetus is at high risk for maternal phenylketonuria (MPKU) syndrome (reported specifically in women who have PAH deficiency as the primary cause of their elevated Phe levels) including malformations and intellectual disability, since Phe is a potent teratogen (see Phenylalanine Hydroxylase Deficiency, Clinical Characteristics,
See
Co-monitor in conjunction with a metabolic dietitian and metabolic physician from a metabolic center with experience in managing a pregnant woman with PTPSD.
Maternal blood Phe concentration of 30-360 µmol/L during pregnancy is recommended.
In unplanned pregnancies, monitoring the Phe concentration is immediately necessary and, if elevated, reducing the Phe concentration using dietary management or pharmacologic therapy is strongly recommended.
Monitor dietary intake of pregnant women with PTPSD to ensure nutrient adequacy with proper proportion of protein, fat, and carbohydrates.
Evaluate for fetal anomalies by high-resolution ultrasound examination and fetal echocardiogram at the appropriate gestational ages.
In addition to lowering Phe levels, sepiapterin could potentially offer the advantage of crossing the blood-brain barrier and activating tyrosine and tryptophan hydroxylase.
Search
• Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended).
• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
• In individuals with hyperphenylalaninemia, immediate therapy involving dietary phenylalanine (Phe) restriction is recommended to lower Phe levels, similar to the approach taken in
• For infants, Phe-free metabolic infant formula in combination with breastmilk and/or infant formula may be used.
• However, once a diagnosis of PTPSD is confirmed, treatment typically involves the administration of oral sapropterin, which is a synthetic form of BH4, or a Phe-reduced diet, if sapropterin is not available.
• BH4 can easily reach the liver and enable the enzyme PAH to function properly.
• Unlike in PAH deficiency, oral sapropterin has the ability to completely normalize Phe levels, eliminating the need for a long-term restricted diet.
• Therefore, after initiating sapropterin therapy, the diet can be liberalized.
• Due to this limitation, therapy with sapropterin does not fully normalize the activity of tyrosine (Tyr) or tryptophan hydroxylase in people with PTPSD.
• Additional treatment strategies are necessary for long-term management and may include the use of neurotransmitter precursors and/or dopamine and serotonin agonists, or other medications to address specific neurotransmitter deficiencies and maintain optimal neurologic function.
• Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
• Start at 0.1 mg/kg/day in 2-3 divided doses.
• Increase every 2 weeks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day.
• Dose at breakfast & lunch; avoid nighttime doses if insomnia is experienced.
• Dose sublingual preparations much lower (see package insert).
• Start w/2 µg/kg/day divided BID.
• Increase by 1 µg/kg every 2 weeks, if tolerated, to max of 10 µg/kg/day
• Start w/2 mg/day.
• Increase weekly by 2 mg up to a max of 8 mg/day.
• Do not cut patches.
• Drug-induced dyskinesias require a lower dose &/or slower dose increase.
• Skin reactions occur in about 30% of people.
• Movement disorders can be confused w/epilepsy.
• Education of parents/caregivers
• Feeding therapy may be considered.
• Gastrostomy tube placement is usually not required.
• 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PTPSD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• 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.
• Age 1-7 yrs: every 3-6 mos
• Age 8-18 yrs: every 6-12 mos
• Measurement of growth parameters
• Eval of nutritional status
• Assess developmental milestones & overall developmental progress.
• Assure that educational needs are being addressed.
• Periodic parathormone level
• DXA scan in adults
• The initial newborn screening (NBS) Phe measurement (collected when the newborn is on a normal formula / breast milk diet) should determine if the Phe concentration is elevated. If the blood Phe concentration is elevated, a Phe-free formula should be provided as soon as possible to quickly reduce the infant's blood Phe concentration (see
• In most circumstances, the NBS blood Phe measurement will be available before the results of molecular genetic testing, even if the familial pathogenic variants are known. Molecular genetic testing can be used to confirm the diagnosis in a newborn with a positive NBS (molecular genetic testing in this circumstance is most informative if the familial
• Review of sib NBS results is recommended to confirm the disease status of at-risk sibs. If older sibs have not undergone NBS, it is important to measure blood Phe concentrations of at-risk sibs to clarify their disease status.
• If the
• Co-monitor in conjunction with a metabolic dietitian and metabolic physician from a metabolic center with experience in managing a pregnant woman with PTPSD.
• Maternal blood Phe concentration of 30-360 µmol/L during pregnancy is recommended.
• In unplanned pregnancies, monitoring the Phe concentration is immediately necessary and, if elevated, reducing the Phe concentration using dietary management or pharmacologic therapy is strongly recommended.
• Maternal blood Phe concentration of 30-360 µmol/L during pregnancy is recommended.
• In unplanned pregnancies, monitoring the Phe concentration is immediately necessary and, if elevated, reducing the Phe concentration using dietary management or pharmacologic therapy is strongly recommended.
• Monitor dietary intake of pregnant women with PTPSD to ensure nutrient adequacy with proper proportion of protein, fat, and carbohydrates.
• Evaluate for fetal anomalies by high-resolution ultrasound examination and fetal echocardiogram at the appropriate gestational ages.
• Maternal blood Phe concentration of 30-360 µmol/L during pregnancy is recommended.
• In unplanned pregnancies, monitoring the Phe concentration is immediately necessary and, if elevated, reducing the Phe concentration using dietary management or pharmacologic therapy is strongly recommended.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with PTPSD, the evaluations summarized in
PTPSD: Recommended Evaluations Following Initial Diagnosis
Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended).
Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
CSF = cerebrospinal fluid; MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist; PTPSD =
After a new diagnosis of PTPSD in a child, the closest hospital and local pediatrician should also be informed.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Transfer to specialist center w/experience in management of inherited metabolic diseases (strongly recommended).
• Consider short hospitalization at center of expertise for inherited metabolic conditions to provide caregivers w/detailed education (natural history, maintenance & emergency treatment, prognosis, & risks for acute encephalopathic crises).
## Treatment of Manifestations
The general concepts of immediate care for children with confirmed PTPSD include supplementation of the missing neurotransmitter precursors (in those who have low neurotransmitter levels in cerebrospinal fluid [CSF]) and restoring deficient cofactors to normalize hyperphenylalaninemia.
In individuals with hyperphenylalaninemia, immediate therapy involving dietary phenylalanine (Phe) restriction is recommended to lower Phe levels, similar to the approach taken in
For infants, Phe-free metabolic infant formula in combination with breastmilk and/or infant formula may be used.
However, once a diagnosis of PTPSD is confirmed, treatment typically involves the administration of oral sapropterin, which is a synthetic form of BH4, or a Phe-reduced diet, if sapropterin is not available.
BH4 can easily reach the liver and enable the enzyme PAH to function properly.
Unlike in PAH deficiency, oral sapropterin has the ability to completely normalize Phe levels, eliminating the need for a long-term restricted diet.
Therefore, after initiating sapropterin therapy, the diet can be liberalized.
Sapropterin has limited access to the central nervous system (CNS), and this access is only achieved at high doses, typically around 40 mg/kg/day (although this would be considered an off-label dose for this medication).
Due to this limitation, therapy with sapropterin does not fully normalize the activity of tyrosine (Tyr) or tryptophan hydroxylase in people with PTPSD.
Additional treatment strategies are necessary for long-term management and may include the use of neurotransmitter precursors and/or dopamine and serotonin agonists, or other medications to address specific neurotransmitter deficiencies and maintain optimal neurologic function.
Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
PTPSD: Targeted Pharmacologic Therapy
Start at 0.1 mg/kg/day in 2-3 divided doses.
Increase every 2 weeks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day.
Dose at breakfast & lunch; avoid nighttime doses if insomnia is experienced.
Dose sublingual preparations much lower (see package insert).
Start w/2 µg/kg/day divided BID.
Increase by 1 µg/kg every 2 weeks, if tolerated, to max of 10 µg/kg/day
Start w/2 mg/day.
Increase weekly by 2 mg up to a max of 8 mg/day.
Do not cut patches.
Drug-induced dyskinesias require a lower dose &/or slower dose increase.
Skin reactions occur in about 30% of people.
BID = twice a day; CSF = cerebrospinal fluid; DCI = decarboxylase inhibitor; PAH = phenylalanine hydroxylase; PTPSD =
Levodopa treatment should be started at 0.5 to 1 mg/kg/day and be stepwise increased to a final dose of up to 10 mg/kg/day (or the individual maximally tolerated dosage) in at least four to five doses per day over a time period of five to 10 (or more) weeks.
The pace of dosage increase depends on individual levodopa sensitivity.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended (see
PTPSD: Supportive Care
Movement disorders can be confused w/epilepsy.
Education of parents/caregivers
Feeding therapy may be considered.
Gastrostomy tube placement is usually not required.
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; PTPSD =
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.
Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
As PTPSD is a lifelong disorder with varying implications according to age, smooth transition of care of affected individuals from a pediatric setting to an adult-centered multidisciplinary care setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Because standardized procedures for transitional care do not exist for PTPSD due to the absence of multidisciplinary outpatient departments and lack of adult-specific metabolic centers in most places, the following have been observed:
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PTPSD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
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.
• In individuals with hyperphenylalaninemia, immediate therapy involving dietary phenylalanine (Phe) restriction is recommended to lower Phe levels, similar to the approach taken in
• For infants, Phe-free metabolic infant formula in combination with breastmilk and/or infant formula may be used.
• However, once a diagnosis of PTPSD is confirmed, treatment typically involves the administration of oral sapropterin, which is a synthetic form of BH4, or a Phe-reduced diet, if sapropterin is not available.
• BH4 can easily reach the liver and enable the enzyme PAH to function properly.
• Unlike in PAH deficiency, oral sapropterin has the ability to completely normalize Phe levels, eliminating the need for a long-term restricted diet.
• Therefore, after initiating sapropterin therapy, the diet can be liberalized.
• Due to this limitation, therapy with sapropterin does not fully normalize the activity of tyrosine (Tyr) or tryptophan hydroxylase in people with PTPSD.
• Additional treatment strategies are necessary for long-term management and may include the use of neurotransmitter precursors and/or dopamine and serotonin agonists, or other medications to address specific neurotransmitter deficiencies and maintain optimal neurologic function.
• Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
• Start at 0.1 mg/kg/day in 2-3 divided doses.
• Increase every 2 weeks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day.
• Dose at breakfast & lunch; avoid nighttime doses if insomnia is experienced.
• Dose sublingual preparations much lower (see package insert).
• Start w/2 µg/kg/day divided BID.
• Increase by 1 µg/kg every 2 weeks, if tolerated, to max of 10 µg/kg/day
• Start w/2 mg/day.
• Increase weekly by 2 mg up to a max of 8 mg/day.
• Do not cut patches.
• Drug-induced dyskinesias require a lower dose &/or slower dose increase.
• Skin reactions occur in about 30% of people.
• Movement disorders can be confused w/epilepsy.
• Education of parents/caregivers
• Feeding therapy may be considered.
• Gastrostomy tube placement is usually not required.
• 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PTPSD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• 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.
## Targeted Pharmacologic Therapy
Sapropterin has limited access to the central nervous system (CNS), and this access is only achieved at high doses, typically around 40 mg/kg/day (although this would be considered an off-label dose for this medication).
Due to this limitation, therapy with sapropterin does not fully normalize the activity of tyrosine (Tyr) or tryptophan hydroxylase in people with PTPSD.
Additional treatment strategies are necessary for long-term management and may include the use of neurotransmitter precursors and/or dopamine and serotonin agonists, or other medications to address specific neurotransmitter deficiencies and maintain optimal neurologic function.
Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
PTPSD: Targeted Pharmacologic Therapy
Start at 0.1 mg/kg/day in 2-3 divided doses.
Increase every 2 weeks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day.
Dose at breakfast & lunch; avoid nighttime doses if insomnia is experienced.
Dose sublingual preparations much lower (see package insert).
Start w/2 µg/kg/day divided BID.
Increase by 1 µg/kg every 2 weeks, if tolerated, to max of 10 µg/kg/day
Start w/2 mg/day.
Increase weekly by 2 mg up to a max of 8 mg/day.
Do not cut patches.
Drug-induced dyskinesias require a lower dose &/or slower dose increase.
Skin reactions occur in about 30% of people.
BID = twice a day; CSF = cerebrospinal fluid; DCI = decarboxylase inhibitor; PAH = phenylalanine hydroxylase; PTPSD =
Levodopa treatment should be started at 0.5 to 1 mg/kg/day and be stepwise increased to a final dose of up to 10 mg/kg/day (or the individual maximally tolerated dosage) in at least four to five doses per day over a time period of five to 10 (or more) weeks.
The pace of dosage increase depends on individual levodopa sensitivity.
• Due to this limitation, therapy with sapropterin does not fully normalize the activity of tyrosine (Tyr) or tryptophan hydroxylase in people with PTPSD.
• Additional treatment strategies are necessary for long-term management and may include the use of neurotransmitter precursors and/or dopamine and serotonin agonists, or other medications to address specific neurotransmitter deficiencies and maintain optimal neurologic function.
• Prolactin secretion increases when there is insufficient dopaminergic action, and plasma levels can be used to assess adequacy of supplements (see
• Start at 0.1 mg/kg/day in 2-3 divided doses.
• Increase every 2 weeks by 0.1 mg/kg/day up to 0.3 mg/kg/day or 10 mg/day.
• Dose at breakfast & lunch; avoid nighttime doses if insomnia is experienced.
• Dose sublingual preparations much lower (see package insert).
• Start w/2 µg/kg/day divided BID.
• Increase by 1 µg/kg every 2 weeks, if tolerated, to max of 10 µg/kg/day
• Start w/2 mg/day.
• Increase weekly by 2 mg up to a max of 8 mg/day.
• Do not cut patches.
• Drug-induced dyskinesias require a lower dose &/or slower dose increase.
• Skin reactions occur in about 30% of people.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is recommended (see
PTPSD: Supportive Care
Movement disorders can be confused w/epilepsy.
Education of parents/caregivers
Feeding therapy may be considered.
Gastrostomy tube placement is usually not required.
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; PTPSD =
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.
Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
As PTPSD is a lifelong disorder with varying implications according to age, smooth transition of care of affected individuals from a pediatric setting to an adult-centered multidisciplinary care setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Because standardized procedures for transitional care do not exist for PTPSD due to the absence of multidisciplinary outpatient departments and lack of adult-specific metabolic centers in most places, the following have been observed:
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PTPSD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
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.
• Movement disorders can be confused w/epilepsy.
• Education of parents/caregivers
• Feeding therapy may be considered.
• Gastrostomy tube placement is usually not required.
• 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should be discussed and incorporated in the IEP. For those receiving IEP services, the public school district is required to provide services until age 21.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PTPSD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• 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.
##
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.
Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical therapy (PT), occupational therapy (OT), and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
##
As PTPSD is a lifelong disorder with varying implications according to age, smooth transition of care of affected individuals from a pediatric setting to an adult-centered multidisciplinary care setting is essential for long-term management and should be organized as a well-planned, continuous, multidisciplinary process integrating resources of all relevant subspecialties. Because standardized procedures for transitional care do not exist for PTPSD due to the absence of multidisciplinary outpatient departments and lack of adult-specific metabolic centers in most places, the following have been observed:
Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PTPSD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
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.
• Transitional care concepts have been developed in which adult internal medicine specialists initially see individuals with PTPSD together with pediatric metabolic experts, dietitians, psychologists, and social workers.
• 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.
## Surveillance
In addition to regular evaluations by a metabolic specialist and metabolic dietician, the evaluations summarized in
PTPSD: Recommended Biochemical Surveillance
Age 1-7 yrs: every 3-6 mos
Age 8-18 yrs: every 6-12 mos
Based on Tables 2 and
Phe = phenylalanine; PTPSD =
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
PTPSD: Recommended Surveillance for Clinical Manifestations
Measurement of growth parameters
Eval of nutritional status
Assess developmental milestones & overall developmental progress.
Assure that educational needs are being addressed.
Periodic parathormone level
DXA scan in adults
DXA = dual-energy x-ray absorptiometry; PTPSD =
• Age 1-7 yrs: every 3-6 mos
• Age 8-18 yrs: every 6-12 mos
• Measurement of growth parameters
• Eval of nutritional status
• Assess developmental milestones & overall developmental progress.
• Assure that educational needs are being addressed.
• Periodic parathormone level
• DXA scan in adults
## Agents/Circumstances to Avoid
Aspartame is an artificial sweetener in widespread use that is often added to soft drinks, foods, and some medications to improve their taste. It is metabolized in the gastrointestinal tract into Phe and other byproducts. Persons with PTPSD on a Phe-reduced diet should either avoid products containing aspartame or calculate total intake of Phe when using such products and adapt diet components accordingly [
Note: Some medications (such as antibiotics) contain aspartame; thus, short treatment courses might need to be given if no alternative antibiotics are readily available.
## Evaluation of Relatives at Risk
The initial newborn screening (NBS) Phe measurement (collected when the newborn is on a normal formula / breast milk diet) should determine if the Phe concentration is elevated. If the blood Phe concentration is elevated, a Phe-free formula should be provided as soon as possible to quickly reduce the infant's blood Phe concentration (see
In most circumstances, the NBS blood Phe measurement will be available before the results of molecular genetic testing, even if the familial pathogenic variants are known. Molecular genetic testing can be used to confirm the diagnosis in a newborn with a positive NBS (molecular genetic testing in this circumstance is most informative if the familial
Review of sib NBS results is recommended to confirm the disease status of at-risk sibs. If older sibs have not undergone NBS, it is important to measure blood Phe concentrations of at-risk sibs to clarify their disease status.
If the
See
• The initial newborn screening (NBS) Phe measurement (collected when the newborn is on a normal formula / breast milk diet) should determine if the Phe concentration is elevated. If the blood Phe concentration is elevated, a Phe-free formula should be provided as soon as possible to quickly reduce the infant's blood Phe concentration (see
• In most circumstances, the NBS blood Phe measurement will be available before the results of molecular genetic testing, even if the familial pathogenic variants are known. Molecular genetic testing can be used to confirm the diagnosis in a newborn with a positive NBS (molecular genetic testing in this circumstance is most informative if the familial
• Review of sib NBS results is recommended to confirm the disease status of at-risk sibs. If older sibs have not undergone NBS, it is important to measure blood Phe concentrations of at-risk sibs to clarify their disease status.
• If the
## Pregnancy Management
Women with PTPSD who have received appropriate treatment throughout childhood and adolescence and during pregnancy may have offspring with normal intellectual and behavioral development, particularly if levels of Phe are kept in the normal range during pregnancy. Intensive clinical and biochemical supervision by a multidisciplinary team before, during, and after pregnancy in a woman with PTPSD is essential to control the symptoms of the disease, adjust the treatment if needed, and monitor the development of the fetus. If the affected woman has elevated blood Phe concentrations during pregnancy, the fetus is at high risk for maternal phenylketonuria (MPKU) syndrome (reported specifically in women who have PAH deficiency as the primary cause of their elevated Phe levels) including malformations and intellectual disability, since Phe is a potent teratogen (see Phenylalanine Hydroxylase Deficiency, Clinical Characteristics,
See
Co-monitor in conjunction with a metabolic dietitian and metabolic physician from a metabolic center with experience in managing a pregnant woman with PTPSD.
Maternal blood Phe concentration of 30-360 µmol/L during pregnancy is recommended.
In unplanned pregnancies, monitoring the Phe concentration is immediately necessary and, if elevated, reducing the Phe concentration using dietary management or pharmacologic therapy is strongly recommended.
Monitor dietary intake of pregnant women with PTPSD to ensure nutrient adequacy with proper proportion of protein, fat, and carbohydrates.
Evaluate for fetal anomalies by high-resolution ultrasound examination and fetal echocardiogram at the appropriate gestational ages.
• Co-monitor in conjunction with a metabolic dietitian and metabolic physician from a metabolic center with experience in managing a pregnant woman with PTPSD.
• Maternal blood Phe concentration of 30-360 µmol/L during pregnancy is recommended.
• In unplanned pregnancies, monitoring the Phe concentration is immediately necessary and, if elevated, reducing the Phe concentration using dietary management or pharmacologic therapy is strongly recommended.
• Maternal blood Phe concentration of 30-360 µmol/L during pregnancy is recommended.
• In unplanned pregnancies, monitoring the Phe concentration is immediately necessary and, if elevated, reducing the Phe concentration using dietary management or pharmacologic therapy is strongly recommended.
• Monitor dietary intake of pregnant women with PTPSD to ensure nutrient adequacy with proper proportion of protein, fat, and carbohydrates.
• Evaluate for fetal anomalies by high-resolution ultrasound examination and fetal echocardiogram at the appropriate gestational ages.
• Maternal blood Phe concentration of 30-360 µmol/L during pregnancy is recommended.
• In unplanned pregnancies, monitoring the Phe concentration is immediately necessary and, if elevated, reducing the Phe concentration using dietary management or pharmacologic therapy is strongly recommended.
## Therapies Under Investigation
In addition to lowering Phe levels, sepiapterin could potentially offer the advantage of crossing the blood-brain barrier and activating tyrosine and tryptophan hydroxylase.
Search
## Genetic Counseling
PTPSD is inherited in an autosomal recessive manner.
The parents of an affected child 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 the proband to confirm that both parents are heterozygous for 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.
Unless an affected individual's reproductive partner is a carrier of a
If the proband is female, fetal exposure to elevated maternal blood phenylalanine (Phe) concentrations during pregnancy is a critical issue (see
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
See Management,
Young women of childbearing age with PTPSD should receive counseling regarding the teratogenic effects of elevated maternal blood Phe concentrations during pregnancy (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 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
• 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
• 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.
• Unless an affected individual's reproductive partner is a carrier of a
• If the proband is female, fetal exposure to elevated maternal blood phenylalanine (Phe) concentrations during pregnancy is a critical issue (see
• Young women of childbearing age with PTPSD should receive counseling regarding the teratogenic effects of elevated maternal blood Phe concentrations during pregnancy (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
PTPSD is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child 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 the proband to confirm that both parents are heterozygous for 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.
Unless an affected individual's reproductive partner is a carrier of a
If the proband is female, fetal exposure to elevated maternal blood phenylalanine (Phe) concentrations during pregnancy is a critical issue (see
• The parents of an affected child 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 the proband to confirm that both parents are heterozygous for 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.
• Unless an affected individual's reproductive partner is a carrier of a
• If the proband is female, fetal exposure to elevated maternal blood phenylalanine (Phe) concentrations during pregnancy is a critical issue (see
## Carrier Detection
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
Young women of childbearing age with PTPSD should receive counseling regarding the teratogenic effects of elevated maternal blood Phe concentrations during pregnancy (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.
• Young women of childbearing age with PTPSD should receive counseling regarding the teratogenic effects of elevated maternal blood Phe concentrations during pregnancy (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 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
Health Resources & Services Administration
•
•
•
• United Kingdom
•
•
• Health Resources & Services Administration
•
•
•
## Molecular Genetics
PTS-Related Tetrahydrobiopterin Deficiency (PTPSD): Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for PTS-Related Tetrahydrobiopterin Deficiency (PTPSD) (
Tetrahydrobiopterin (BH4) can be synthesized directly from guanosine triphosphate (GTP) by GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase, or it can be produced through a salvage pathway by sepiapterin reductase and dihyrofolate reductase.
One of the functions of BH4 is as a cofactor for the enzyme phenylalanine hydroxylase. Deficiency of this cofactor can lead to accumulation of phenylalanine in the blood, which can cause central nervous system (CNS) dysfunction.
BH4 is also a cofactor for tyrosine and tryptophan hydroxylase, enzymes involved in the synthesis of monoamine neurotransmitters whose deficiency can cause CNS dysfunction independently from hyperphenylalaninemia and for all three forms of nitric oxide synthase.
## Molecular Pathogenesis
Tetrahydrobiopterin (BH4) can be synthesized directly from guanosine triphosphate (GTP) by GTP cyclohydrolase I, 6-pyruvoyl-tetrahydropterin synthase and sepiapterin reductase, or it can be produced through a salvage pathway by sepiapterin reductase and dihyrofolate reductase.
One of the functions of BH4 is as a cofactor for the enzyme phenylalanine hydroxylase. Deficiency of this cofactor can lead to accumulation of phenylalanine in the blood, which can cause central nervous system (CNS) dysfunction.
BH4 is also a cofactor for tyrosine and tryptophan hydroxylase, enzymes involved in the synthesis of monoamine neurotransmitters whose deficiency can cause CNS dysfunction independently from hyperphenylalaninemia and for all three forms of nitric oxide synthase.
## Chapter Notes
Nicola Longo is supported in part by the Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) Consortium funded by the National Institutes of Health (U54HD100982).
Thomas Opladen is subnet coordinator with the framework of MetabERN, the European Reference Network for Hereditary Metabolic Disorders, Subnetwork NOMS (Disorders of Neuromodulators and Other Small Molecules), and coordinator of the International Working Group on Neurotransmitter-Related Disorders (iNTD).
Nenad Blau is supported by the Nenad Blau IEMbase Endowment Fund of the MCF, Marin County, California.
10 July 2025 (ma) Review posted live
21 June 2024 (nb) Original submission
• 10 July 2025 (ma) Review posted live
• 21 June 2024 (nb) Original submission
## Acknowledgments
Nicola Longo is supported in part by the Phenylalanine Families and Researchers Exploring Evidence (PHEFREE) Consortium funded by the National Institutes of Health (U54HD100982).
Thomas Opladen is subnet coordinator with the framework of MetabERN, the European Reference Network for Hereditary Metabolic Disorders, Subnetwork NOMS (Disorders of Neuromodulators and Other Small Molecules), and coordinator of the International Working Group on Neurotransmitter-Related Disorders (iNTD).
Nenad Blau is supported by the Nenad Blau IEMbase Endowment Fund of the MCF, Marin County, California.
## Revision History
10 July 2025 (ma) Review posted live
21 June 2024 (nb) Original submission
• 10 July 2025 (ma) Review posted live
• 21 June 2024 (nb) Original submission
## References
## Literature Cited
|
[] |
10/7/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
ptt
|
ptt
|
[
"Prothrombin G20210A Thrombophilia",
"Prothrombin G20210A Thrombophilia",
"Prothrombin",
"F2",
"Prothrombin Thrombophilia"
] |
Prothrombin Thrombophilia
|
Jody L Kujovich
|
Summary Prothrombin thrombophilia is characterized by venous thromboembolism (VTE) manifest most commonly in adults as deep-vein thrombosis (DVT) in the legs or pulmonary embolism. The clinical expression of prothrombin thrombophilia is variable; many individuals heterozygous or homozygous for the 20210G>A The diagnosis of prothrombin thrombophilia is established in a proband by identification of a heterozygous or homozygous 20210G>A variant (also known as c.*97G>A) in Prothrombin thrombophilia is inherited in an autosomal dominant manner: heterozygosity for the 20210G>A variant results in an increased risk for thrombosis; homozygosity for this variant confers a higher risk for thrombosis than heterozygosity. Occasionally (because of the relatively high frequency of the 20210G>A variant in the general population) one parent is homozygous for the 20210G>A variant or both parents are heterozygous for the 20210G>A variant. The genetic status of both parents and/or the reproductive partner of an affected individual needs to be evaluated before information regarding potential risks to sibs or offspring can be provided. If one parent of a heterozygous proband is heterozygous for the 20210G>A variant, the sibs of the proband are at 50% risk of being heterozygous; if one parent is homozygous, the sibs of the proband will be heterozygous. Once the 20210G>A variant has been identified in a family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible.
|
## Diagnosis
No clinical features are specific for prothrombin thrombophilia. The diagnosis
A first unprovoked venous thromboembolism (VTE) before age 50 years
A history of recurrent VTE
Venous thrombosis at certain unusual sites such as the cerebral, mesenteric, portal, or hepatic veins
VTE during pregnancy or the puerperium
VTE associated with the use of estrogen-containing oral contraceptives or hormone replacement therapy (HRT)
An unprovoked VTE at any age in an individual with a first-degree family member with a VTE before age 50 years
Prothrombin thrombophilia testing
A history of unprovoked VTE considering discontinuation of anticoagulation
A first VTE related to use of tamoxifen or other selective estrogen receptor modulators
Age greater than 50 years with a first unprovoked VTE
Neonates and children with non-catheter related idiopathic VTE or stroke
Molecular genetic testing for the
General population screening
Routine initial testing prior to the use of estrogen-containing contraceptives, HRT, or selective estrogen receptor modulators
Adults with VTE occurring in the setting of major transient risk factors (e.g., surgery, trauma)
Routine initial testing in adults with arterial thrombosis
Individuals with unprovoked VTE already receiving long-term anticoagulation treatment
Routine initial testing during pregnancy
Routine testing in women with recurrent fetal loss, placental abruption, fetal growth restriction, or preeclampsia
Prenatal or newborn testing
Neonates and children with asymptomatic central venous catheter-related thrombosis
Routine testing in asymptomatic children
Routine testing of unselected children with a first episode of VTE
The diagnosis of prothrombin thrombophilia
Note: The range of plasma concentrations of prothrombin in heterozygotes overlaps with the normal range. Therefore, plasma prothrombin concentration is not reliable for diagnosis.
Molecular genetic testing approaches can include
Note: The diagnosis of prothrombin thrombophilia in the setting of liver transplantation requires molecular genetic testing of donor liver, the site of prothrombin synthesis.
Molecular Genetic Testing Used in Prothrombin Thrombophilia
See
See
The official designation of the pathogenic variant is c.*97G>A per
• A first unprovoked venous thromboembolism (VTE) before age 50 years
• A history of recurrent VTE
• Venous thrombosis at certain unusual sites such as the cerebral, mesenteric, portal, or hepatic veins
• VTE during pregnancy or the puerperium
• VTE associated with the use of estrogen-containing oral contraceptives or hormone replacement therapy (HRT)
• An unprovoked VTE at any age in an individual with a first-degree family member with a VTE before age 50 years
• A history of unprovoked VTE considering discontinuation of anticoagulation
• A first VTE related to use of tamoxifen or other selective estrogen receptor modulators
• Age greater than 50 years with a first unprovoked VTE
• Neonates and children with non-catheter related idiopathic VTE or stroke
• General population screening
• Routine initial testing prior to the use of estrogen-containing contraceptives, HRT, or selective estrogen receptor modulators
• Adults with VTE occurring in the setting of major transient risk factors (e.g., surgery, trauma)
• Routine initial testing in adults with arterial thrombosis
• Individuals with unprovoked VTE already receiving long-term anticoagulation treatment
• Routine initial testing during pregnancy
• Routine testing in women with recurrent fetal loss, placental abruption, fetal growth restriction, or preeclampsia
• Prenatal or newborn testing
• Neonates and children with asymptomatic central venous catheter-related thrombosis
• Routine testing in asymptomatic children
• Routine testing of unselected children with a first episode of VTE
## Suggestive Findings
No clinical features are specific for prothrombin thrombophilia. The diagnosis
A first unprovoked venous thromboembolism (VTE) before age 50 years
A history of recurrent VTE
Venous thrombosis at certain unusual sites such as the cerebral, mesenteric, portal, or hepatic veins
VTE during pregnancy or the puerperium
VTE associated with the use of estrogen-containing oral contraceptives or hormone replacement therapy (HRT)
An unprovoked VTE at any age in an individual with a first-degree family member with a VTE before age 50 years
Prothrombin thrombophilia testing
A history of unprovoked VTE considering discontinuation of anticoagulation
A first VTE related to use of tamoxifen or other selective estrogen receptor modulators
Age greater than 50 years with a first unprovoked VTE
Neonates and children with non-catheter related idiopathic VTE or stroke
Molecular genetic testing for the
General population screening
Routine initial testing prior to the use of estrogen-containing contraceptives, HRT, or selective estrogen receptor modulators
Adults with VTE occurring in the setting of major transient risk factors (e.g., surgery, trauma)
Routine initial testing in adults with arterial thrombosis
Individuals with unprovoked VTE already receiving long-term anticoagulation treatment
Routine initial testing during pregnancy
Routine testing in women with recurrent fetal loss, placental abruption, fetal growth restriction, or preeclampsia
Prenatal or newborn testing
Neonates and children with asymptomatic central venous catheter-related thrombosis
Routine testing in asymptomatic children
Routine testing of unselected children with a first episode of VTE
• A first unprovoked venous thromboembolism (VTE) before age 50 years
• A history of recurrent VTE
• Venous thrombosis at certain unusual sites such as the cerebral, mesenteric, portal, or hepatic veins
• VTE during pregnancy or the puerperium
• VTE associated with the use of estrogen-containing oral contraceptives or hormone replacement therapy (HRT)
• An unprovoked VTE at any age in an individual with a first-degree family member with a VTE before age 50 years
• A history of unprovoked VTE considering discontinuation of anticoagulation
• A first VTE related to use of tamoxifen or other selective estrogen receptor modulators
• Age greater than 50 years with a first unprovoked VTE
• Neonates and children with non-catheter related idiopathic VTE or stroke
• General population screening
• Routine initial testing prior to the use of estrogen-containing contraceptives, HRT, or selective estrogen receptor modulators
• Adults with VTE occurring in the setting of major transient risk factors (e.g., surgery, trauma)
• Routine initial testing in adults with arterial thrombosis
• Individuals with unprovoked VTE already receiving long-term anticoagulation treatment
• Routine initial testing during pregnancy
• Routine testing in women with recurrent fetal loss, placental abruption, fetal growth restriction, or preeclampsia
• Prenatal or newborn testing
• Neonates and children with asymptomatic central venous catheter-related thrombosis
• Routine testing in asymptomatic children
• Routine testing of unselected children with a first episode of VTE
## Establishing the Diagnosis
The diagnosis of prothrombin thrombophilia
Note: The range of plasma concentrations of prothrombin in heterozygotes overlaps with the normal range. Therefore, plasma prothrombin concentration is not reliable for diagnosis.
Molecular genetic testing approaches can include
Note: The diagnosis of prothrombin thrombophilia in the setting of liver transplantation requires molecular genetic testing of donor liver, the site of prothrombin synthesis.
Molecular Genetic Testing Used in Prothrombin Thrombophilia
See
See
The official designation of the pathogenic variant is c.*97G>A per
## Clinical Characteristics
The clinical expression of prothrombin thrombophilia is variable. Many individuals who are heterozygous or homozygous for the
The primary clinical manifestation of prothrombin thrombophilia is VTE. The relative risk for VTE is increased two- to fivefold in 20210G>A heterozygotes [
Among individuals with DVT, 20210G>A heterozygotes had a significantly higher rate of PE (32%) than those with the factor V Leiden variant (19%) or those without thrombophilia (17%). 20210G>A heterozygotes are also at increased risk of developing isolated PE [
Asymptomatic healthy children heterozygous or homozygous for 20210G>A are at low risk for thrombosis. Heterozygous children were found to have a three- to fourfold increase in relative risk for VTE [
During pregnancy women with a prior history of VTE have an increased recurrence risk ranging from 0% to 15% in published studies. The risk is higher in women with a prior unprovoked episode or an estrogen-related VTE, and in those with coexisting genetic or acquired risk factors [
In addition to the number of variants, the clinical expression of prothrombin thrombophilia is influenced by:
A family history of thrombosis affecting at least one first-degree relative is an additional risk factor for VTE even in those with a known inherited thrombophilic disorder (including 20210A heterozygosity) [
Another inherited thrombophilic disorder is present in 8%-14% of 20210G>A heterozygotes, creating an additive effect on overall thrombotic risk. Individuals with multiple thrombophilic disorders develop VTE at a younger age and are at higher risk for recurrent thrombosis than those with a single thrombophilic variant [
Acquired thrombophilic disorders include antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders, and increased levels of clotting factors.
The 20210G>A variant interacts with multiple environmental risk factors to increase the risk for VTE. At least 50% of thrombotic episodes in individuals with the 20210G>A variant are provoked by additional risk factors, with pregnancy being the most common [
Circumstantial Risk Factors: Increased Risk for Thrombophilia in Persons with the 20210G>A Variant
3x-15x ↑ risk (heterozygotes)
31x ↑ risk during pregnancy or postpartum
26x ↑ risk (homozygotes)
8-47x ↑ risk in compound heterozygotes (w/
During pregnancy: 1:200 to 1:300
Post partum:1:66 (highest risk: 1st 6 wks post partum)
In homozygotes: 1:40
In compound heterozygotes (w/factor V Leiden): 1:20 to 1:125
Higher risk during 1st yr of use than subsequent yrs
Incidence 1/500/yr
Unopposed progestin is assoc w/↓ risk for thrombosis vs estrogen-containing contraception.
3x ↑ risk (heterozygotes) vs women using HRT w/o 20210G>A variant
8x-25x ↑ risk (heterozygotes) vs women w/o 20210G>A variant not using HRT
7x ↑ risk if BMI >30 kg/m
5x ↑ risk if BMI 25-30 kg/m
17x ↑ risk of VTE
20x ↑ risk of UE VTE
5x ↑ risk of CVC thrombosis
BMI = body mass index; CVC = central venous catheter; HRT = hormone replacement therapy; SERMS = selective estrogen receptor modulators; UE = upper-extremity; VTE = venous thromboembolism
Women homozygous for 20210G>A or compound heterozygous for 20210G>A and factor V Leiden have a higher relative risk for pregnancy-associated VTE, but the absolute risk is less well defined [
Other newer forms of combined hormonal, transdermal, and vaginal ring contraception have not been studied in 20210G>A heterozygotes but the risk is likely at least as great as the risk associated with COC use.
The available evidence indicates that the 20210G>A variant is not a major risk factor for arterial thrombosis of any sort including myocardial infarction and stroke in fetuses, children, and adults.
No genotype-phenotype correlations have been identified for other
Prothrombin thrombophilia may also be referred to as
The 20210G>A variant is present in:
8.2% of Americans of European origin with VTE;
1.1% of African Americans with VTE;
6%-14% of adults with a first VTE;
18%-21% of adults with VTE and a personal or family history of recurrent VTE [
3.7% of children with a first spontaneous VTE [
The frequency of homozygosity for the 20210G>A variant is 1:10,000. 20210G>A homozygosity is found in 1.8%-4.5% of individuals with VTE [
• 3x-15x ↑ risk (heterozygotes)
• 31x ↑ risk during pregnancy or postpartum
• 26x ↑ risk (homozygotes)
• 8-47x ↑ risk in compound heterozygotes (w/
• During pregnancy: 1:200 to 1:300
• Post partum:1:66 (highest risk: 1st 6 wks post partum)
• In homozygotes: 1:40
• In compound heterozygotes (w/factor V Leiden): 1:20 to 1:125
• Higher risk during 1st yr of use than subsequent yrs
• Incidence 1/500/yr
• Unopposed progestin is assoc w/↓ risk for thrombosis vs estrogen-containing contraception.
• 3x ↑ risk (heterozygotes) vs women using HRT w/o 20210G>A variant
• 8x-25x ↑ risk (heterozygotes) vs women w/o 20210G>A variant not using HRT
• 7x ↑ risk if BMI >30 kg/m
• 5x ↑ risk if BMI 25-30 kg/m
• 17x ↑ risk of VTE
• 20x ↑ risk of UE VTE
• 5x ↑ risk of CVC thrombosis
• 8.2% of Americans of European origin with VTE;
• 1.1% of African Americans with VTE;
• 6%-14% of adults with a first VTE;
• 18%-21% of adults with VTE and a personal or family history of recurrent VTE [
• 3.7% of children with a first spontaneous VTE [
## Clinical Description
The clinical expression of prothrombin thrombophilia is variable. Many individuals who are heterozygous or homozygous for the
The primary clinical manifestation of prothrombin thrombophilia is VTE. The relative risk for VTE is increased two- to fivefold in 20210G>A heterozygotes [
Among individuals with DVT, 20210G>A heterozygotes had a significantly higher rate of PE (32%) than those with the factor V Leiden variant (19%) or those without thrombophilia (17%). 20210G>A heterozygotes are also at increased risk of developing isolated PE [
Asymptomatic healthy children heterozygous or homozygous for 20210G>A are at low risk for thrombosis. Heterozygous children were found to have a three- to fourfold increase in relative risk for VTE [
During pregnancy women with a prior history of VTE have an increased recurrence risk ranging from 0% to 15% in published studies. The risk is higher in women with a prior unprovoked episode or an estrogen-related VTE, and in those with coexisting genetic or acquired risk factors [
## Venous Thromboembolism (VTE)
The primary clinical manifestation of prothrombin thrombophilia is VTE. The relative risk for VTE is increased two- to fivefold in 20210G>A heterozygotes [
Among individuals with DVT, 20210G>A heterozygotes had a significantly higher rate of PE (32%) than those with the factor V Leiden variant (19%) or those without thrombophilia (17%). 20210G>A heterozygotes are also at increased risk of developing isolated PE [
Asymptomatic healthy children heterozygous or homozygous for 20210G>A are at low risk for thrombosis. Heterozygous children were found to have a three- to fourfold increase in relative risk for VTE [
During pregnancy women with a prior history of VTE have an increased recurrence risk ranging from 0% to 15% in published studies. The risk is higher in women with a prior unprovoked episode or an estrogen-related VTE, and in those with coexisting genetic or acquired risk factors [
## Additional Factors that Predispose to Thrombosis
In addition to the number of variants, the clinical expression of prothrombin thrombophilia is influenced by:
A family history of thrombosis affecting at least one first-degree relative is an additional risk factor for VTE even in those with a known inherited thrombophilic disorder (including 20210A heterozygosity) [
Another inherited thrombophilic disorder is present in 8%-14% of 20210G>A heterozygotes, creating an additive effect on overall thrombotic risk. Individuals with multiple thrombophilic disorders develop VTE at a younger age and are at higher risk for recurrent thrombosis than those with a single thrombophilic variant [
Acquired thrombophilic disorders include antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders, and increased levels of clotting factors.
The 20210G>A variant interacts with multiple environmental risk factors to increase the risk for VTE. At least 50% of thrombotic episodes in individuals with the 20210G>A variant are provoked by additional risk factors, with pregnancy being the most common [
Circumstantial Risk Factors: Increased Risk for Thrombophilia in Persons with the 20210G>A Variant
3x-15x ↑ risk (heterozygotes)
31x ↑ risk during pregnancy or postpartum
26x ↑ risk (homozygotes)
8-47x ↑ risk in compound heterozygotes (w/
During pregnancy: 1:200 to 1:300
Post partum:1:66 (highest risk: 1st 6 wks post partum)
In homozygotes: 1:40
In compound heterozygotes (w/factor V Leiden): 1:20 to 1:125
Higher risk during 1st yr of use than subsequent yrs
Incidence 1/500/yr
Unopposed progestin is assoc w/↓ risk for thrombosis vs estrogen-containing contraception.
3x ↑ risk (heterozygotes) vs women using HRT w/o 20210G>A variant
8x-25x ↑ risk (heterozygotes) vs women w/o 20210G>A variant not using HRT
7x ↑ risk if BMI >30 kg/m
5x ↑ risk if BMI 25-30 kg/m
17x ↑ risk of VTE
20x ↑ risk of UE VTE
5x ↑ risk of CVC thrombosis
BMI = body mass index; CVC = central venous catheter; HRT = hormone replacement therapy; SERMS = selective estrogen receptor modulators; UE = upper-extremity; VTE = venous thromboembolism
Women homozygous for 20210G>A or compound heterozygous for 20210G>A and factor V Leiden have a higher relative risk for pregnancy-associated VTE, but the absolute risk is less well defined [
Other newer forms of combined hormonal, transdermal, and vaginal ring contraception have not been studied in 20210G>A heterozygotes but the risk is likely at least as great as the risk associated with COC use.
• 3x-15x ↑ risk (heterozygotes)
• 31x ↑ risk during pregnancy or postpartum
• 26x ↑ risk (homozygotes)
• 8-47x ↑ risk in compound heterozygotes (w/
• During pregnancy: 1:200 to 1:300
• Post partum:1:66 (highest risk: 1st 6 wks post partum)
• In homozygotes: 1:40
• In compound heterozygotes (w/factor V Leiden): 1:20 to 1:125
• Higher risk during 1st yr of use than subsequent yrs
• Incidence 1/500/yr
• Unopposed progestin is assoc w/↓ risk for thrombosis vs estrogen-containing contraception.
• 3x ↑ risk (heterozygotes) vs women using HRT w/o 20210G>A variant
• 8x-25x ↑ risk (heterozygotes) vs women w/o 20210G>A variant not using HRT
• 7x ↑ risk if BMI >30 kg/m
• 5x ↑ risk if BMI 25-30 kg/m
• 17x ↑ risk of VTE
• 20x ↑ risk of UE VTE
• 5x ↑ risk of CVC thrombosis
## Family History
A family history of thrombosis affecting at least one first-degree relative is an additional risk factor for VTE even in those with a known inherited thrombophilic disorder (including 20210A heterozygosity) [
## Coexisting Genetic Abnormalities
Another inherited thrombophilic disorder is present in 8%-14% of 20210G>A heterozygotes, creating an additive effect on overall thrombotic risk. Individuals with multiple thrombophilic disorders develop VTE at a younger age and are at higher risk for recurrent thrombosis than those with a single thrombophilic variant [
## Acquired Thrombophilic Disorders
Acquired thrombophilic disorders include antiphospholipid antibody syndrome, paroxysmal nocturnal hemoglobinuria, myeloproliferative disorders, and increased levels of clotting factors.
## Circumstantial Risk Factors for VTE
The 20210G>A variant interacts with multiple environmental risk factors to increase the risk for VTE. At least 50% of thrombotic episodes in individuals with the 20210G>A variant are provoked by additional risk factors, with pregnancy being the most common [
Circumstantial Risk Factors: Increased Risk for Thrombophilia in Persons with the 20210G>A Variant
3x-15x ↑ risk (heterozygotes)
31x ↑ risk during pregnancy or postpartum
26x ↑ risk (homozygotes)
8-47x ↑ risk in compound heterozygotes (w/
During pregnancy: 1:200 to 1:300
Post partum:1:66 (highest risk: 1st 6 wks post partum)
In homozygotes: 1:40
In compound heterozygotes (w/factor V Leiden): 1:20 to 1:125
Higher risk during 1st yr of use than subsequent yrs
Incidence 1/500/yr
Unopposed progestin is assoc w/↓ risk for thrombosis vs estrogen-containing contraception.
3x ↑ risk (heterozygotes) vs women using HRT w/o 20210G>A variant
8x-25x ↑ risk (heterozygotes) vs women w/o 20210G>A variant not using HRT
7x ↑ risk if BMI >30 kg/m
5x ↑ risk if BMI 25-30 kg/m
17x ↑ risk of VTE
20x ↑ risk of UE VTE
5x ↑ risk of CVC thrombosis
BMI = body mass index; CVC = central venous catheter; HRT = hormone replacement therapy; SERMS = selective estrogen receptor modulators; UE = upper-extremity; VTE = venous thromboembolism
Women homozygous for 20210G>A or compound heterozygous for 20210G>A and factor V Leiden have a higher relative risk for pregnancy-associated VTE, but the absolute risk is less well defined [
Other newer forms of combined hormonal, transdermal, and vaginal ring contraception have not been studied in 20210G>A heterozygotes but the risk is likely at least as great as the risk associated with COC use.
• 3x-15x ↑ risk (heterozygotes)
• 31x ↑ risk during pregnancy or postpartum
• 26x ↑ risk (homozygotes)
• 8-47x ↑ risk in compound heterozygotes (w/
• During pregnancy: 1:200 to 1:300
• Post partum:1:66 (highest risk: 1st 6 wks post partum)
• In homozygotes: 1:40
• In compound heterozygotes (w/factor V Leiden): 1:20 to 1:125
• Higher risk during 1st yr of use than subsequent yrs
• Incidence 1/500/yr
• Unopposed progestin is assoc w/↓ risk for thrombosis vs estrogen-containing contraception.
• 3x ↑ risk (heterozygotes) vs women using HRT w/o 20210G>A variant
• 8x-25x ↑ risk (heterozygotes) vs women w/o 20210G>A variant not using HRT
• 7x ↑ risk if BMI >30 kg/m
• 5x ↑ risk if BMI 25-30 kg/m
• 17x ↑ risk of VTE
• 20x ↑ risk of UE VTE
• 5x ↑ risk of CVC thrombosis
## Arterial Thrombosis: NOT Convincingly Associated with Prothrombin Thrombophilia
The available evidence indicates that the 20210G>A variant is not a major risk factor for arterial thrombosis of any sort including myocardial infarction and stroke in fetuses, children, and adults.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified for other
## Nomenclature
Prothrombin thrombophilia may also be referred to as
## Prevalence
The 20210G>A variant is present in:
8.2% of Americans of European origin with VTE;
1.1% of African Americans with VTE;
6%-14% of adults with a first VTE;
18%-21% of adults with VTE and a personal or family history of recurrent VTE [
3.7% of children with a first spontaneous VTE [
The frequency of homozygosity for the 20210G>A variant is 1:10,000. 20210G>A homozygosity is found in 1.8%-4.5% of individuals with VTE [
• 8.2% of Americans of European origin with VTE;
• 1.1% of African Americans with VTE;
• 6%-14% of adults with a first VTE;
• 18%-21% of adults with VTE and a personal or family history of recurrent VTE [
• 3.7% of children with a first spontaneous VTE [
## Genetically Related (Allelic) Disorders
Prothrombin deficiency (OMIM
## Differential Diagnosis
The differential diagnosis of venous thromboembolism (VTE) includes several other inherited thrombophilic disorders (discussed here) and acquired thrombophilic disorders (outside of the scope of this GeneReview).
See
## Management
To assess the risk for venous thromboembolism (VTE) in an individual found to have the
An activated protein C resistance or DNA assay for
Serologic assays for anticardiolipin antibodies and anti-beta
Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
For high-risk individuals (e.g., 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 the following:
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, since 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 thrombosis in individuals with prothrombin thrombophilia depends on the clinical circumstances.
The first acute thrombosis should be treated according to standard guidelines [
For individuals not treated with one of the direct oral anticoagulants, administration of warfarin is started concurrently with LMWH or fonadaparinux, a pentasaccharide (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
Note: LMWH and warfarin are both safe in women who are breast-feeding (see
20210G>A heterozygosity alone is not an indication for long-term anticoagulation in the absence of other risk factors according to American College of Chest Physicians guidelines on antithrombotic therapy and American Society of Hematology guidelines for management of venous thromboembolism (see
Anticoagulation for at least three months is recommended for persons with DVT and/or PE associated with a transient (reversible) risk factor [
Treatment recommendations for children with VTE are largely adapted from studies in adults. There is no evidence that identification of a 20210G>A variant should influence decisions about the intensity or duration of anticoagulation in children [
Children with a first VTE should receive initial treatment with either unfractionated heparin or LMWH for at least five days. American Society of Hematology guidelines suggest using either LMWH or warfarin in children with symptomatic DVT or PE. The decision on anticoagulant should be individualized based on preference of the affected individual, underlying condition, comorbidities, and other medications [
Anticoagulation is recommended:
For 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 ongoing but potentially reversible risk factor;
For 6-12 months after a first unprovoked VTE.
Consensus guidelines and expert opinion emphasize the importance of a careful risk/benefit assessment in each individual.
In the absence of a history of thrombosis, long-term anticoagulation is not recommended for asymptomatic 20210G>A heterozygotes because the 1%-3%/year risk for major bleeding from anticoagulation is greater than the estimated less than 1%/year risk for thrombosis [
Prophylactic anticoagulation may be considered in high-risk clinical settings such as surgery, pregnancy, or prolonged immobilization, although currently no evidence confirms the benefit of primary prophylaxis for asymptomatic 20210G>A heterozygotes. Factors that may influence decisions about the indication for and duration of anticoagulation include age, family history, and other coexisting risk factors. Recommendations for prophylaxis at the time of surgery and other high-risk situations are available in the American College of Chest Physicians and American Society of Hematology consensus guidelines [
Individuals receiving long-term anticoagulation require periodic reevaluation to confirm that the benefits of anticoagulation continue to outweigh the risk of bleeding.
20210G>A heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy (see
Women with a history of VTE who are heterozygous for 20210G>A should avoid estrogen-containing contraception and hormone replacement therapy (HRT).
Women homozygous for 20210G>A with or without prior VTE should avoid estrogen-containing contraception and HRT.
Asymptomatic women heterozygous for 20210G>A:
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 hormone replacement therapy for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations [
The genetic status of apparently asymptomatic at-risk family members can be established using molecular genetic testing for the 20210G>A variant.
Note: The indications for family testing are unresolved.
In the absence of evidence that early identification of the 20210G>A variant reduces morbidity or mortality, decisions regarding testing should be made on an individual basis.
Clarification of 20210G>A variant status may be useful in at-risk female relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age if the results are likely to affect management.
See
No consensus exists on the optimal management of prothrombin thrombophilia during pregnancy; guidelines are derived from studies in non-pregnant individuals [
LMWH is the preferred antithrombotic agent for prophylaxis during pregnancy. The oral direct thrombin inhibitor, dabigatran, and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) are contraindicated during pregnancy and breastfeeding because of (1) absence of data on fetal and neonatal safety and (2) animial studies that showed reproductive toxicity [
Prophylactic anticoagulation during pregnancy
With a history of unprovoked VTE, including those heterozygous for 20210G>A. LMWH should be given during pregnancy followed by six weeks of postpartum anticoagulation [
Heterozygous for 20210G>A with a prior pregnancy or estrogen-related thrombosis who are also at an increased risk for recurrence [
Prophylactic anticoagulation during pregnancy
Are homozygous for 20210G>A and have a family history of thrombosis [
Are compound heterozygotes for 20210G>A and factor V Leiden, especially those with coexisting circumstantial risk factors (obesity, immobilization, multiple gestation) [
Prophylactic anticoagulation during pregnancy
All women heterozygous for 20210G>A women with a prior history of VTE;
All asymptomatic homozygous women and those with combined thrombophilia;
Postpartum prophylaxis may be considered in asymptomatic women heterozygous for 20210G>A with a positive family history of VTE, although consensus guideline suggestions differ for this group [
Search
• An activated protein C resistance or DNA assay for
• Serologic assays for anticardiolipin antibodies and anti-beta
• Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
• Protein C activity
• Antithrombin activity
• Protein S activity or free protein S antigen
• Plasma concentration of homocysteine, since 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 [
• 20210G>A heterozygosity alone is not an indication for long-term anticoagulation in the absence of other risk factors according to American College of Chest Physicians guidelines on antithrombotic therapy and American Society of Hematology guidelines for management of venous thromboembolism (see
• Anticoagulation for at least three months is recommended for persons with DVT and/or PE associated with a transient (reversible) risk factor [
• For 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 ongoing but potentially reversible risk factor;
• For 6-12 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 hormone replacement therapy for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations [
• In the absence of evidence that early identification of the 20210G>A variant reduces morbidity or mortality, decisions regarding testing should be made on an individual basis.
• Clarification of 20210G>A variant status may be useful in at-risk female relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age if the results are likely to affect management.
• With a history of unprovoked VTE, including those heterozygous for 20210G>A. LMWH should be given during pregnancy followed by six weeks of postpartum anticoagulation [
• Heterozygous for 20210G>A with a prior pregnancy or estrogen-related thrombosis who are also at an increased risk for recurrence [
• Are homozygous for 20210G>A and have a family history of thrombosis [
• Are compound heterozygotes for 20210G>A and factor V Leiden, especially those with coexisting circumstantial risk factors (obesity, immobilization, multiple gestation) [
• All women heterozygous for 20210G>A women with a prior history of VTE;
• All asymptomatic homozygous women and those with combined thrombophilia;
## Evaluations Following Initial Diagnosis
To assess the risk for venous thromboembolism (VTE) in an individual found to have the
An activated protein C resistance or DNA assay for
Serologic assays for anticardiolipin antibodies and anti-beta
Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
For high-risk individuals (e.g., 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 the following:
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, since 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 [
• An activated protein C resistance or DNA assay for
• Serologic assays for anticardiolipin antibodies and anti-beta
• Multiple phospholipid-dependent coagulation assays for a lupus inhibitor
• Protein C activity
• Antithrombin activity
• Protein S activity or free protein S antigen
• Plasma concentration of homocysteine, since 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 thrombosis in individuals with prothrombin thrombophilia depends on the clinical circumstances.
The first acute thrombosis should be treated according to standard guidelines [
For individuals not treated with one of the direct oral anticoagulants, administration of warfarin is started concurrently with LMWH or fonadaparinux, a pentasaccharide (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
Note: LMWH and warfarin are both safe in women who are breast-feeding (see
20210G>A heterozygosity alone is not an indication for long-term anticoagulation in the absence of other risk factors according to American College of Chest Physicians guidelines on antithrombotic therapy and American Society of Hematology guidelines for management of venous thromboembolism (see
Anticoagulation for at least three months is recommended for persons with DVT and/or PE associated with a transient (reversible) risk factor [
Treatment recommendations for children with VTE are largely adapted from studies in adults. There is no evidence that identification of a 20210G>A variant should influence decisions about the intensity or duration of anticoagulation in children [
Children with a first VTE should receive initial treatment with either unfractionated heparin or LMWH for at least five days. American Society of Hematology guidelines suggest using either LMWH or warfarin in children with symptomatic DVT or PE. The decision on anticoagulant should be individualized based on preference of the affected individual, underlying condition, comorbidities, and other medications [
Anticoagulation is recommended:
For 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 ongoing but potentially reversible risk factor;
For 6-12 months after a first unprovoked VTE.
Consensus guidelines and expert opinion emphasize the importance of a careful risk/benefit assessment in each individual.
• 20210G>A heterozygosity alone is not an indication for long-term anticoagulation in the absence of other risk factors according to American College of Chest Physicians guidelines on antithrombotic therapy and American Society of Hematology guidelines for management of venous thromboembolism (see
• Anticoagulation for at least three months is recommended for persons with DVT and/or PE associated with a transient (reversible) risk factor [
• For 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 ongoing but potentially reversible risk factor;
• For 6-12 months after a first unprovoked VTE.
## Treatment of VTE in Adults
The management of thrombosis in individuals with prothrombin thrombophilia depends on the clinical circumstances.
The first acute thrombosis should be treated according to standard guidelines [
For individuals not treated with one of the direct oral anticoagulants, administration of warfarin is started concurrently with LMWH or fonadaparinux, a pentasaccharide (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
Note: LMWH and warfarin are both safe in women who are breast-feeding (see
20210G>A heterozygosity alone is not an indication for long-term anticoagulation in the absence of other risk factors according to American College of Chest Physicians guidelines on antithrombotic therapy and American Society of Hematology guidelines for management of venous thromboembolism (see
Anticoagulation for at least three months is recommended for persons with DVT and/or PE associated with a transient (reversible) risk factor [
• 20210G>A heterozygosity alone is not an indication for long-term anticoagulation in the absence of other risk factors according to American College of Chest Physicians guidelines on antithrombotic therapy and American Society of Hematology guidelines for management of venous thromboembolism (see
• Anticoagulation for at least three months is recommended for persons with DVT and/or PE associated with a transient (reversible) risk factor [
## Treatment of VTE in Children
Treatment recommendations for children with VTE are largely adapted from studies in adults. There is no evidence that identification of a 20210G>A variant should influence decisions about the intensity or duration of anticoagulation in children [
Children with a first VTE should receive initial treatment with either unfractionated heparin or LMWH for at least five days. American Society of Hematology guidelines suggest using either LMWH or warfarin in children with symptomatic DVT or PE. The decision on anticoagulant should be individualized based on preference of the affected individual, underlying condition, comorbidities, and other medications [
Anticoagulation is recommended:
For 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 ongoing but potentially reversible risk factor;
For 6-12 months after a first unprovoked VTE.
Consensus guidelines and expert opinion emphasize the importance of a careful risk/benefit assessment in each individual.
• For 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 ongoing but potentially reversible risk factor;
• For 6-12 months after a first unprovoked VTE.
## Prevention of Primary Manifestations
In the absence of a history of thrombosis, long-term anticoagulation is not recommended for asymptomatic 20210G>A heterozygotes because the 1%-3%/year risk for major bleeding from anticoagulation is greater than the estimated less than 1%/year risk for thrombosis [
Prophylactic anticoagulation may be considered in high-risk clinical settings such as surgery, pregnancy, or prolonged immobilization, although currently no evidence confirms the benefit of primary prophylaxis for asymptomatic 20210G>A heterozygotes. Factors that may influence decisions about the indication for and duration of anticoagulation include age, family history, and other coexisting risk factors. Recommendations for prophylaxis at the time of surgery and other high-risk situations are available in the American College of Chest Physicians and American Society of Hematology consensus guidelines [
## Surveillance
Individuals receiving long-term anticoagulation require periodic reevaluation to confirm that the benefits of anticoagulation continue to outweigh the risk of bleeding.
20210G>A heterozygotes who do not require long-term anticoagulation may benefit from evaluation prior to exposure to circumstantial risk factors such as surgery or pregnancy (see
## Agents/Circumstances to Avoid
Women with a history of VTE who are heterozygous for 20210G>A should avoid estrogen-containing contraception and hormone replacement therapy (HRT).
Women homozygous for 20210G>A with or without prior VTE should avoid estrogen-containing contraception and HRT.
Asymptomatic women heterozygous for 20210G>A:
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 hormone replacement therapy for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations [
• 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 hormone replacement therapy for severe menopausal symptoms should use a low-dose transdermal preparation, which has a lower thrombotic risk than oral formulations [
## Evaluation of Relatives at Risk
The genetic status of apparently asymptomatic at-risk family members can be established using molecular genetic testing for the 20210G>A variant.
Note: The indications for family testing are unresolved.
In the absence of evidence that early identification of the 20210G>A variant reduces morbidity or mortality, decisions regarding testing should be made on an individual basis.
Clarification of 20210G>A variant status may be useful in at-risk female relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age if the results are likely to affect management.
See
• In the absence of evidence that early identification of the 20210G>A variant reduces morbidity or mortality, decisions regarding testing should be made on an individual basis.
• Clarification of 20210G>A variant status may be useful in at-risk female relatives considering hormonal contraception or pregnancy or in families with a strong history of recurrent venous thrombosis at a young age if the results are likely to affect management.
## Pregnancy Management
No consensus exists on the optimal management of prothrombin thrombophilia during pregnancy; guidelines are derived from studies in non-pregnant individuals [
LMWH is the preferred antithrombotic agent for prophylaxis during pregnancy. The oral direct thrombin inhibitor, dabigatran, and the direct factor Xa inhibitors (rivaroxaban, apixaban, and edoxaban) are contraindicated during pregnancy and breastfeeding because of (1) absence of data on fetal and neonatal safety and (2) animial studies that showed reproductive toxicity [
Prophylactic anticoagulation during pregnancy
With a history of unprovoked VTE, including those heterozygous for 20210G>A. LMWH should be given during pregnancy followed by six weeks of postpartum anticoagulation [
Heterozygous for 20210G>A with a prior pregnancy or estrogen-related thrombosis who are also at an increased risk for recurrence [
Prophylactic anticoagulation during pregnancy
Are homozygous for 20210G>A and have a family history of thrombosis [
Are compound heterozygotes for 20210G>A and factor V Leiden, especially those with coexisting circumstantial risk factors (obesity, immobilization, multiple gestation) [
Prophylactic anticoagulation during pregnancy
All women heterozygous for 20210G>A women with a prior history of VTE;
All asymptomatic homozygous women and those with combined thrombophilia;
Postpartum prophylaxis may be considered in asymptomatic women heterozygous for 20210G>A with a positive family history of VTE, although consensus guideline suggestions differ for this group [
• With a history of unprovoked VTE, including those heterozygous for 20210G>A. LMWH should be given during pregnancy followed by six weeks of postpartum anticoagulation [
• Heterozygous for 20210G>A with a prior pregnancy or estrogen-related thrombosis who are also at an increased risk for recurrence [
• Are homozygous for 20210G>A and have a family history of thrombosis [
• Are compound heterozygotes for 20210G>A and factor V Leiden, especially those with coexisting circumstantial risk factors (obesity, immobilization, multiple gestation) [
• All women heterozygous for 20210G>A women with a prior history of VTE;
• All asymptomatic homozygous women and those with combined thrombophilia;
## Prevention of Thrombosis During the Postpartum Period
All women heterozygous for 20210G>A women with a prior history of VTE;
All asymptomatic homozygous women and those with combined thrombophilia;
Postpartum prophylaxis may be considered in asymptomatic women heterozygous for 20210G>A with a positive family history of VTE, although consensus guideline suggestions differ for this group [
• All women heterozygous for 20210G>A women with a prior history of VTE;
• All asymptomatic homozygous women and those with combined thrombophilia;
## Other
## Therapies Under Investigation
Search
## Genetic Counseling
Prothrombin thrombophilia (i.e., predisposition to the development of venous thrombosis) is inherited in an autosomal dominant manner.
All individuals reported to date with prothrombin thrombophilia have had a parent who is heterozygous or homozygous for the
Prothrombin thrombophilia as the result of a
Occasionally (because of the relatively high prevalence of the 20210G>A variant in the general population) one parent is homozygous for the 20210G>A variant or both parents are heterozygous for the 20210G>A variant.
The family history of some individuals diagnosed with prothrombin thrombophilia may appear to be negative because no other family members developed thrombosis or because of failure to recognize prothrombin thrombophilia in affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing for the 20210G>A variant has been performed on the parents of the proband.
If one parent is heterozygous for the 20210G>A variant, each sib of the proband is at a 50% risk of being heterozygous for the 20210G>A variant.
If one parent is homozygous for the 20210G>A variant, each sib of the proband has a 100% chance of being heterozygous for the 20210G>A variant.
If both parents are heterozygous for the 20210G>A variant, each sib of the proband has a 25% chance of being homozygous for the 20210G>A variant, a 50% chance of being heterozygous for the 20210G>A variant, and a 25% chance of inheriting both normal
Each child has a 50% chance of inheriting the 20210G>A variant.
If the proband's reproductive partner is also heterozygous for the 20210G>A variant, each of their children has a 25% chance of inheriting two 20210G>A variants, a 50% chance of inheriting one 20210G>A variant, and a 25% chance of inheriting neither 20210G>A variant.
A proband homozygous for the 20210G>A variant will transmit the 20210G>A variant to all offspring.
If the proband's reproductive partner is heterozygous for the 20210G>A variant, each of their children has a 50% chance of inheriting two 20210G>A variants and a 50% chance of inheriting one 20210G>A 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 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.
• All individuals reported to date with prothrombin thrombophilia have had a parent who is heterozygous or homozygous for the
• Prothrombin thrombophilia as the result of a
• Occasionally (because of the relatively high prevalence of the 20210G>A variant in the general population) one parent is homozygous for the 20210G>A variant or both parents are heterozygous for the 20210G>A variant.
• The family history of some individuals diagnosed with prothrombin thrombophilia may appear to be negative because no other family members developed thrombosis or because of failure to recognize prothrombin thrombophilia in affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing for the 20210G>A variant has been performed on the parents of the proband.
• If one parent is heterozygous for the 20210G>A variant, each sib of the proband is at a 50% risk of being heterozygous for the 20210G>A variant.
• If one parent is homozygous for the 20210G>A variant, each sib of the proband has a 100% chance of being heterozygous for the 20210G>A variant.
• If both parents are heterozygous for the 20210G>A variant, each sib of the proband has a 25% chance of being homozygous for the 20210G>A variant, a 50% chance of being heterozygous for the 20210G>A variant, and a 25% chance of inheriting both normal
• Each child has a 50% chance of inheriting the 20210G>A variant.
• If the proband's reproductive partner is also heterozygous for the 20210G>A variant, each of their children has a 25% chance of inheriting two 20210G>A variants, a 50% chance of inheriting one 20210G>A variant, and a 25% chance of inheriting neither 20210G>A variant.
• A proband homozygous for the 20210G>A variant will transmit the 20210G>A variant to all offspring.
• If the proband's reproductive partner is heterozygous for the 20210G>A variant, each of their children has a 50% chance of inheriting two 20210G>A variants and a 50% chance of inheriting one 20210G>A 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
Prothrombin thrombophilia (i.e., predisposition to the development of venous thrombosis) is inherited in an autosomal dominant manner.
## Risk to Family Members
All individuals reported to date with prothrombin thrombophilia have had a parent who is heterozygous or homozygous for the
Prothrombin thrombophilia as the result of a
Occasionally (because of the relatively high prevalence of the 20210G>A variant in the general population) one parent is homozygous for the 20210G>A variant or both parents are heterozygous for the 20210G>A variant.
The family history of some individuals diagnosed with prothrombin thrombophilia may appear to be negative because no other family members developed thrombosis or because of failure to recognize prothrombin thrombophilia in affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing for the 20210G>A variant has been performed on the parents of the proband.
If one parent is heterozygous for the 20210G>A variant, each sib of the proband is at a 50% risk of being heterozygous for the 20210G>A variant.
If one parent is homozygous for the 20210G>A variant, each sib of the proband has a 100% chance of being heterozygous for the 20210G>A variant.
If both parents are heterozygous for the 20210G>A variant, each sib of the proband has a 25% chance of being homozygous for the 20210G>A variant, a 50% chance of being heterozygous for the 20210G>A variant, and a 25% chance of inheriting both normal
Each child has a 50% chance of inheriting the 20210G>A variant.
If the proband's reproductive partner is also heterozygous for the 20210G>A variant, each of their children has a 25% chance of inheriting two 20210G>A variants, a 50% chance of inheriting one 20210G>A variant, and a 25% chance of inheriting neither 20210G>A variant.
A proband homozygous for the 20210G>A variant will transmit the 20210G>A variant to all offspring.
If the proband's reproductive partner is heterozygous for the 20210G>A variant, each of their children has a 50% chance of inheriting two 20210G>A variants and a 50% chance of inheriting one 20210G>A variant.
• All individuals reported to date with prothrombin thrombophilia have had a parent who is heterozygous or homozygous for the
• Prothrombin thrombophilia as the result of a
• Occasionally (because of the relatively high prevalence of the 20210G>A variant in the general population) one parent is homozygous for the 20210G>A variant or both parents are heterozygous for the 20210G>A variant.
• The family history of some individuals diagnosed with prothrombin thrombophilia may appear to be negative because no other family members developed thrombosis or because of failure to recognize prothrombin thrombophilia in affected family members. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing for the 20210G>A variant has been performed on the parents of the proband.
• If one parent is heterozygous for the 20210G>A variant, each sib of the proband is at a 50% risk of being heterozygous for the 20210G>A variant.
• If one parent is homozygous for the 20210G>A variant, each sib of the proband has a 100% chance of being heterozygous for the 20210G>A variant.
• If both parents are heterozygous for the 20210G>A variant, each sib of the proband has a 25% chance of being homozygous for the 20210G>A variant, a 50% chance of being heterozygous for the 20210G>A variant, and a 25% chance of inheriting both normal
• Each child has a 50% chance of inheriting the 20210G>A variant.
• If the proband's reproductive partner is also heterozygous for the 20210G>A variant, each of their children has a 25% chance of inheriting two 20210G>A variants, a 50% chance of inheriting one 20210G>A variant, and a 25% chance of inheriting neither 20210G>A variant.
• A proband homozygous for the 20210G>A variant will transmit the 20210G>A variant to all offspring.
• If the proband's reproductive partner is heterozygous for the 20210G>A variant, each of their children has a 50% chance of inheriting two 20210G>A variants and a 50% chance of inheriting one 20210G>A 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 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
United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
Prothrombin Thrombophilia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Prothrombin Thrombophilia (
The 20210G>A variant is associated with elevated plasma levels of prothrombin [
Most
Individuals with one or two 20210G>A alleles often have elevated plasma levels of the prothrombin fragment F1+2, and other coagulation activation markers, reflecting the resulting mild hypercoagulable state [
Notable
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
* indicates that the variant is in the 3’ untranslated region of
Haplotype analysis of
Although the high prevalence of the 20210G>A allele among individuals of European ancestry suggests a balanced nucleotide variant with some type of survival advantage associated with the heterozygous state, no such advantage has been confirmed. Some investigators speculate that the mild hypercoagulable state conferred by the allele may have had a beneficial effect in reducing mortality from bleeding associated with childbirth or trauma in premodern times [
c.1621C>T, a novel missense variant in exon 12 resulting in increased thrombin potential and resistance to heparin was identified in a Dutch family with unexplained thrombosis [
c.1787G>T, a novel missense variant in exon 14 (prothrombin Yukuhashi) results in resistance to antithrombin and a prothrombotic state. Prothrombin Yukuhashi (p.Arg596Leu) was identified in a Japanese family in which five members developed thrombosis at a very young age [
20209C>T in the 3' untranslated region of the gene is a rare variant of unclear significance reported primarily in individuals of African descent with a history of thrombosis or obstetric complications. Data as to whether this variant is an independent risk factor for thrombosis are conflicting [
• c.1621C>T, a novel missense variant in exon 12 resulting in increased thrombin potential and resistance to heparin was identified in a Dutch family with unexplained thrombosis [
• c.1787G>T, a novel missense variant in exon 14 (prothrombin Yukuhashi) results in resistance to antithrombin and a prothrombotic state. Prothrombin Yukuhashi (p.Arg596Leu) was identified in a Japanese family in which five members developed thrombosis at a very young age [
• 20209C>T in the 3' untranslated region of the gene is a rare variant of unclear significance reported primarily in individuals of African descent with a history of thrombosis or obstetric complications. Data as to whether this variant is an independent risk factor for thrombosis are conflicting [
## Molecular Pathogenesis
The 20210G>A variant is associated with elevated plasma levels of prothrombin [
Most
Individuals with one or two 20210G>A alleles often have elevated plasma levels of the prothrombin fragment F1+2, and other coagulation activation markers, reflecting the resulting mild hypercoagulable state [
Notable
Variants listed in the table have been provided by the author.
Variant designation that does not conform to current naming conventions
* indicates that the variant is in the 3’ untranslated region of
Haplotype analysis of
Although the high prevalence of the 20210G>A allele among individuals of European ancestry suggests a balanced nucleotide variant with some type of survival advantage associated with the heterozygous state, no such advantage has been confirmed. Some investigators speculate that the mild hypercoagulable state conferred by the allele may have had a beneficial effect in reducing mortality from bleeding associated with childbirth or trauma in premodern times [
c.1621C>T, a novel missense variant in exon 12 resulting in increased thrombin potential and resistance to heparin was identified in a Dutch family with unexplained thrombosis [
c.1787G>T, a novel missense variant in exon 14 (prothrombin Yukuhashi) results in resistance to antithrombin and a prothrombotic state. Prothrombin Yukuhashi (p.Arg596Leu) was identified in a Japanese family in which five members developed thrombosis at a very young age [
20209C>T in the 3' untranslated region of the gene is a rare variant of unclear significance reported primarily in individuals of African descent with a history of thrombosis or obstetric complications. Data as to whether this variant is an independent risk factor for thrombosis are conflicting [
• c.1621C>T, a novel missense variant in exon 12 resulting in increased thrombin potential and resistance to heparin was identified in a Dutch family with unexplained thrombosis [
• c.1787G>T, a novel missense variant in exon 14 (prothrombin Yukuhashi) results in resistance to antithrombin and a prothrombotic state. Prothrombin Yukuhashi (p.Arg596Leu) was identified in a Japanese family in which five members developed thrombosis at a very young age [
• 20209C>T in the 3' untranslated region of the gene is a rare variant of unclear significance reported primarily in individuals of African descent with a history of thrombosis or obstetric complications. Data as to whether this variant is an independent risk factor for thrombosis are conflicting [
## Chapter Notes
4 February 2021 (sw) Comprehensive update posted live
14 August 2014 (me) Comprehensive update posted live
29 March 2011 (me) Comprehensive update posted live
25 July 2006 (me) Review posted live
25 April 2005 (jk) Original submission
• 4 February 2021 (sw) Comprehensive update posted live
• 14 August 2014 (me) Comprehensive update posted live
• 29 March 2011 (me) Comprehensive update posted live
• 25 July 2006 (me) Review posted live
• 25 April 2005 (jk) Original submission
## Revision History
4 February 2021 (sw) Comprehensive update posted live
14 August 2014 (me) Comprehensive update posted live
29 March 2011 (me) Comprehensive update posted live
25 July 2006 (me) Review posted live
25 April 2005 (jk) Original submission
• 4 February 2021 (sw) Comprehensive update posted live
• 14 August 2014 (me) Comprehensive update posted live
• 29 March 2011 (me) Comprehensive update posted live
• 25 July 2006 (me) Review posted live
• 25 April 2005 (jk) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
|
[
"Practice Bulletin No.138: Inherited thrombophilias in pregnancy.. Obstet Gynecol. 2013;122:706-17"
] |
25/7/2006
|
4/2/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
pura-dis
|
pura-dis
|
[
"PURA Syndrome",
"5q31.3 Deletion Syndrome",
"Transcriptional activator protein Pur-alpha",
"PURA",
"PURA-Related Neurodevelopmental Disorders"
] |
Margot RF Reijnders, Richard J Leventer, Bo Hoon Lee, Diana Baralle, Paulo Selber, Alex R Paciorkowski, David Hunt
|
Summary The diagnosis of a
|
5q31.3 deletion syndrome
For synonyms and outdated names see
• 5q31.3 deletion syndrome
## Diagnosis
No formal clinical diagnostic criteria have been published for
Hypotonia
Neonatal hypoventilation
Hypothermia
Hypersomnolence
Feeding difficulties, including gastroesophageal reflux disease (GERD)
Hypotonia
Moderate-to-severe intellectual disability, including absent speech
Seizures
Abnormal nonepileptic movements (e.g., dystonia, dyskinesia, and dysconjugate eye movements)
The diagnosis of a
A heterozygous
Nonrecurrent deletion of 5q31.3 that encompasses all or part 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 the clinician to determine which specific gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of many genetic intellectual disability disorders overlap, most children with a
For an introduction to multigene panels click
Note: Single-gene testing (sequence analysis of
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
n=11 [
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.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 5q31.3 region.
n=2 [
• Hypotonia
• Neonatal hypoventilation
• Hypothermia
• Hypersomnolence
• Feeding difficulties, including gastroesophageal reflux disease (GERD)
• Hypotonia
• Moderate-to-severe intellectual disability, including absent speech
• Seizures
• Abnormal nonepileptic movements (e.g., dystonia, dyskinesia, and dysconjugate eye movements)
• A heterozygous
• Nonrecurrent deletion of 5q31.3 that encompasses all or part of
## Suggestive Findings
Hypotonia
Neonatal hypoventilation
Hypothermia
Hypersomnolence
Feeding difficulties, including gastroesophageal reflux disease (GERD)
Hypotonia
Moderate-to-severe intellectual disability, including absent speech
Seizures
Abnormal nonepileptic movements (e.g., dystonia, dyskinesia, and dysconjugate eye movements)
• Hypotonia
• Neonatal hypoventilation
• Hypothermia
• Hypersomnolence
• Feeding difficulties, including gastroesophageal reflux disease (GERD)
• Hypotonia
• Moderate-to-severe intellectual disability, including absent speech
• Seizures
• Abnormal nonepileptic movements (e.g., dystonia, dyskinesia, and dysconjugate eye movements)
## Establishing the Diagnosis
The diagnosis of a
A heterozygous
Nonrecurrent deletion of 5q31.3 that encompasses all or part 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 the clinician to determine which specific gene(s) are likely involved, whereas genomic testing does not. Because the phenotypes of many genetic intellectual disability disorders overlap, most children with a
For an introduction to multigene panels click
Note: Single-gene testing (sequence analysis of
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
n=11 [
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.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 5q31.3 region.
n=2 [
• A heterozygous
• Nonrecurrent deletion of 5q31.3 that encompasses all or part of
## Recommended Testing
For an introduction to multigene panels click
## Testing to Consider
Note: Single-gene testing (sequence analysis of
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
n=11 [
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.
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 5q31.3 region.
n=2 [
## Clinical Characteristics
Early-onset issues are wide ranging and can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal nonepileptic movements, and visual problems.
Congenital heart defects, urogenital malformations, skeletal abnormalities, and endocrine disorders occur, but are less common [
The figures given for the following clinical features are based on observed frequencies in individuals with
Speech is absent in most; however, the use of augmentative and alternative communication aids has proved beneficial in some children. Many children have relatively good receptive language skills and may follow simple instructions, despite having no overt expressive language.
Motor development is delayed, but with variable severity. Some individuals never achieve independent ambulation. In those who do, the age ranges from 22 months to seven years. The gait of affected children is typically broad-based.
Many individuals have poor fine-motor skills, which can hinder the use of some types of communication aids.
Epilepsy has been reported in at least 50% of the individuals (42/71) and usually starts with myoclonic jerks progressing to other seizure types including generalized tonic-clonic seizures, tonic seizures, and epileptic spasms. In some instances, the seizure disorder progresses to the Lennox-Gastaut syndrome.
The age of seizure onset ranges between the neonatal period and 16 years, although most of those who develop epilepsy do so in the first five years, many in infancy.
The seizures are often drug resistant.
Nonepileptic movements that may be seen include dystonia, dyskinesia, and dysconjugate eye movements.
Nonepileptic exaggerated startle response is present in several children.
Nystagmus is present in 17/71 individuals.
MRI findings include the following:
Delayed myelination or nonspecific subtle white matter hyperintensities, which constitute the most frequently reported brain abnormalities (23/71)
Excessive extra-axial fluid spaces (7/71)
Volume loss of the corpus callosum (4/71)
Cerebellar tonsillar ectopia (1/71)
Possible cerebral atrophy (1/71)
Absent septum pellucidum (1/71)
Early cortical visual impairment (7/71), hypermetropia (6/71), and optic nerve pallor (1/71) have also been reported.
For the majority of affected individuals, the episodes of apnea and hypoventilation resolve after the first year of life; however, in a minority, apnea may persist or recur during an acute respiratory illness.
Aspiration pneumonia due to hypotonia and dysphagia has been reported.
Dysphagia often persists throughout life. Drooling is common; however, the cause (either excessive salivation or oromotor dyspraxia / swallowing problems) requires further investigation.
Constipation has been reported in the majority of individuals [
Disturbed levels of gonadotropins (2/71) and medical treatment for precocious puberty (3/71)
A blunted cortisol response (2/71)
Hypothyroidism (2/71)
Elevated prolactin levels (1/71)
Although low vitamin D levels (7/71) and anemia and/or low iron levels (4/71) have been reported, the true prevalence may be higher as vitamin D and iron levels are often not measured routinely and deficiency may not be obvious clinically.
Neonatal hypothermia. Difficulties in regulating body temperature in the neonatal period have not yet been reported in the literature, but appear to occur frequently [Author, personal observation].
Excessive hiccups in utero and in the neonatal period have been observed in a significant proportion of the individuals [Author, personal observation].
Current data suggest that
The features of individuals with a 5q31.3 deletion that overlap with those of individuals with a
Of note, individuals with a deletion that also includes the neighboring gene
To the authors' knowledge, the penetrance of all intragenic
The OMIM designation for
To date, 71 individuals are known to have
Based on the study of
• Delayed myelination or nonspecific subtle white matter hyperintensities, which constitute the most frequently reported brain abnormalities (23/71)
• Excessive extra-axial fluid spaces (7/71)
• Volume loss of the corpus callosum (4/71)
• Cerebellar tonsillar ectopia (1/71)
• Possible cerebral atrophy (1/71)
• Absent septum pellucidum (1/71)
• Disturbed levels of gonadotropins (2/71) and medical treatment for precocious puberty (3/71)
• A blunted cortisol response (2/71)
• Hypothyroidism (2/71)
• Elevated prolactin levels (1/71)
• Neonatal hypothermia. Difficulties in regulating body temperature in the neonatal period have not yet been reported in the literature, but appear to occur frequently [Author, personal observation].
• Excessive hiccups in utero and in the neonatal period have been observed in a significant proportion of the individuals [Author, personal observation].
## Clinical Description
Early-onset issues are wide ranging and can include hypotonia, hypothermia, hypersomnolence, feeding difficulties, excessive hiccups, recurrent central and obstructive apneas, epileptic seizures, abnormal nonepileptic movements, and visual problems.
Congenital heart defects, urogenital malformations, skeletal abnormalities, and endocrine disorders occur, but are less common [
The figures given for the following clinical features are based on observed frequencies in individuals with
Speech is absent in most; however, the use of augmentative and alternative communication aids has proved beneficial in some children. Many children have relatively good receptive language skills and may follow simple instructions, despite having no overt expressive language.
Motor development is delayed, but with variable severity. Some individuals never achieve independent ambulation. In those who do, the age ranges from 22 months to seven years. The gait of affected children is typically broad-based.
Many individuals have poor fine-motor skills, which can hinder the use of some types of communication aids.
Epilepsy has been reported in at least 50% of the individuals (42/71) and usually starts with myoclonic jerks progressing to other seizure types including generalized tonic-clonic seizures, tonic seizures, and epileptic spasms. In some instances, the seizure disorder progresses to the Lennox-Gastaut syndrome.
The age of seizure onset ranges between the neonatal period and 16 years, although most of those who develop epilepsy do so in the first five years, many in infancy.
The seizures are often drug resistant.
Nonepileptic movements that may be seen include dystonia, dyskinesia, and dysconjugate eye movements.
Nonepileptic exaggerated startle response is present in several children.
Nystagmus is present in 17/71 individuals.
MRI findings include the following:
Delayed myelination or nonspecific subtle white matter hyperintensities, which constitute the most frequently reported brain abnormalities (23/71)
Excessive extra-axial fluid spaces (7/71)
Volume loss of the corpus callosum (4/71)
Cerebellar tonsillar ectopia (1/71)
Possible cerebral atrophy (1/71)
Absent septum pellucidum (1/71)
Early cortical visual impairment (7/71), hypermetropia (6/71), and optic nerve pallor (1/71) have also been reported.
For the majority of affected individuals, the episodes of apnea and hypoventilation resolve after the first year of life; however, in a minority, apnea may persist or recur during an acute respiratory illness.
Aspiration pneumonia due to hypotonia and dysphagia has been reported.
Dysphagia often persists throughout life. Drooling is common; however, the cause (either excessive salivation or oromotor dyspraxia / swallowing problems) requires further investigation.
Constipation has been reported in the majority of individuals [
Disturbed levels of gonadotropins (2/71) and medical treatment for precocious puberty (3/71)
A blunted cortisol response (2/71)
Hypothyroidism (2/71)
Elevated prolactin levels (1/71)
Although low vitamin D levels (7/71) and anemia and/or low iron levels (4/71) have been reported, the true prevalence may be higher as vitamin D and iron levels are often not measured routinely and deficiency may not be obvious clinically.
Neonatal hypothermia. Difficulties in regulating body temperature in the neonatal period have not yet been reported in the literature, but appear to occur frequently [Author, personal observation].
Excessive hiccups in utero and in the neonatal period have been observed in a significant proportion of the individuals [Author, personal observation].
• Delayed myelination or nonspecific subtle white matter hyperintensities, which constitute the most frequently reported brain abnormalities (23/71)
• Excessive extra-axial fluid spaces (7/71)
• Volume loss of the corpus callosum (4/71)
• Cerebellar tonsillar ectopia (1/71)
• Possible cerebral atrophy (1/71)
• Absent septum pellucidum (1/71)
• Disturbed levels of gonadotropins (2/71) and medical treatment for precocious puberty (3/71)
• A blunted cortisol response (2/71)
• Hypothyroidism (2/71)
• Elevated prolactin levels (1/71)
• Neonatal hypothermia. Difficulties in regulating body temperature in the neonatal period have not yet been reported in the literature, but appear to occur frequently [Author, personal observation].
• Excessive hiccups in utero and in the neonatal period have been observed in a significant proportion of the individuals [Author, personal observation].
## Genotype-Phenotype Correlations
Current data suggest that
The features of individuals with a 5q31.3 deletion that overlap with those of individuals with a
Of note, individuals with a deletion that also includes the neighboring gene
## Penetrance
To the authors' knowledge, the penetrance of all intragenic
## Nomenclature
The OMIM designation for
## Prevalence
To date, 71 individuals are known to have
Based on the study of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Disorders in the differential diagnosis of
Lower extremity-predominant autosomal dominant spinal muscular atrophy 1 (OMIM
Myotonic dystrophy in the newborn (see
Neurotransmitter disorder [
See
•
•
• Lower extremity-predominant autosomal dominant spinal muscular atrophy 1 (OMIM
• Myotonic dystrophy in the newborn (see
• Neurotransmitter disorder [
•
•
•
## Management
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis
Feeding assessment w/analysis of swallowing & eval for possible aspiration
Assessment for constipation
Individuals often benefit when management is provided by a multidisciplinary team including relevant specialists, which may include, but is not limited to, a pediatrician, clinical geneticist, child neurologist, pulmonologist, ophthalmologist, orthopedic surgeon, physiotherapist, occupational therapist, and speech and language therapist.
Treatment of Manifestations in Individuals with
See
Mgmt by a neurologist
May include video EEG monitoring to help distinguish epileptic from nonepileptic events (e.g., dystonia, dyskinesia, dysconjugate eye movements)
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.
In the US, an IEP should be developed by the local public school district based on each individual's level of function. 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 and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation).
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of medications or orthopedic procedures.
Recommended Surveillance for Individuals with
See
Search
• Feeding assessment w/analysis of swallowing & eval for possible aspiration
• Assessment for constipation
• In the US, an IEP should be developed by the local public school district based on each individual's level of function. 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 and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of medications or orthopedic procedures.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis
Feeding assessment w/analysis of swallowing & eval for possible aspiration
Assessment for constipation
• Feeding assessment w/analysis of swallowing & eval for possible aspiration
• Assessment for constipation
## Treatment of Manifestations
Individuals often benefit when management is provided by a multidisciplinary team including relevant specialists, which may include, but is not limited to, a pediatrician, clinical geneticist, child neurologist, pulmonologist, ophthalmologist, orthopedic surgeon, physiotherapist, occupational therapist, and speech and language therapist.
Treatment of Manifestations in Individuals with
See
Mgmt by a neurologist
May include video EEG monitoring to help distinguish epileptic from nonepileptic events (e.g., dystonia, dyskinesia, dysconjugate eye movements)
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.
In the US, an IEP should be developed by the local public school district based on each individual's level of function. 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 and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation).
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of medications or orthopedic procedures.
• In the US, an IEP should be developed by the local public school district based on each individual's level of function. 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 and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of medications or orthopedic procedures.
## Developmental Delay / Intellectual Disability Educational 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.
In the US, an IEP should be developed by the local public school district based on each individual's level of function. 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 should be developed by the local public school district based on each individual's level of function. 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 and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation).
Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of medications or orthopedic procedures.
• Physical therapy is recommended to maximize mobility and to reduce the risk for later-onset orthopedic complications (e.g., scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities including dystonia, consider involving appropriate specialists to aid in management of medications or orthopedic procedures.
## Surveillance
Recommended Surveillance for Individuals with
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
In almost all probands with a
The exception is a child who inherited a
Evaluation of parents of a proband with an apparent
If the
The risk to the sibs of the proband depends on the genetic status of the parents.
Because almost all
To date, all reported 5q31.3 deletions have been
Evaluation of the parents by genomic testing that will detect the 5q31.3 deletion identified in the proband is recommended. It is also important to exclude a balanced chromosome rearrangement that may have predisposed to a deletion encompassing 5q31.3 in the proband.
If the 5q31.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
If a predisposing balanced chromosome rearrangement is identified in a parent, genetic counseling is important as there may be a significant risk to the sibs of the proband.
Given that all probands with 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 parents of affected individuals.
Risk to future pregnancies is presumed to be low as the familial 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.
• In almost all probands with a
• The exception is a child who inherited a
• Evaluation of parents of a proband with an apparent
• If the
• The risk to the sibs of the proband depends on the genetic status of the parents.
• Because almost all
• To date, all reported 5q31.3 deletions have been
• Evaluation of the parents by genomic testing that will detect the 5q31.3 deletion identified in the proband is recommended. It is also important to exclude a balanced chromosome rearrangement that may have predisposed to a deletion encompassing 5q31.3 in the proband.
• If the 5q31.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
• If a predisposing balanced chromosome rearrangement is identified in a parent, genetic counseling is important as there may be a significant risk to the sibs of the proband.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/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
In almost all probands with a
The exception is a child who inherited a
Evaluation of parents of a proband with an apparent
If the
The risk to the sibs of the proband depends on the genetic status of the parents.
Because almost all
To date, all reported 5q31.3 deletions have been
Evaluation of the parents by genomic testing that will detect the 5q31.3 deletion identified in the proband is recommended. It is also important to exclude a balanced chromosome rearrangement that may have predisposed to a deletion encompassing 5q31.3 in the proband.
If the 5q31.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
If a predisposing balanced chromosome rearrangement is identified in a parent, genetic counseling is important as there may be a significant risk to the sibs of the proband.
Given that all probands with a
• In almost all probands with a
• The exception is a child who inherited a
• Evaluation of parents of a proband with an apparent
• If the
• The risk to the sibs of the proband depends on the genetic status of the parents.
• Because almost all
• To date, all reported 5q31.3 deletions have been
• Evaluation of the parents by genomic testing that will detect the 5q31.3 deletion identified in the proband is recommended. It is also important to exclude a balanced chromosome rearrangement that may have predisposed to a deletion encompassing 5q31.3 in the proband.
• If the 5q31.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
• If a predisposing balanced chromosome rearrangement is identified in a parent, genetic counseling is important as there may be a significant risk to the sibs of the proband.
In almost all probands with a
The exception is a child who inherited a
Evaluation of parents of a proband with an apparent
If the
The risk to the sibs of the proband depends on the genetic status of the parents.
Because almost all
• In almost all probands with a
• The exception is a child who inherited a
• Evaluation of parents of a proband with an apparent
• If the
• The risk to the sibs of the proband depends on the genetic status of the parents.
• Because almost all
## 5q31.3 Deletion Encompassing All or Part of
To date, all reported 5q31.3 deletions have been
Evaluation of the parents by genomic testing that will detect the 5q31.3 deletion identified in the proband is recommended. It is also important to exclude a balanced chromosome rearrangement that may have predisposed to a deletion encompassing 5q31.3 in the proband.
If the 5q31.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
If a predisposing balanced chromosome rearrangement is identified in a parent, genetic counseling is important as there may be a significant risk to the sibs of the proband.
• To date, all reported 5q31.3 deletions have been
• Evaluation of the parents by genomic testing that will detect the 5q31.3 deletion identified in the proband is recommended. It is also important to exclude a balanced chromosome rearrangement that may have predisposed to a deletion encompassing 5q31.3 in the proband.
• If the 5q31.3 deletion found in the proband is not identified in one of the parents, the risk to sibs is presumed to be low (<1%) but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
• If a predisposing balanced chromosome rearrangement is identified in a parent, genetic counseling is important as there may be a significant risk to the sibs of the proband.
## Other Family Members
Given that all probands with a
## 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 familial 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
•
•
•
•
•
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
## Molecular Genetics
PURA-Related Neurodevelopmental Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for PURA-Related Neurodevelopmental Disorders (
All missense variants occur in regions encoding one of the three PUR repeats (see
Variants listed in the table have been provided by the authors.
## Chapter Notes
27 April 2017 (bp) Review posted live
13 May 2016 (dh) Original submission
• 27 April 2017 (bp) Review posted live
• 13 May 2016 (dh) Original submission
## Revision History
27 April 2017 (bp) Review posted live
13 May 2016 (dh) Original submission
• 27 April 2017 (bp) Review posted live
• 13 May 2016 (dh) Original submission
## References
|
[
"MC Bonaglia, N Zanotta, R Giorda, G D'Angelo, C Zucca. Long-term follow-up of a patient with 5q31.3 microdeletion syndrome and the smallest de novo 5q31.2q31.3 deletion involving PURA.. Mol Cytogenet 2015;8:89",
"N Brown, T Burgess, R Forbes, G McGillivray, A Kornberg, S Mandelstam, Z. Starl. 5q31.3 Microdeletion syndrome: clinical and molecular characterization of two further cases.. Am J Med Genet A 2013;161A:2604-8",
"A Graebsch, S Roche, D. Niessing. X-ray structure of Pur-alpha reveals a Whirly-like fold and an unusual nucleic-acid binding surface.. Proc Natl Acad Sci U S A 2009;106:18521-6",
"S Hokkanen, HM Feldmann, H Ding, CK Jung, L Bojarski, I Renner-Müller, U Schüller, H Kretzschmar, E Wolf, J Herms. Lack of Pur-alpha alters postnatal brain development and causes megalencephaly.. Hum Mol Genet 2012;21:473-84",
"K Hosoki, T Ohta, J Natsume, S Imai, A Okumura, T Matsui, N Harda, CA Bacino, F Scaglia, JY Jones, N Niikawa, S Saitoh. Clinical phenotype and candidate genes for the 5q31.3 microdeletion syndrome.. Am J Med Genet A 2012;158A:1891-6",
"D Hunt, RJ Leventer, C Simons, R Taft, KJ Swoboda, M Gawne-Cain, DDD Study, AC Magee, PD Turnpenny, D Baralle. Whole exome sequencing in family trios reveals de novo mutations in PURA as a cause of severe neurodevelopmental delay and learning disability.. J Med Genet 2014;51:806-13",
"K Khalili, L Del Valle, V Muralidharan, WJ Gault, N Darbinian, J Otte, E Meier, EM Johnson, DC Daniel, Y Kinoshita, S Amini, J Gordon. Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse.. Mol Cell Biol 2003;23:6857-75",
"SR Lalani, J Zhang, CP Schaaf, CW Brown, P Magoulas, AC Tsai, A El-Gharbawy, KJ Wierenga, D Bartholomew, CT Fong, T Barbaro-Dieber, MK Kukolich, LC Burrage, E Austin, K Keller, M Pastore, F Fernandez, T Lotze, A Wilfong, G Purcarin, W Zhu, WJ Craigen, M Mcguire, M Jain, E Cooney, M Azamian, MN Bainbridge, DM Muzny, E Boerwinkle, RE Person, Z Niu, CM Eng, JR Lupski, RA Gibbs, AL Beaudet, Y Yang, MC Wang, F Xia. Mutations in PURA cause profound neonatal hypotonia, seizures, and encephalopathy in 5q31.3 microdeletion syndrome.. Am J Hum Genet 2014;95:579-83",
"N Okamoto, H Nakao, T Niihori, Y Aoki. Patient with a novel purine-rich element binding protein A mutation.. Congenit Anom (Kyoto) 2017;57:201-4",
"PL Pearl, JL Taylor, S Trzcinski, S Sokohl. The pediatric neurotransmitter disorders.. J Child Neurol 2007;22:606-16",
"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",
"K Shimojima, B Isidor, C Le Caignec, A Kondo, S Sakata, K Ohno, T. Yamamoto. A new microdeletion syndrome of 5q31.3 characterized by severe developmental delays, distinctive facial features, and delayed myelinisation.. Am J Med Genet A 2011;155A:732-6",
"AJ Tanaka, R Bai, MT Cho, K Anyane-Yeboa, P Ahimaz, AL Wilson, F Kendall, B Hay, T Moss, M Nardini, M Bauer, K Retterer, J Juusola, WK Chung. De novo mutations in PURA are associated with hypotonia and developmental delay.. Cold Spring Harb Mol Case Stud. 2015;1",
"J Weber, H Bao, C Hartlmüller, Z Wang, A Windhager, R Janowski, T Madl, P Jin, D Niessing. Structural basis of nucleic-acid recognition and double-strand unwinding by the essential neuronal protein Pur-alpha.. Elife. 2016;5",
"MK White, EM Johnson, K Khalili. Multiple roles for Puralpha in cellular and viral regulation.. Cell Cycle. 2009;8:1-7"
] |
27/4/2017
|
GeneReviews®
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
pws
|
pws
|
[
"Prader-Labhart-Willi Syndrome",
"Prader-Labhart-Willi Syndrome",
"Prader-Willi Syndrome"
] |
Prader-Willi Syndrome
|
Daniel J Driscoll, Jennifer L Miller, Suzanne B Cassidy
|
Summary Prader-Willi syndrome (PWS) is characterized by severe hypotonia, poor appetite, and feeding difficulties in early infancy, followed in early childhood by excessive eating and gradual development of morbid obesity (unless food intake is strictly controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone). A distinctive behavioral phenotype (temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Characteristic facial features, strabismus, and scoliosis are often present. PWS is a contiguous gene syndrome due to abnormal DNA methylation within the Prader-Willi critical region (PWCR) at 15q11.2-q13. The diagnosis and molecular cause can be identified in a proband by simultaneous DNA methylation analysis and oligo-SNP combination array (OSA). DNA methylation analysis identifies maternal-only imprinting within the PWCR. OSA can identify the molecular cause in those with a 15q11.2-q13 deletion, imprinting center deletion, and uniparental isodisomy and segmental isodisomy. In individuals with maternal-only imprinting identified on DNA methylation analysis and a normal OSA, DNA polymorphism analysis can be used to distinguish uniparental heterodisomy from an imprinting defect by epimutation. Individuals with PWS typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a
|
## Diagnosis
Prader-Willi syndrome (PWS)
Clinical findings differ by age group. The presence of
Hypotonia with poor appetite and suck in the neonatal period
Developmental delay
Hypotonia with history of poor suck
Developmental delay
History of hypotonia with poor suck (hypotonia often persists)
Developmental delay
Excessive eating with central obesity if uncontrolled externally
Cognitive impairment, usually mild intellectual disability
Excessive eating and hyperphagia with central obesity if uncontrolled externally
Hypothalamic hypogonadism and/or typical behavioral findings
Deletion of the 15q11.2-q13 genomic region is suggestive of PWS but not diagnostic.
The diagnosis of PWS
Deletion of the paternally inherited 15q11.2-q13 region
Uniparental disomy of the maternal chromosome 15q11.2-q13 region (UPD 15)
An imprinting defect of the paternal chromosome 15q11.2-q13 region either due to an imprinting center deletion or epimutation
Note: The underlying genetic etiology of PWS is important to discern for genetic counseling (see
Molecular Genetic Testing Used in Prader-Willi Syndrome
+ = mechanism can be identified by test method; MS-MLPA = methylation-specific multiplex ligation-dependent probe amplification; OSA = oligo-small nucleotide polymorphism (SNP) combination array; PWS = Prader-Willi syndrome; UPD = uniparental disomy
See
Typically by methylation-specific PCR (MSP).
OSA can detect genome-wide large deletions/duplications that cannot be detected by sequence analysis and provide detailed information regarding the size of the deletion, including most imprinting center deletions (see
Not a first-tier test; performed after DNA methylation analysis establishes the diagnosis of PWS to distinguish between methylation abnormalities due to UPD 15 heterodisomy and imprinting defect by epimutation.
Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) can identify 15q deletions and most imprinting center deletions (see
Includes UPD 15 without any regions of isodisomy (i.e., resulting in absence of heterozygosity)
• Hypotonia with poor appetite and suck in the neonatal period
• Developmental delay
• Hypotonia with history of poor suck
• Developmental delay
• History of hypotonia with poor suck (hypotonia often persists)
• Developmental delay
• Excessive eating with central obesity if uncontrolled externally
• Cognitive impairment, usually mild intellectual disability
• Excessive eating and hyperphagia with central obesity if uncontrolled externally
• Hypothalamic hypogonadism and/or typical behavioral findings
• Deletion of the paternally inherited 15q11.2-q13 region
• Uniparental disomy of the maternal chromosome 15q11.2-q13 region (UPD 15)
• An imprinting defect of the paternal chromosome 15q11.2-q13 region either due to an imprinting center deletion or epimutation
## Suggestive Findings
Prader-Willi syndrome (PWS)
Clinical findings differ by age group. The presence of
Hypotonia with poor appetite and suck in the neonatal period
Developmental delay
Hypotonia with history of poor suck
Developmental delay
History of hypotonia with poor suck (hypotonia often persists)
Developmental delay
Excessive eating with central obesity if uncontrolled externally
Cognitive impairment, usually mild intellectual disability
Excessive eating and hyperphagia with central obesity if uncontrolled externally
Hypothalamic hypogonadism and/or typical behavioral findings
Deletion of the 15q11.2-q13 genomic region is suggestive of PWS but not diagnostic.
• Hypotonia with poor appetite and suck in the neonatal period
• Developmental delay
• Hypotonia with history of poor suck
• Developmental delay
• History of hypotonia with poor suck (hypotonia often persists)
• Developmental delay
• Excessive eating with central obesity if uncontrolled externally
• Cognitive impairment, usually mild intellectual disability
• Excessive eating and hyperphagia with central obesity if uncontrolled externally
• Hypothalamic hypogonadism and/or typical behavioral findings
## Clinical Findings
Clinical findings differ by age group. The presence of
Hypotonia with poor appetite and suck in the neonatal period
Developmental delay
Hypotonia with history of poor suck
Developmental delay
History of hypotonia with poor suck (hypotonia often persists)
Developmental delay
Excessive eating with central obesity if uncontrolled externally
Cognitive impairment, usually mild intellectual disability
Excessive eating and hyperphagia with central obesity if uncontrolled externally
Hypothalamic hypogonadism and/or typical behavioral findings
• Hypotonia with poor appetite and suck in the neonatal period
• Developmental delay
• Hypotonia with history of poor suck
• Developmental delay
• History of hypotonia with poor suck (hypotonia often persists)
• Developmental delay
• Excessive eating with central obesity if uncontrolled externally
• Cognitive impairment, usually mild intellectual disability
• Excessive eating and hyperphagia with central obesity if uncontrolled externally
• Hypothalamic hypogonadism and/or typical behavioral findings
## Laboratory Findings
Deletion of the 15q11.2-q13 genomic region is suggestive of PWS but not diagnostic.
## Establishing the Diagnosis
The diagnosis of PWS
Deletion of the paternally inherited 15q11.2-q13 region
Uniparental disomy of the maternal chromosome 15q11.2-q13 region (UPD 15)
An imprinting defect of the paternal chromosome 15q11.2-q13 region either due to an imprinting center deletion or epimutation
Note: The underlying genetic etiology of PWS is important to discern for genetic counseling (see
Molecular Genetic Testing Used in Prader-Willi Syndrome
+ = mechanism can be identified by test method; MS-MLPA = methylation-specific multiplex ligation-dependent probe amplification; OSA = oligo-small nucleotide polymorphism (SNP) combination array; PWS = Prader-Willi syndrome; UPD = uniparental disomy
See
Typically by methylation-specific PCR (MSP).
OSA can detect genome-wide large deletions/duplications that cannot be detected by sequence analysis and provide detailed information regarding the size of the deletion, including most imprinting center deletions (see
Not a first-tier test; performed after DNA methylation analysis establishes the diagnosis of PWS to distinguish between methylation abnormalities due to UPD 15 heterodisomy and imprinting defect by epimutation.
Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) can identify 15q deletions and most imprinting center deletions (see
Includes UPD 15 without any regions of isodisomy (i.e., resulting in absence of heterozygosity)
• Deletion of the paternally inherited 15q11.2-q13 region
• Uniparental disomy of the maternal chromosome 15q11.2-q13 region (UPD 15)
• An imprinting defect of the paternal chromosome 15q11.2-q13 region either due to an imprinting center deletion or epimutation
## Clinical Characteristics
Prader-Willi syndrome (PWS) is a complex, multisystem disorder characterized by neonatal hypotonia with poor suck and poor weight gain without nutritional support, developmental delay, mild cognitive impairment, hypogonadism leading to genital hypoplasia and pubertal insufficiency, short stature if untreated with growth hormone (GH), childhood-onset obesity if excessive eating is not limited, behavioral findings, and typically a characteristic facial appearance. Less consistent but common features include decreased fetal movements, small hands and/or feet, hypopigmentation compared to the affected individual's family members, skin picking, strabismus and visual acuity abnormalities, sleep disturbance (including daytime sleepiness and sometimes sleep apnea), thick, viscous saliva, and articulation differences. There is some variability in clinical findings depending on the molecular cause of PWS.
Prader-Willi Syndrome: Frequency of Select Features
ADHD = attention-deficit/hyperactivity disorder; GH = growth hormone; OCD = obsessive-compulsive disorder; UPD = uniparental disomy
Poor suck, dysphagia, lethargy, and poor appetite result in poor weight gain in early infancy without assisted feeding. Feeding difficulties are reported in 99% of infants; nasogastric tube feeding (a gastrostomy tube is rarely needed) or the use of special nipples is generally required for a variable period of time, usually weeks to months. By the time the child is drinking from a cup or eating solids, a period of approximately normal eating behavior occurs.
The hypotonia improves over time. However, children and adults remain mildly hypotonic, with decreased muscle bulk and tone.
Hypogonadism is usually associated with low serum concentration of gonadotropins and causes incomplete, delayed, and sometimes disordered pubertal development. Infertility is almost universal, although a few instances of reproduction in females have been reported [
Male infants with PWS and cryptorchidism can be treated with human chorionic gonadotropin (hCG), which results in anatomically lower testes as well as improvement in the size of the penis and scrotal sac, prior to urologic surgery. Undergoing orchiopexy at a younger age, as well as higher levels of inhibin B and testosterone after hCG treatment, have been associated with a greater number of germ cell-containing tubules on testicular histology [
Premature pubarche has been reported in 15%-20% of males and 30% of females. Premature adrenarche was reported in 15%-20% of individuals with PWS. Premature pubarche and adrenarche have been associated with elevated dehydroepiandrosterone sulfate levels. Advanced bone age is also reported. Central precocious puberty, typically idiopathic, has been reported in 5% of individuals.
The hands and feet grow slowly and are generally below the fifth centile by age ten years (70%-90% of individuals) in the absence of GH treatment, with an average adult female foot size of 20.3 cm and average adult male foot size of 22.3 cm.
Nutritional Phases in Prader-Willi Syndrome
Adapted from
Early diagnosis allows the clinician to begin anticipatory guidance concerning the natural history of PWS, and in particular the nutritional phases (see
If started at a young age, GH treatment, along with good dietary control, may prevent obesity and the high proportion of fat mass. It may also modify the typical PWS facial appearance, improve motor milestones, and improve some cognitive abilities [
Many of the behavioral characteristics are suggestive of autism. A recent meta-analysis including 786 individuals with PWS reported that 26.7% met criteria for autism spectrum disorder, including 18.5% of those with 15q deletion and 35.3% of those with UPD 15 [
Attention-deficit/hyperactivity disorder is common and of early onset.
Psychosis is evident by young adulthood in some affected individuals and is significantly more frequent in those with UPD 15. A meta-analysis of 95 individuals with PWS from five studies suggested an overall incidence of psychosis of about 25% in those with 15q deletion and 64% in those with UPD 15 [
Behavioral and psychiatric issues interfere most with the quality of life in adolescence and adulthood, including affecting ability to live independently.
Hypopigmentation of hair, eyes, and skin is frequently found in individuals with 15q deletion due to the deletion of
Peripheral edema is not uncommon in obese individuals with PWS and may lead to chronic changes of the legs.
Acute gastric distention with gastric rupture and necrosis has been reported as a cause of death in several individuals with PWS, particularly following an eating binge among those who are thin but were previously obese. It may be unrecognized because of a high pain threshold.
Choking, especially on hot dogs, has been reported as cause of death in approximately 8% of deaths in individuals with PWS. Disordered pharyngeal and esophageal swallowing and lack of attempt to clear residue or coughing is common in PWS [
Concern about the possible contribution of GH administration to unexpected death has been raised by reported deaths of individuals within a few months of starting GH therapy. The few reported deaths were mostly in obese individuals who had preexisting respiratory or cardiac disorders with evidence of upper airway obstruction and uncorrected tonsillar and adenoidal hypertrophy. In other studies, the rate of death in affected individuals on and off GH therapy did not differ; thus, the relationship of GH administration to unexpected death remains unclear. See
No phenotypic feature is known to correlate exclusively with any one of the three main molecular mechanisms that result in PWS. However, some statistical differences in the frequency or severity of certain features between the two largest molecular classes (15q deletion and UPD 15) have been observed.
Post-term delivery [
Individuals with UPD 15 are less likely to have the typical facial appearance, hypopigmentation [
Individuals with UPD 15 are more likely to have psychosis [
Penetrance is complete.
The term "HHHO" (
PWS is sometimes called Willi-Prader syndrome or Prader-Labhart-Willi syndrome.
The estimated prevalence of PWS is 1:10,000-30,000 in a number of populations.
A recent study screening 16,579 newborns for PWS in Australia found a birth incidence of 1:8,290 [
• Hypogonadism is usually associated with low serum concentration of gonadotropins and causes incomplete, delayed, and sometimes disordered pubertal development. Infertility is almost universal, although a few instances of reproduction in females have been reported [
• Male infants with PWS and cryptorchidism can be treated with human chorionic gonadotropin (hCG), which results in anatomically lower testes as well as improvement in the size of the penis and scrotal sac, prior to urologic surgery. Undergoing orchiopexy at a younger age, as well as higher levels of inhibin B and testosterone after hCG treatment, have been associated with a greater number of germ cell-containing tubules on testicular histology [
• Premature pubarche has been reported in 15%-20% of males and 30% of females. Premature adrenarche was reported in 15%-20% of individuals with PWS. Premature pubarche and adrenarche have been associated with elevated dehydroepiandrosterone sulfate levels. Advanced bone age is also reported. Central precocious puberty, typically idiopathic, has been reported in 5% of individuals.
• The hands and feet grow slowly and are generally below the fifth centile by age ten years (70%-90% of individuals) in the absence of GH treatment, with an average adult female foot size of 20.3 cm and average adult male foot size of 22.3 cm.
• Early diagnosis allows the clinician to begin anticipatory guidance concerning the natural history of PWS, and in particular the nutritional phases (see
• If started at a young age, GH treatment, along with good dietary control, may prevent obesity and the high proportion of fat mass. It may also modify the typical PWS facial appearance, improve motor milestones, and improve some cognitive abilities [
• Many of the behavioral characteristics are suggestive of autism. A recent meta-analysis including 786 individuals with PWS reported that 26.7% met criteria for autism spectrum disorder, including 18.5% of those with 15q deletion and 35.3% of those with UPD 15 [
• Attention-deficit/hyperactivity disorder is common and of early onset.
• Psychosis is evident by young adulthood in some affected individuals and is significantly more frequent in those with UPD 15. A meta-analysis of 95 individuals with PWS from five studies suggested an overall incidence of psychosis of about 25% in those with 15q deletion and 64% in those with UPD 15 [
• Post-term delivery [
• Individuals with UPD 15 are less likely to have the typical facial appearance, hypopigmentation [
• Individuals with UPD 15 are more likely to have psychosis [
## Clinical Description
Prader-Willi syndrome (PWS) is a complex, multisystem disorder characterized by neonatal hypotonia with poor suck and poor weight gain without nutritional support, developmental delay, mild cognitive impairment, hypogonadism leading to genital hypoplasia and pubertal insufficiency, short stature if untreated with growth hormone (GH), childhood-onset obesity if excessive eating is not limited, behavioral findings, and typically a characteristic facial appearance. Less consistent but common features include decreased fetal movements, small hands and/or feet, hypopigmentation compared to the affected individual's family members, skin picking, strabismus and visual acuity abnormalities, sleep disturbance (including daytime sleepiness and sometimes sleep apnea), thick, viscous saliva, and articulation differences. There is some variability in clinical findings depending on the molecular cause of PWS.
Prader-Willi Syndrome: Frequency of Select Features
ADHD = attention-deficit/hyperactivity disorder; GH = growth hormone; OCD = obsessive-compulsive disorder; UPD = uniparental disomy
Poor suck, dysphagia, lethargy, and poor appetite result in poor weight gain in early infancy without assisted feeding. Feeding difficulties are reported in 99% of infants; nasogastric tube feeding (a gastrostomy tube is rarely needed) or the use of special nipples is generally required for a variable period of time, usually weeks to months. By the time the child is drinking from a cup or eating solids, a period of approximately normal eating behavior occurs.
The hypotonia improves over time. However, children and adults remain mildly hypotonic, with decreased muscle bulk and tone.
Hypogonadism is usually associated with low serum concentration of gonadotropins and causes incomplete, delayed, and sometimes disordered pubertal development. Infertility is almost universal, although a few instances of reproduction in females have been reported [
Male infants with PWS and cryptorchidism can be treated with human chorionic gonadotropin (hCG), which results in anatomically lower testes as well as improvement in the size of the penis and scrotal sac, prior to urologic surgery. Undergoing orchiopexy at a younger age, as well as higher levels of inhibin B and testosterone after hCG treatment, have been associated with a greater number of germ cell-containing tubules on testicular histology [
Premature pubarche has been reported in 15%-20% of males and 30% of females. Premature adrenarche was reported in 15%-20% of individuals with PWS. Premature pubarche and adrenarche have been associated with elevated dehydroepiandrosterone sulfate levels. Advanced bone age is also reported. Central precocious puberty, typically idiopathic, has been reported in 5% of individuals.
The hands and feet grow slowly and are generally below the fifth centile by age ten years (70%-90% of individuals) in the absence of GH treatment, with an average adult female foot size of 20.3 cm and average adult male foot size of 22.3 cm.
Nutritional Phases in Prader-Willi Syndrome
Adapted from
Early diagnosis allows the clinician to begin anticipatory guidance concerning the natural history of PWS, and in particular the nutritional phases (see
If started at a young age, GH treatment, along with good dietary control, may prevent obesity and the high proportion of fat mass. It may also modify the typical PWS facial appearance, improve motor milestones, and improve some cognitive abilities [
Many of the behavioral characteristics are suggestive of autism. A recent meta-analysis including 786 individuals with PWS reported that 26.7% met criteria for autism spectrum disorder, including 18.5% of those with 15q deletion and 35.3% of those with UPD 15 [
Attention-deficit/hyperactivity disorder is common and of early onset.
Psychosis is evident by young adulthood in some affected individuals and is significantly more frequent in those with UPD 15. A meta-analysis of 95 individuals with PWS from five studies suggested an overall incidence of psychosis of about 25% in those with 15q deletion and 64% in those with UPD 15 [
Behavioral and psychiatric issues interfere most with the quality of life in adolescence and adulthood, including affecting ability to live independently.
Hypopigmentation of hair, eyes, and skin is frequently found in individuals with 15q deletion due to the deletion of
Peripheral edema is not uncommon in obese individuals with PWS and may lead to chronic changes of the legs.
Acute gastric distention with gastric rupture and necrosis has been reported as a cause of death in several individuals with PWS, particularly following an eating binge among those who are thin but were previously obese. It may be unrecognized because of a high pain threshold.
Choking, especially on hot dogs, has been reported as cause of death in approximately 8% of deaths in individuals with PWS. Disordered pharyngeal and esophageal swallowing and lack of attempt to clear residue or coughing is common in PWS [
Concern about the possible contribution of GH administration to unexpected death has been raised by reported deaths of individuals within a few months of starting GH therapy. The few reported deaths were mostly in obese individuals who had preexisting respiratory or cardiac disorders with evidence of upper airway obstruction and uncorrected tonsillar and adenoidal hypertrophy. In other studies, the rate of death in affected individuals on and off GH therapy did not differ; thus, the relationship of GH administration to unexpected death remains unclear. See
• Hypogonadism is usually associated with low serum concentration of gonadotropins and causes incomplete, delayed, and sometimes disordered pubertal development. Infertility is almost universal, although a few instances of reproduction in females have been reported [
• Male infants with PWS and cryptorchidism can be treated with human chorionic gonadotropin (hCG), which results in anatomically lower testes as well as improvement in the size of the penis and scrotal sac, prior to urologic surgery. Undergoing orchiopexy at a younger age, as well as higher levels of inhibin B and testosterone after hCG treatment, have been associated with a greater number of germ cell-containing tubules on testicular histology [
• Premature pubarche has been reported in 15%-20% of males and 30% of females. Premature adrenarche was reported in 15%-20% of individuals with PWS. Premature pubarche and adrenarche have been associated with elevated dehydroepiandrosterone sulfate levels. Advanced bone age is also reported. Central precocious puberty, typically idiopathic, has been reported in 5% of individuals.
• The hands and feet grow slowly and are generally below the fifth centile by age ten years (70%-90% of individuals) in the absence of GH treatment, with an average adult female foot size of 20.3 cm and average adult male foot size of 22.3 cm.
• Early diagnosis allows the clinician to begin anticipatory guidance concerning the natural history of PWS, and in particular the nutritional phases (see
• If started at a young age, GH treatment, along with good dietary control, may prevent obesity and the high proportion of fat mass. It may also modify the typical PWS facial appearance, improve motor milestones, and improve some cognitive abilities [
• Many of the behavioral characteristics are suggestive of autism. A recent meta-analysis including 786 individuals with PWS reported that 26.7% met criteria for autism spectrum disorder, including 18.5% of those with 15q deletion and 35.3% of those with UPD 15 [
• Attention-deficit/hyperactivity disorder is common and of early onset.
• Psychosis is evident by young adulthood in some affected individuals and is significantly more frequent in those with UPD 15. A meta-analysis of 95 individuals with PWS from five studies suggested an overall incidence of psychosis of about 25% in those with 15q deletion and 64% in those with UPD 15 [
## Genotype-Phenotype Correlations
No phenotypic feature is known to correlate exclusively with any one of the three main molecular mechanisms that result in PWS. However, some statistical differences in the frequency or severity of certain features between the two largest molecular classes (15q deletion and UPD 15) have been observed.
Post-term delivery [
Individuals with UPD 15 are less likely to have the typical facial appearance, hypopigmentation [
Individuals with UPD 15 are more likely to have psychosis [
• Post-term delivery [
• Individuals with UPD 15 are less likely to have the typical facial appearance, hypopigmentation [
• Individuals with UPD 15 are more likely to have psychosis [
## Penetrance
Penetrance is complete.
## Nomenclature
The term "HHHO" (
PWS is sometimes called Willi-Prader syndrome or Prader-Labhart-Willi syndrome.
## Prevalence
The estimated prevalence of PWS is 1:10,000-30,000 in a number of populations.
A recent study screening 16,579 newborns for PWS in Australia found a birth incidence of 1:8,290 [
## Genetically Related Disorders
Maternally inherited duplication of the PWS/AS critical region causes intellectual disability, seizures, and autism [
## Differential Diagnosis
Many disorders can mimic
Genetic Disorders with Hypotonia in Infancy in the Differential Diagnosis of Prader-Willi Syndrome
AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PWS = Prader-Willi syndrome; SMA = spinal muscular atrophy; XL = X-linked
Angelman syndrome (AS) is associated with deficient expression or function of the maternally inherited
Individuals with AS typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a
Congenital myasthenic syndromes (CMS) are typically inherited in an autosomal recessive manner. Less commonly, CMS are inherited in an autosomal dominant manner.
Schaaf-Yang syndrome is inherited in an autosomal dominant imprinted manner (a heterozygous pathogenic variant on the paternally derived
Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner (one
Genetic Disorders with Developmental Delay / Intellectual Disability and Obesity with or without Hypogonadism in the Differential Diagnosis of Prader-Willi Syndrome
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; PWS = Prader-Willi syndrome; UPD = uniparental disomy; SNHL = sensorineural hearing loss; DM = diabetes mellitus; XL = X-linked
Disorders of
Angelman syndrome (AS) is associated with deficient expression or function of the maternally inherited
Individuals with AS typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a
Listed genes represent the most commonly associated genes.
A "PWS-like phenotype" of syndromic obesity has been identified in individuals with 6q16.2 deletions involving
A PWS-like phenotype was reported in an individual with a 6q16.3q23.3 duplication (the duplication did not encompass
Several reports have associated a PWS-like phenotype with 1p36 deletion; findings include hypotonia, developmental delay, obesity, hyperphagia, and behavioral issues [
Multiple reports describe a PWS-like phenotype with deletions at 16p11.2 including
Reports of other cytogenetic anomalies in individuals with a PWS-like phenotype have included dupXq27.2-ter and del10q26 [
• A PWS-like phenotype was reported in an individual with a 6q16.3q23.3 duplication (the duplication did not encompass
• Several reports have associated a PWS-like phenotype with 1p36 deletion; findings include hypotonia, developmental delay, obesity, hyperphagia, and behavioral issues [
• Multiple reports describe a PWS-like phenotype with deletions at 16p11.2 including
• Reports of other cytogenetic anomalies in individuals with a PWS-like phenotype have included dupXq27.2-ter and del10q26 [
## Management
Management of the manifestations of Prader-Willi syndrome (PWS) is age dependent and should include both addressing the consequences of PWS and anticipatory guidance. A team approach is recommended. Several approaches to management have been published [
To establish the extent of disease and needs in an individual diagnosed with PWS, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Prader-Willi Syndrome
Assessment of newborns & young infants for sucking issues & poor growth
Nutrition consultation
PT eval
If prolonged, eval for hypothyroidism
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assessment of males for presence of cryptorchidism regardless of age
Assessment of pubertal stage
Urologic consultation for consideration of orchiopexy
If pubertal stage is not age appropriate, refer to endocrinologist for eval & potential hormone therapy.
Referral to endocrinologist for treatment w/GH therapy to be considered at diagnosis
Glycosylated hemoglobin concentration &/or glucose tolerance test to assess for diabetes if obese at diagnosis
Free thyroxine & TSH levels to assess for hypothyroidism
Assessment for manifestations of central adrenal insufficiency
Assessment of height & weight
Plot height, weight, head circumference, & BMI on either age-appropriate growth charts &/or charts developed for PWS
Growth charts for affected infants & children not treated w/GH have been published.
Growth charts for GH-treated children w/PWS have been developed.
Assess for behavioral findings & obsessive-compulsive features after age 2 yrs.
Assess family support, parenting skills, & psychosocial/emotional needs to assist in designing family interventions.
Evaluate respiratory status during sleep w/sleep study prior to initiation of GH therapy.
Evaluate excessive daytime sleepiness / narcolepsy / cataplexy w/overnight sleep study followed by multiple sleep latency testing & video EEG.
Assess infants for hip dysplasia.
Hip ultrasound at age 6 wks
Community or
Social work involvement for parental support;
Home nursing referral.
BMI = body mass index; GH = growth hormone; MOI= mode of inheritance; PT = physical therapy; PWS = Prader-Willi syndrome; TSH = thyroid-stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Management by multidisciplinary specialists typically starting with neonatologists and followed by medical geneticists and genetic counselors, primary care physicians, endocrinologists, orthopedists, nutritionists, psychologists, psychiatrists, physical, occupational, and speech therapists, and educators is recommended.
Treatment of Manifestations in Individuals with Prader-Willi Syndrome
Consider hCG treatment in infancy for cryptorchidism.
Orchiopexy as needed for cryptorchidism
Normalizes height, ↑ lean body mass, ↓ fat mass, & ↑ mobility, which are beneficial to weight mgmt.
Treatment in 1st yr of life assists in developmental milestones.
In young children, dose is similar to that for persons w/isolated GH deficiency (i.e., ~1 mg/m
The adult dose of GH is 20%-25% of the dose recommended in children.
Therapy can be started in infancy or at time of diagnosis.
Obtain sleep study before initiation of GH therapy & 4-8 wks after starting GH therapy to ensure that GH treatment has not caused or worsened sleep-disordered breathing.
To avoid overtreatment, monitor growth velocity, head circumference, & serum IGF-1.
Consultation w/dietician w/close follow up when weight centiles begin ↑ (typically age 18-36 mos)
Well-balanced, low-calorie diet,
Adequate intake of vitamins & minerals as assessed by dietician; prescription for vitamin/mineral supplementation when indicated, esp for calcium & vitamin D
The same program is appropriate if obesity is present at any time.
Locking the kitchen, refrigerator, &/or cupboards is often needed once the child can open the refrigerator & cupboards.
Gastric bypass is not recommended in PWS, as it does not appear to correct the lack of satiety & will not prevent overeating. In addition, complication rates are high.
ABA therapy in childhood helps ameliorate some of the common behavioral issues.
Standard pharmacologic therapy for behavioral issues is helpful in many persons.
Affected persons generally require a sheltered employment environment.
Individualized treatment depending on cause, which may incl tonsillectomy & adenoidectomy &/or CPAP or BiPAP, as in general population.
Modafinil can be used to treat excessive daytime sleepiness that is unrelated to degree of sleep apnea.
Spinal casting & bracing are typically undertaken early in life, depending on degree of spine curvature.
Nonsurgical treatment for hip dysplasia is usually adequate.
Calcium & vitamin D supplementation
Low bone density: implementation of sex steroid therapy, GH therapy, or bisphosphonate therapy as clinically indicated
Many ASMs may be effective; none has been demonstrated effective specifically for PWS.
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.
Issues of guardianship, wills, trusts, & advocacy should be investigated no later than adolescence.
Ongoing assessment of need for home nursing
Consider involvement in adaptive sports or
ABA = applied behavioral analysis; ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; BMI = body mass index; CPAP = continuous positive airway pressure; GH = growth hormone; hGC = human chorionic gonadotropin; IGF-1 = insulin-like growth factor 1; PWS = Prader-Willi syndrome
Caloric needs of infants and children with PWS are typically 60%-80% of the recommended daily allowance. The energy requirement of adults with PWS rarely exceeds 1,200-1,400 kcal/day.
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.
Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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 obsessive-compulsive symptoms or psychosis, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
Health supervision guidelines from the American Academy of Pediatrics (AAP) have been published [
Recommended Surveillance for Individuals with Prader-Willi Syndrome
Monitor height, weight, & BMI.
Growth charts for affected infants & children not treated w/GH have been published,
Every month in infancy
Every 6 mos in 1st decade of life
At least annually thereafter
More frequently if caregivers identify rapid weight gain
Assess for psychosis.
Evidence of radical behavior change, hallucinations, delusions, or disorientation should prompt psychiatry eval.
Clinical findings suggestive of scoliosis
Obesity
BMI = body mass index; DXA = dual-energy x-ray absorptiometry; GH = growth hormone; TSH = thyroid-stimulating hormone
Weight in kg, height in m
See
Pregnancy is rare in women with PWS. Pregnancies in those with PWS require more frequent monitoring, given the high pain threshold observed in individuals with PWS, particularly in those who are obese.
To date, the most promising data for treatment of hyperphagia has been reported in trials of
Some reduction of hyperphagia was also demonstrated with
Several additional Phase II clinical trials are ongoing for treatment of hyperphagia in individuals with PWS, including investigations of oxytocin, canabadiolvarin, a melanin-concentrating hormone receptor 1 antagonist, a compound that activates bitter taste receptors in the gut, and cannabidiol.
There is an ongoing Phase II clinical trial of pitolisant for treatment of excessive daytime somnolence, as well as narcolepsy/cataplexy.
Transcutaneous vagal nerve stimulation showed significant positive effects on decreasing the frequency and intensity of temper outbursts in a small study in adults with PWS. Larger, placebo-controlled studies are being planned to determine the reproducibility and duration of effects [
Search
• Assessment of newborns & young infants for sucking issues & poor growth
• Nutrition consultation
• PT eval
• If prolonged, eval for hypothyroidism
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assessment of males for presence of cryptorchidism regardless of age
• Assessment of pubertal stage
• Urologic consultation for consideration of orchiopexy
• If pubertal stage is not age appropriate, refer to endocrinologist for eval & potential hormone therapy.
• Referral to endocrinologist for treatment w/GH therapy to be considered at diagnosis
• Glycosylated hemoglobin concentration &/or glucose tolerance test to assess for diabetes if obese at diagnosis
• Free thyroxine & TSH levels to assess for hypothyroidism
• Assessment for manifestations of central adrenal insufficiency
• Assessment of height & weight
• Plot height, weight, head circumference, & BMI on either age-appropriate growth charts &/or charts developed for PWS
• Growth charts for affected infants & children not treated w/GH have been published.
• Growth charts for GH-treated children w/PWS have been developed.
• Assess for behavioral findings & obsessive-compulsive features after age 2 yrs.
• Assess family support, parenting skills, & psychosocial/emotional needs to assist in designing family interventions.
• Evaluate respiratory status during sleep w/sleep study prior to initiation of GH therapy.
• Evaluate excessive daytime sleepiness / narcolepsy / cataplexy w/overnight sleep study followed by multiple sleep latency testing & video EEG.
• Assess infants for hip dysplasia.
• Hip ultrasound at age 6 wks
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Consider hCG treatment in infancy for cryptorchidism.
• Orchiopexy as needed for cryptorchidism
• Normalizes height, ↑ lean body mass, ↓ fat mass, & ↑ mobility, which are beneficial to weight mgmt.
• Treatment in 1st yr of life assists in developmental milestones.
• In young children, dose is similar to that for persons w/isolated GH deficiency (i.e., ~1 mg/m
• The adult dose of GH is 20%-25% of the dose recommended in children.
• Therapy can be started in infancy or at time of diagnosis.
• Obtain sleep study before initiation of GH therapy & 4-8 wks after starting GH therapy to ensure that GH treatment has not caused or worsened sleep-disordered breathing.
• To avoid overtreatment, monitor growth velocity, head circumference, & serum IGF-1.
• Consultation w/dietician w/close follow up when weight centiles begin ↑ (typically age 18-36 mos)
• Well-balanced, low-calorie diet,
• Adequate intake of vitamins & minerals as assessed by dietician; prescription for vitamin/mineral supplementation when indicated, esp for calcium & vitamin D
• The same program is appropriate if obesity is present at any time.
• Locking the kitchen, refrigerator, &/or cupboards is often needed once the child can open the refrigerator & cupboards.
• Gastric bypass is not recommended in PWS, as it does not appear to correct the lack of satiety & will not prevent overeating. In addition, complication rates are high.
• ABA therapy in childhood helps ameliorate some of the common behavioral issues.
• Standard pharmacologic therapy for behavioral issues is helpful in many persons.
• Affected persons generally require a sheltered employment environment.
• Individualized treatment depending on cause, which may incl tonsillectomy & adenoidectomy &/or CPAP or BiPAP, as in general population.
• Modafinil can be used to treat excessive daytime sleepiness that is unrelated to degree of sleep apnea.
• Spinal casting & bracing are typically undertaken early in life, depending on degree of spine curvature.
• Nonsurgical treatment for hip dysplasia is usually adequate.
• Calcium & vitamin D supplementation
• Low bone density: implementation of sex steroid therapy, GH therapy, or bisphosphonate therapy as clinically indicated
• Many ASMs may be effective; none has been demonstrated effective specifically for PWS.
• 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.
• Issues of guardianship, wills, trusts, & advocacy should be investigated no later than adolescence.
• Ongoing assessment of need for 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.
• Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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 height, weight, & BMI.
• Growth charts for affected infants & children not treated w/GH have been published,
• Every month in infancy
• Every 6 mos in 1st decade of life
• At least annually thereafter
• More frequently if caregivers identify rapid weight gain
• Assess for psychosis.
• Evidence of radical behavior change, hallucinations, delusions, or disorientation should prompt psychiatry eval.
• Clinical findings suggestive of scoliosis
• Obesity
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with PWS, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Prader-Willi Syndrome
Assessment of newborns & young infants for sucking issues & poor growth
Nutrition consultation
PT eval
If prolonged, eval for hypothyroidism
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Assessment of males for presence of cryptorchidism regardless of age
Assessment of pubertal stage
Urologic consultation for consideration of orchiopexy
If pubertal stage is not age appropriate, refer to endocrinologist for eval & potential hormone therapy.
Referral to endocrinologist for treatment w/GH therapy to be considered at diagnosis
Glycosylated hemoglobin concentration &/or glucose tolerance test to assess for diabetes if obese at diagnosis
Free thyroxine & TSH levels to assess for hypothyroidism
Assessment for manifestations of central adrenal insufficiency
Assessment of height & weight
Plot height, weight, head circumference, & BMI on either age-appropriate growth charts &/or charts developed for PWS
Growth charts for affected infants & children not treated w/GH have been published.
Growth charts for GH-treated children w/PWS have been developed.
Assess for behavioral findings & obsessive-compulsive features after age 2 yrs.
Assess family support, parenting skills, & psychosocial/emotional needs to assist in designing family interventions.
Evaluate respiratory status during sleep w/sleep study prior to initiation of GH therapy.
Evaluate excessive daytime sleepiness / narcolepsy / cataplexy w/overnight sleep study followed by multiple sleep latency testing & video EEG.
Assess infants for hip dysplasia.
Hip ultrasound at age 6 wks
Community or
Social work involvement for parental support;
Home nursing referral.
BMI = body mass index; GH = growth hormone; MOI= mode of inheritance; PT = physical therapy; PWS = Prader-Willi syndrome; TSH = thyroid-stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assessment of newborns & young infants for sucking issues & poor growth
• Nutrition consultation
• PT eval
• If prolonged, eval for hypothyroidism
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Assessment of males for presence of cryptorchidism regardless of age
• Assessment of pubertal stage
• Urologic consultation for consideration of orchiopexy
• If pubertal stage is not age appropriate, refer to endocrinologist for eval & potential hormone therapy.
• Referral to endocrinologist for treatment w/GH therapy to be considered at diagnosis
• Glycosylated hemoglobin concentration &/or glucose tolerance test to assess for diabetes if obese at diagnosis
• Free thyroxine & TSH levels to assess for hypothyroidism
• Assessment for manifestations of central adrenal insufficiency
• Assessment of height & weight
• Plot height, weight, head circumference, & BMI on either age-appropriate growth charts &/or charts developed for PWS
• Growth charts for affected infants & children not treated w/GH have been published.
• Growth charts for GH-treated children w/PWS have been developed.
• Assess for behavioral findings & obsessive-compulsive features after age 2 yrs.
• Assess family support, parenting skills, & psychosocial/emotional needs to assist in designing family interventions.
• Evaluate respiratory status during sleep w/sleep study prior to initiation of GH therapy.
• Evaluate excessive daytime sleepiness / narcolepsy / cataplexy w/overnight sleep study followed by multiple sleep latency testing & video EEG.
• Assess infants for hip dysplasia.
• Hip ultrasound at age 6 wks
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Management by multidisciplinary specialists typically starting with neonatologists and followed by medical geneticists and genetic counselors, primary care physicians, endocrinologists, orthopedists, nutritionists, psychologists, psychiatrists, physical, occupational, and speech therapists, and educators is recommended.
Treatment of Manifestations in Individuals with Prader-Willi Syndrome
Consider hCG treatment in infancy for cryptorchidism.
Orchiopexy as needed for cryptorchidism
Normalizes height, ↑ lean body mass, ↓ fat mass, & ↑ mobility, which are beneficial to weight mgmt.
Treatment in 1st yr of life assists in developmental milestones.
In young children, dose is similar to that for persons w/isolated GH deficiency (i.e., ~1 mg/m
The adult dose of GH is 20%-25% of the dose recommended in children.
Therapy can be started in infancy or at time of diagnosis.
Obtain sleep study before initiation of GH therapy & 4-8 wks after starting GH therapy to ensure that GH treatment has not caused or worsened sleep-disordered breathing.
To avoid overtreatment, monitor growth velocity, head circumference, & serum IGF-1.
Consultation w/dietician w/close follow up when weight centiles begin ↑ (typically age 18-36 mos)
Well-balanced, low-calorie diet,
Adequate intake of vitamins & minerals as assessed by dietician; prescription for vitamin/mineral supplementation when indicated, esp for calcium & vitamin D
The same program is appropriate if obesity is present at any time.
Locking the kitchen, refrigerator, &/or cupboards is often needed once the child can open the refrigerator & cupboards.
Gastric bypass is not recommended in PWS, as it does not appear to correct the lack of satiety & will not prevent overeating. In addition, complication rates are high.
ABA therapy in childhood helps ameliorate some of the common behavioral issues.
Standard pharmacologic therapy for behavioral issues is helpful in many persons.
Affected persons generally require a sheltered employment environment.
Individualized treatment depending on cause, which may incl tonsillectomy & adenoidectomy &/or CPAP or BiPAP, as in general population.
Modafinil can be used to treat excessive daytime sleepiness that is unrelated to degree of sleep apnea.
Spinal casting & bracing are typically undertaken early in life, depending on degree of spine curvature.
Nonsurgical treatment for hip dysplasia is usually adequate.
Calcium & vitamin D supplementation
Low bone density: implementation of sex steroid therapy, GH therapy, or bisphosphonate therapy as clinically indicated
Many ASMs may be effective; none has been demonstrated effective specifically for PWS.
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.
Issues of guardianship, wills, trusts, & advocacy should be investigated no later than adolescence.
Ongoing assessment of need for home nursing
Consider involvement in adaptive sports or
ABA = applied behavioral analysis; ASM = anti-seizure medication; BiPAP = bilevel positive airway pressure; BMI = body mass index; CPAP = continuous positive airway pressure; GH = growth hormone; hGC = human chorionic gonadotropin; IGF-1 = insulin-like growth factor 1; PWS = Prader-Willi syndrome
Caloric needs of infants and children with PWS are typically 60%-80% of the recommended daily allowance. The energy requirement of adults with PWS rarely exceeds 1,200-1,400 kcal/day.
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.
Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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 obsessive-compulsive symptoms or psychosis, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Consider hCG treatment in infancy for cryptorchidism.
• Orchiopexy as needed for cryptorchidism
• Normalizes height, ↑ lean body mass, ↓ fat mass, & ↑ mobility, which are beneficial to weight mgmt.
• Treatment in 1st yr of life assists in developmental milestones.
• In young children, dose is similar to that for persons w/isolated GH deficiency (i.e., ~1 mg/m
• The adult dose of GH is 20%-25% of the dose recommended in children.
• Therapy can be started in infancy or at time of diagnosis.
• Obtain sleep study before initiation of GH therapy & 4-8 wks after starting GH therapy to ensure that GH treatment has not caused or worsened sleep-disordered breathing.
• To avoid overtreatment, monitor growth velocity, head circumference, & serum IGF-1.
• Consultation w/dietician w/close follow up when weight centiles begin ↑ (typically age 18-36 mos)
• Well-balanced, low-calorie diet,
• Adequate intake of vitamins & minerals as assessed by dietician; prescription for vitamin/mineral supplementation when indicated, esp for calcium & vitamin D
• The same program is appropriate if obesity is present at any time.
• Locking the kitchen, refrigerator, &/or cupboards is often needed once the child can open the refrigerator & cupboards.
• Gastric bypass is not recommended in PWS, as it does not appear to correct the lack of satiety & will not prevent overeating. In addition, complication rates are high.
• ABA therapy in childhood helps ameliorate some of the common behavioral issues.
• Standard pharmacologic therapy for behavioral issues is helpful in many persons.
• Affected persons generally require a sheltered employment environment.
• Individualized treatment depending on cause, which may incl tonsillectomy & adenoidectomy &/or CPAP or BiPAP, as in general population.
• Modafinil can be used to treat excessive daytime sleepiness that is unrelated to degree of sleep apnea.
• Spinal casting & bracing are typically undertaken early in life, depending on degree of spine curvature.
• Nonsurgical treatment for hip dysplasia is usually adequate.
• Calcium & vitamin D supplementation
• Low bone density: implementation of sex steroid therapy, GH therapy, or bisphosphonate therapy as clinically indicated
• Many ASMs may be effective; none has been demonstrated effective specifically for PWS.
• 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.
• Issues of guardianship, wills, trusts, & advocacy should be investigated no later than adolescence.
• Ongoing assessment of need for 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.
• Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
• Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical and occupational therapy and speech services will be provided in the IEP to the extent that the need affects the child’s access to academic material. Beyond that, private supportive therapies based on the affected individual’s needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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 obsessive-compulsive symptoms or psychosis, when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
## Surveillance
Health supervision guidelines from the American Academy of Pediatrics (AAP) have been published [
Recommended Surveillance for Individuals with Prader-Willi Syndrome
Monitor height, weight, & BMI.
Growth charts for affected infants & children not treated w/GH have been published,
Every month in infancy
Every 6 mos in 1st decade of life
At least annually thereafter
More frequently if caregivers identify rapid weight gain
Assess for psychosis.
Evidence of radical behavior change, hallucinations, delusions, or disorientation should prompt psychiatry eval.
Clinical findings suggestive of scoliosis
Obesity
BMI = body mass index; DXA = dual-energy x-ray absorptiometry; GH = growth hormone; TSH = thyroid-stimulating hormone
Weight in kg, height in m
• Monitor height, weight, & BMI.
• Growth charts for affected infants & children not treated w/GH have been published,
• Every month in infancy
• Every 6 mos in 1st decade of life
• At least annually thereafter
• More frequently if caregivers identify rapid weight gain
• Assess for psychosis.
• Evidence of radical behavior change, hallucinations, delusions, or disorientation should prompt psychiatry eval.
• Clinical findings suggestive of scoliosis
• Obesity
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Pregnancy is rare in women with PWS. Pregnancies in those with PWS require more frequent monitoring, given the high pain threshold observed in individuals with PWS, particularly in those who are obese.
## Therapies Under Investigation
To date, the most promising data for treatment of hyperphagia has been reported in trials of
Some reduction of hyperphagia was also demonstrated with
Several additional Phase II clinical trials are ongoing for treatment of hyperphagia in individuals with PWS, including investigations of oxytocin, canabadiolvarin, a melanin-concentrating hormone receptor 1 antagonist, a compound that activates bitter taste receptors in the gut, and cannabidiol.
There is an ongoing Phase II clinical trial of pitolisant for treatment of excessive daytime somnolence, as well as narcolepsy/cataplexy.
Transcutaneous vagal nerve stimulation showed significant positive effects on decreasing the frequency and intensity of temper outbursts in a small study in adults with PWS. Larger, placebo-controlled studies are being planned to determine the reproducibility and duration of effects [
Search
## Genetic Counseling
Individuals with Prader-Willi syndrome (PWS) typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a
The risk to sibs of a proband with PWS depends on the underlying genetic mechanism and genetic etiology of PWS in the proband and the genetic status of the parents (see
Once a diagnosis of PWS is established in the proband through identification of abnormal DNA methylation at 15q11.2-q13 and an underlying genetic mechanism (15q deletion, maternal UPD 15, or an imprinting defect) has been identified on oligo-SNP combination array (OSA), the genetic etiology should be determined for recurrence risk assessment. Recommended testing to discern genetic etiology in the proband and the genetic status of the parents is summarized in
Risks to Sibs of a Proband with Prader-Willi Syndrome by Genetic Mechanism
Proband: karyotype & FISH
Father: karyotype & FISH (to identify cryptic translocation or paracentric inversion of 15q11.2)
If proband has normal karyotype, then karyotype in father
If proband has marker chromosome, then karyotype in both parents
If proband has 15/15 Robertsonian translocation, then karyotype in mother
Proband: no additional testing
Father: DNA methylation & OSA or MS-MLPA.
MS-MLPA = methylation-specific multiplex ligation-dependent probe amplification; OSA = oligo-small nucleotide polymorphism (SNP) combination array; PWS = Prader-Willi syndrome; UPD = uniparental disomy
Oligo-SNP combination array (OSA) does not detect translocations & inversions involving proximal 15q.
Germline mosaicism in the father is rare but has been observed in cases of 15q11.2 deletions [
If the father has a 15/15 Robertsonian translocation, aberrant segregation at meiosis I could result in a nullisomic sperm; this, combined with monosomy rescue to disomy, would result in an embryo with maternal isodisomic UPD 15.
Empiric data suggest that the risk for recurrence in most of these cases would also be less than 1%, although the theoretic risk would be much higher.
Half of imprinting center (IC) deletions are inherited from the father; the other half are
Risks to Sibs of a Proband with Prader-Willi Syndrome by Genetic Mechanism and Genetic Etiology
Proband: karyotype & FISH
Father: karyotype & FISH (to identify cryptic translocation or paracentric inversion of 15q11.2)
If proband has normal karyotype, then karyotype in father
If proband has marker chromosome, then karyotype in both parents
If proband has 15/15 Robertsonian translocation, then karyotype in mother
Proband: no additional testing
Father: DNA methylation & OSA (or MS-MLPA)
MS-MLPA = methylation-specific multiplex ligation-dependent probe amplification; OSA = oligo-small nucleotide polymorphism (SNP) combination array; PWS = Prader-Willi syndrome; UPD = uniparental disomy
Oligo-SNP combination array (OSA) does not detect translocations & inversions involving proximal 15q.
Germline mosaicism in the father is rare but has been observed in cases of 15q11.2 deletions [
If the father has a 15/15 Robertsonian translocation, aberrant segregation at meiosis I could result in a nullisomic sperm; this, combined with monosomy rescue to disomy, would result in an embryo with maternal isodisomic UPD 15.
Empiric data suggest that the risk for recurrence in most of these cases would also be less than 1%, although the theoretic risk would be much higher.
Half of IC deletions are inherited from the father; the other half are
With rare exceptions in females, individuals with PWS do not reproduce. No male with genetically confirmed PWS has ever been reported to have reproduced.
The risk to offspring should be determined in the context of formal genetic counseling.
If a chromosome rearrangement (e.g., translocation or inversion) is identified in the proband and a parent, the sibs of the carrier parent should be offered genetic counseling and the option of genetic testing.
If a proband's father is heterozygous for an imprinting center deletion, the father's sibs are also at risk of having the imprinting center deletion.
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 the parents of affected individuals.
If a 15q11.2 deletion is suspected on cytogenetic studies from testing of cells obtained by chorionic villus sampling (CVS) or amniocentesis, OSA is indicated. In this instance, parent-of-origin studies should be performed after confirmation of a deletion to determine if the deletion is maternally derived (fetus has
If trisomy 15 or mosaic trisomy 15 is detected on testing of cells obtained by CVS, and if subsequent testing of cells obtained by amniocentesis reveals 46 chromosomes, the possibility of trisomy rescue leading to Angelman syndrome (paternal UPD) through loss of a maternal chromosome 15 or PWS (maternal UPD) through loss of a paternal chromosome 15 should be considered. In this instance, parent-of-origin (UPD) studies or DNA methylation analysis on amniocytes should be considered.
If an inherited or
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 risk to sibs of a proband with PWS depends on the underlying genetic mechanism and genetic etiology of PWS in the proband and the genetic status of the parents (see
• Once a diagnosis of PWS is established in the proband through identification of abnormal DNA methylation at 15q11.2-q13 and an underlying genetic mechanism (15q deletion, maternal UPD 15, or an imprinting defect) has been identified on oligo-SNP combination array (OSA), the genetic etiology should be determined for recurrence risk assessment. Recommended testing to discern genetic etiology in the proband and the genetic status of the parents is summarized in
• Proband: karyotype & FISH
• Father: karyotype & FISH (to identify cryptic translocation or paracentric inversion of 15q11.2)
• If proband has normal karyotype, then karyotype in father
• If proband has marker chromosome, then karyotype in both parents
• If proband has 15/15 Robertsonian translocation, then karyotype in mother
• Proband: no additional testing
• Father: DNA methylation & OSA or MS-MLPA.
• Proband: karyotype & FISH
• Father: karyotype & FISH (to identify cryptic translocation or paracentric inversion of 15q11.2)
• If proband has normal karyotype, then karyotype in father
• If proband has marker chromosome, then karyotype in both parents
• If proband has 15/15 Robertsonian translocation, then karyotype in mother
• Proband: no additional testing
• Father: DNA methylation & OSA (or MS-MLPA)
• With rare exceptions in females, individuals with PWS do not reproduce. No male with genetically confirmed PWS has ever been reported to have reproduced.
• The risk to offspring should be determined in the context of formal genetic counseling.
• If a chromosome rearrangement (e.g., translocation or inversion) is identified in the proband and a parent, the sibs of the carrier parent should be offered genetic counseling and the option of genetic testing.
• If a proband's father is heterozygous for an imprinting center deletion, the father's sibs are also at risk of having the imprinting center deletion.
• 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 the parents of affected individuals.
• If a 15q11.2 deletion is suspected on cytogenetic studies from testing of cells obtained by chorionic villus sampling (CVS) or amniocentesis, OSA is indicated. In this instance, parent-of-origin studies should be performed after confirmation of a deletion to determine if the deletion is maternally derived (fetus has
• If trisomy 15 or mosaic trisomy 15 is detected on testing of cells obtained by CVS, and if subsequent testing of cells obtained by amniocentesis reveals 46 chromosomes, the possibility of trisomy rescue leading to Angelman syndrome (paternal UPD) through loss of a maternal chromosome 15 or PWS (maternal UPD) through loss of a paternal chromosome 15 should be considered. In this instance, parent-of-origin (UPD) studies or DNA methylation analysis on amniocytes should be considered.
• If an inherited or
## Mode of Inheritance
Individuals with Prader-Willi syndrome (PWS) typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a
## Risk to Family Members
The risk to sibs of a proband with PWS depends on the underlying genetic mechanism and genetic etiology of PWS in the proband and the genetic status of the parents (see
Once a diagnosis of PWS is established in the proband through identification of abnormal DNA methylation at 15q11.2-q13 and an underlying genetic mechanism (15q deletion, maternal UPD 15, or an imprinting defect) has been identified on oligo-SNP combination array (OSA), the genetic etiology should be determined for recurrence risk assessment. Recommended testing to discern genetic etiology in the proband and the genetic status of the parents is summarized in
Risks to Sibs of a Proband with Prader-Willi Syndrome by Genetic Mechanism
Proband: karyotype & FISH
Father: karyotype & FISH (to identify cryptic translocation or paracentric inversion of 15q11.2)
If proband has normal karyotype, then karyotype in father
If proband has marker chromosome, then karyotype in both parents
If proband has 15/15 Robertsonian translocation, then karyotype in mother
Proband: no additional testing
Father: DNA methylation & OSA or MS-MLPA.
MS-MLPA = methylation-specific multiplex ligation-dependent probe amplification; OSA = oligo-small nucleotide polymorphism (SNP) combination array; PWS = Prader-Willi syndrome; UPD = uniparental disomy
Oligo-SNP combination array (OSA) does not detect translocations & inversions involving proximal 15q.
Germline mosaicism in the father is rare but has been observed in cases of 15q11.2 deletions [
If the father has a 15/15 Robertsonian translocation, aberrant segregation at meiosis I could result in a nullisomic sperm; this, combined with monosomy rescue to disomy, would result in an embryo with maternal isodisomic UPD 15.
Empiric data suggest that the risk for recurrence in most of these cases would also be less than 1%, although the theoretic risk would be much higher.
Half of imprinting center (IC) deletions are inherited from the father; the other half are
Risks to Sibs of a Proband with Prader-Willi Syndrome by Genetic Mechanism and Genetic Etiology
Proband: karyotype & FISH
Father: karyotype & FISH (to identify cryptic translocation or paracentric inversion of 15q11.2)
If proband has normal karyotype, then karyotype in father
If proband has marker chromosome, then karyotype in both parents
If proband has 15/15 Robertsonian translocation, then karyotype in mother
Proband: no additional testing
Father: DNA methylation & OSA (or MS-MLPA)
MS-MLPA = methylation-specific multiplex ligation-dependent probe amplification; OSA = oligo-small nucleotide polymorphism (SNP) combination array; PWS = Prader-Willi syndrome; UPD = uniparental disomy
Oligo-SNP combination array (OSA) does not detect translocations & inversions involving proximal 15q.
Germline mosaicism in the father is rare but has been observed in cases of 15q11.2 deletions [
If the father has a 15/15 Robertsonian translocation, aberrant segregation at meiosis I could result in a nullisomic sperm; this, combined with monosomy rescue to disomy, would result in an embryo with maternal isodisomic UPD 15.
Empiric data suggest that the risk for recurrence in most of these cases would also be less than 1%, although the theoretic risk would be much higher.
Half of IC deletions are inherited from the father; the other half are
With rare exceptions in females, individuals with PWS do not reproduce. No male with genetically confirmed PWS has ever been reported to have reproduced.
The risk to offspring should be determined in the context of formal genetic counseling.
If a chromosome rearrangement (e.g., translocation or inversion) is identified in the proband and a parent, the sibs of the carrier parent should be offered genetic counseling and the option of genetic testing.
If a proband's father is heterozygous for an imprinting center deletion, the father's sibs are also at risk of having the imprinting center deletion.
• The risk to sibs of a proband with PWS depends on the underlying genetic mechanism and genetic etiology of PWS in the proband and the genetic status of the parents (see
• Once a diagnosis of PWS is established in the proband through identification of abnormal DNA methylation at 15q11.2-q13 and an underlying genetic mechanism (15q deletion, maternal UPD 15, or an imprinting defect) has been identified on oligo-SNP combination array (OSA), the genetic etiology should be determined for recurrence risk assessment. Recommended testing to discern genetic etiology in the proband and the genetic status of the parents is summarized in
• Proband: karyotype & FISH
• Father: karyotype & FISH (to identify cryptic translocation or paracentric inversion of 15q11.2)
• If proband has normal karyotype, then karyotype in father
• If proband has marker chromosome, then karyotype in both parents
• If proband has 15/15 Robertsonian translocation, then karyotype in mother
• Proband: no additional testing
• Father: DNA methylation & OSA or MS-MLPA.
• Proband: karyotype & FISH
• Father: karyotype & FISH (to identify cryptic translocation or paracentric inversion of 15q11.2)
• If proband has normal karyotype, then karyotype in father
• If proband has marker chromosome, then karyotype in both parents
• If proband has 15/15 Robertsonian translocation, then karyotype in mother
• Proband: no additional testing
• Father: DNA methylation & OSA (or MS-MLPA)
• With rare exceptions in females, individuals with PWS do not reproduce. No male with genetically confirmed PWS has ever been reported to have reproduced.
• The risk to offspring should be determined in the context of formal genetic counseling.
• If a chromosome rearrangement (e.g., translocation or inversion) is identified in the proband and a parent, the sibs of the carrier parent should be offered genetic counseling and the option of genetic testing.
• If a proband's father is heterozygous for an imprinting center deletion, the father's sibs are also at risk of having the imprinting center deletion.
## 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 the parents of affected individuals.
• 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 the parents of affected individuals.
## Prenatal Testing
If a 15q11.2 deletion is suspected on cytogenetic studies from testing of cells obtained by chorionic villus sampling (CVS) or amniocentesis, OSA is indicated. In this instance, parent-of-origin studies should be performed after confirmation of a deletion to determine if the deletion is maternally derived (fetus has
If trisomy 15 or mosaic trisomy 15 is detected on testing of cells obtained by CVS, and if subsequent testing of cells obtained by amniocentesis reveals 46 chromosomes, the possibility of trisomy rescue leading to Angelman syndrome (paternal UPD) through loss of a maternal chromosome 15 or PWS (maternal UPD) through loss of a paternal chromosome 15 should be considered. In this instance, parent-of-origin (UPD) studies or DNA methylation analysis on amniocytes should be considered.
If an inherited or
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.
• If a 15q11.2 deletion is suspected on cytogenetic studies from testing of cells obtained by chorionic villus sampling (CVS) or amniocentesis, OSA is indicated. In this instance, parent-of-origin studies should be performed after confirmation of a deletion to determine if the deletion is maternally derived (fetus has
• If trisomy 15 or mosaic trisomy 15 is detected on testing of cells obtained by CVS, and if subsequent testing of cells obtained by amniocentesis reveals 46 chromosomes, the possibility of trisomy rescue leading to Angelman syndrome (paternal UPD) through loss of a maternal chromosome 15 or PWS (maternal UPD) through loss of a paternal chromosome 15 should be considered. In this instance, parent-of-origin (UPD) studies or DNA methylation analysis on amniocytes should be considered.
• If an inherited or
## Resources
Salisbury House
Station Road
United Kingdom
United Kingdom
•
• Salisbury House
• Station Road
• United Kingdom
•
•
•
•
•
•
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
Prader-Willi Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Prader-Willi Syndrome (
The Prader-Willi syndrome (PWS) critical region (PWCR) is localized to a 5- to 6-Mb genomic region on the proximal long arm of chromosome 15 (15q11.2-q13) (see
The genomic and epigenetic changes causing PWS all lead to a loss of expression of the normally paternally expressed genes on chromosome 15q11.2-q13. Absence of the paternally inherited copy of these genes, or failure to express them, causes total absence of expression for those genes in the affected individual because the maternal contribution for these genes has been programmed by epigenetic factors to be silenced [
Other individuals have biparental inheritance but maternal-only DNA methylation patterns in this region without detectable abnormalities in the imprinting center. These individuals are considered to have an imprinting defect by an epimutation.
## Molecular Pathogenesis
The Prader-Willi syndrome (PWS) critical region (PWCR) is localized to a 5- to 6-Mb genomic region on the proximal long arm of chromosome 15 (15q11.2-q13) (see
The genomic and epigenetic changes causing PWS all lead to a loss of expression of the normally paternally expressed genes on chromosome 15q11.2-q13. Absence of the paternally inherited copy of these genes, or failure to express them, causes total absence of expression for those genes in the affected individual because the maternal contribution for these genes has been programmed by epigenetic factors to be silenced [
Other individuals have biparental inheritance but maternal-only DNA methylation patterns in this region without detectable abnormalities in the imprinting center. These individuals are considered to have an imprinting defect by an epimutation.
## Chapter Notes
Dr Driscoll is board certified in Pediatrics, Clinical Genetics, and Clinical Cytogenetics. He has been conducting clinical and laboratory research on Prader-Willi syndrome (PWS) since the late 1980s. He has been a major contributor to the understanding of the genetics of PWS and genomic imprinting in the PWS critical region, as well as to the elucidation of the natural history of PWS. His group first developed the technique (DNA methylation analysis) that is used around the world to diagnose PWS and also elucidated the nutritional phases of PWS that has gained wide acceptance by PWS experts.
Dr Driscoll is widely published on PWS and a major spokesperson on PWS in the US and internationally. He has had an active PWS clinic for the last 32 years and was the principal investigator for the PWS component of the NIH-funded 12-year national Rare Disease Center grant on the natural history of PWS. He served on the Prader-Willi Syndrome Association | USA (PWSA | USA) Board of Directors for 21 years and as Chair of the Clinical Advisory Board for PWSA | USA for 23 years. He is currently the Chair of the Clinical and Scientific Advisory Board for the International Prader-Willi Syndrome Organization (IPWSO).
Dr Miller is a Pediatric Endocrinologist who specializes in the care and treatment of individuals with PWS and other causes of childhood obesity. She has conducted many clinical trials for individuals with PWS, as well as clinical trials for other genetic obesity conditions and hypothalamic obesity. She is a member of the Scientific Advisory Board for the Foundation for Prader-Willi Syndrome Research (FPWR) and the Clinical Advisory Board for PWSA | USA.
Dr Cassidy is a Clinical Geneticist who has specialized in PWS clinically and in her clinical research throughout her career in academic medicine. She has conducted multidisciplinary clinics for people with PWS for 40 years. A founding member of IPWSO, she is currently on the IPWSO Clinical and Scientific Advisory Board and the PWSA | USA Clinical and Scientific Advisory Board. She has been a frequent speaker about PWS at educational and medical conferences around the world. She is an editor of
All the authors of this
Much knowledge of clinical findings and insight into management has been gleaned from families of people with PWS over many years of contact. We are all grateful to the colleagues who worked with us in our respective PWS clinics and in our clinical and laboratory research on PWS throughout the years, as well as the knowledge gained from other experts on PWS whom we have consulted on a wide range of issues over the years. The authors would also like to acknowledge Carlos Sulsona for his expert assistance with the figures.
Suzanne B Cassidy, MD, FFACMGG (1998-present)Daniel J Driscoll, MD, PhD, FFACMGG, FAAP (2012-present)Jennifer L Miller, MD, MS, FAAP (2012-present)Stuart Schwartz, PhD, FACMG; Laboratory Corporation of America (1998-2023)
5 December 2024 (ma) Revision: PWS growth charts added to
2 November 2023 (dd) Revision: Angelman syndrome added to
9 March 2023 (sw) Comprehensive update posted live
4 February 2016 (ha) Comprehensive update posted live
11 October 2012 (me) Comprehensive update posted live
24 March 2008 (me) Comprehensive update posted live
16 June 2005 (me) Comprehensive update posted live
1 May 2003 (me) Comprehensive update posted live
13 November 2000 (me) Comprehensive update posted live
6 October 1998 (pb) Review posted live
Spring 1997 (sc) Original submission
• 5 December 2024 (ma) Revision: PWS growth charts added to
• 2 November 2023 (dd) Revision: Angelman syndrome added to
• 9 March 2023 (sw) Comprehensive update posted live
• 4 February 2016 (ha) Comprehensive update posted live
• 11 October 2012 (me) Comprehensive update posted live
• 24 March 2008 (me) Comprehensive update posted live
• 16 June 2005 (me) Comprehensive update posted live
• 1 May 2003 (me) Comprehensive update posted live
• 13 November 2000 (me) Comprehensive update posted live
• 6 October 1998 (pb) Review posted live
• Spring 1997 (sc) Original submission
## Author Notes
Dr Driscoll is board certified in Pediatrics, Clinical Genetics, and Clinical Cytogenetics. He has been conducting clinical and laboratory research on Prader-Willi syndrome (PWS) since the late 1980s. He has been a major contributor to the understanding of the genetics of PWS and genomic imprinting in the PWS critical region, as well as to the elucidation of the natural history of PWS. His group first developed the technique (DNA methylation analysis) that is used around the world to diagnose PWS and also elucidated the nutritional phases of PWS that has gained wide acceptance by PWS experts.
Dr Driscoll is widely published on PWS and a major spokesperson on PWS in the US and internationally. He has had an active PWS clinic for the last 32 years and was the principal investigator for the PWS component of the NIH-funded 12-year national Rare Disease Center grant on the natural history of PWS. He served on the Prader-Willi Syndrome Association | USA (PWSA | USA) Board of Directors for 21 years and as Chair of the Clinical Advisory Board for PWSA | USA for 23 years. He is currently the Chair of the Clinical and Scientific Advisory Board for the International Prader-Willi Syndrome Organization (IPWSO).
Dr Miller is a Pediatric Endocrinologist who specializes in the care and treatment of individuals with PWS and other causes of childhood obesity. She has conducted many clinical trials for individuals with PWS, as well as clinical trials for other genetic obesity conditions and hypothalamic obesity. She is a member of the Scientific Advisory Board for the Foundation for Prader-Willi Syndrome Research (FPWR) and the Clinical Advisory Board for PWSA | USA.
Dr Cassidy is a Clinical Geneticist who has specialized in PWS clinically and in her clinical research throughout her career in academic medicine. She has conducted multidisciplinary clinics for people with PWS for 40 years. A founding member of IPWSO, she is currently on the IPWSO Clinical and Scientific Advisory Board and the PWSA | USA Clinical and Scientific Advisory Board. She has been a frequent speaker about PWS at educational and medical conferences around the world. She is an editor of
## Acknowledgments
All the authors of this
Much knowledge of clinical findings and insight into management has been gleaned from families of people with PWS over many years of contact. We are all grateful to the colleagues who worked with us in our respective PWS clinics and in our clinical and laboratory research on PWS throughout the years, as well as the knowledge gained from other experts on PWS whom we have consulted on a wide range of issues over the years. The authors would also like to acknowledge Carlos Sulsona for his expert assistance with the figures.
## Author History
Suzanne B Cassidy, MD, FFACMGG (1998-present)Daniel J Driscoll, MD, PhD, FFACMGG, FAAP (2012-present)Jennifer L Miller, MD, MS, FAAP (2012-present)Stuart Schwartz, PhD, FACMG; Laboratory Corporation of America (1998-2023)
## Revision History
5 December 2024 (ma) Revision: PWS growth charts added to
2 November 2023 (dd) Revision: Angelman syndrome added to
9 March 2023 (sw) Comprehensive update posted live
4 February 2016 (ha) Comprehensive update posted live
11 October 2012 (me) Comprehensive update posted live
24 March 2008 (me) Comprehensive update posted live
16 June 2005 (me) Comprehensive update posted live
1 May 2003 (me) Comprehensive update posted live
13 November 2000 (me) Comprehensive update posted live
6 October 1998 (pb) Review posted live
Spring 1997 (sc) Original submission
• 5 December 2024 (ma) Revision: PWS growth charts added to
• 2 November 2023 (dd) Revision: Angelman syndrome added to
• 9 March 2023 (sw) Comprehensive update posted live
• 4 February 2016 (ha) Comprehensive update posted live
• 11 October 2012 (me) Comprehensive update posted live
• 24 March 2008 (me) Comprehensive update posted live
• 16 June 2005 (me) Comprehensive update posted live
• 1 May 2003 (me) Comprehensive update posted live
• 13 November 2000 (me) Comprehensive update posted live
• 6 October 1998 (pb) Review posted live
• Spring 1997 (sc) Original submission
## References
Beygo J, Buiting K, Ramsden SC, Ellis R, Clayton-Smith J, Kanber D. Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. Eur J Hum Genet. 2019;27:1326-40. [
Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS; 2011 Growth hormone in Prader-Willi Syndrome Clinical Care Guidelines Workshop Participants. Growth Hormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. Available
Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, Childers A, Shelton AR, Bingham NC, Shoemaker AH, Miller JL. A multidisciplinary approach to the clinical management of Prader-Willi syndrome. Mol Genet Genomic Med. 2019;7:e514. [
International Prader-Willi Syndrome Organization Clinical and Scientific Advisory Board. Guides for doctors: consensus documents for infants, children, adolescents, and adults with PWS. Available
McCandless SE, Committee on Genetics. Clinical report -- health supervision for children with Prader-Willi Syndrome. Available
• Beygo J, Buiting K, Ramsden SC, Ellis R, Clayton-Smith J, Kanber D. Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. Eur J Hum Genet. 2019;27:1326-40. [
• Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS; 2011 Growth hormone in Prader-Willi Syndrome Clinical Care Guidelines Workshop Participants. Growth Hormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. Available
• Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, Childers A, Shelton AR, Bingham NC, Shoemaker AH, Miller JL. A multidisciplinary approach to the clinical management of Prader-Willi syndrome. Mol Genet Genomic Med. 2019;7:e514. [
• International Prader-Willi Syndrome Organization Clinical and Scientific Advisory Board. Guides for doctors: consensus documents for infants, children, adolescents, and adults with PWS. Available
• McCandless SE, Committee on Genetics. Clinical report -- health supervision for children with Prader-Willi Syndrome. Available
## Published Guidelines / Consensus Statements
Beygo J, Buiting K, Ramsden SC, Ellis R, Clayton-Smith J, Kanber D. Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. Eur J Hum Genet. 2019;27:1326-40. [
Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS; 2011 Growth hormone in Prader-Willi Syndrome Clinical Care Guidelines Workshop Participants. Growth Hormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. Available
Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, Childers A, Shelton AR, Bingham NC, Shoemaker AH, Miller JL. A multidisciplinary approach to the clinical management of Prader-Willi syndrome. Mol Genet Genomic Med. 2019;7:e514. [
International Prader-Willi Syndrome Organization Clinical and Scientific Advisory Board. Guides for doctors: consensus documents for infants, children, adolescents, and adults with PWS. Available
McCandless SE, Committee on Genetics. Clinical report -- health supervision for children with Prader-Willi Syndrome. Available
• Beygo J, Buiting K, Ramsden SC, Ellis R, Clayton-Smith J, Kanber D. Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. Eur J Hum Genet. 2019;27:1326-40. [
• Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS; 2011 Growth hormone in Prader-Willi Syndrome Clinical Care Guidelines Workshop Participants. Growth Hormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. Available
• Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, Childers A, Shelton AR, Bingham NC, Shoemaker AH, Miller JL. A multidisciplinary approach to the clinical management of Prader-Willi syndrome. Mol Genet Genomic Med. 2019;7:e514. [
• International Prader-Willi Syndrome Organization Clinical and Scientific Advisory Board. Guides for doctors: consensus documents for infants, children, adolescents, and adults with PWS. Available
• McCandless SE, Committee on Genetics. Clinical report -- health supervision for children with Prader-Willi Syndrome. Available
## Literature Cited
Comprehensive testing strategy to diagnose Prader-Willi syndrome and to establish the genetic mechanism
AOH = absence of heterozygosity; chrom abn = chromosomal abnormality; IC = imprinting center; OSA = oligo-SNP array; PWS = Prader-Willi syndrome; UPD = uniparental disomy; W/U = workup
Summary of the genetic and expression map of chromosome region 15q11.2-q13.3
The Prader-Willi syndrome (PWS) critical region (shown in blue) has several paternally (PWS region) expressed genes (
|
[] |
6/10/1998
|
9/3/2023
|
5/12/2024
|
GeneReviews®
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
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[
"Review",
"Clinical Review"
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pxe
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pxe
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[
"PXE",
"PXE",
"ATP-binding cassette sub-family C member 6",
"ABCC6",
"Pseudoxanthoma Elasticum"
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Pseudoxanthoma Elasticum
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Sharon F Terry, Jouni Uitto
|
Summary Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and vascular system. Individuals most commonly present with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage and/or characteristic papules in the skin. The most frequent cause of morbidity and disability in PXE is reduced vision due to complications of subretinal neovascularizations and macular atrophy. Other manifestations include premature gastrointestinal angina and/or bleeding, intermittent claudication of arm and leg muscles, stroke, renovascular hypertension, and cardiovascular complications (angina/myocardial infarction). Most affected individuals live a normal life span. The clinical diagnosis of PXE is established in a proband with characteristic skin lesions and at least one characteristic retinal finding. When eye findings are characteristic, but skin findings are equivocal, identification of calcified dystrophic elastic fibers using a von Kossa or similar stain on a biopsy of potentially lesional skin establishes the diagnosis. The molecular diagnosis of PXE is established in a proband by the presence of biallelic PXE 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 heterozygote (carrier), and a 25% chance of being unaffected and not a carrier. If both
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## Diagnosis
Formal diagnostic criteria for pseudoxanthoma elasticum (PXE) have been established [
PXE
Papules (darker than the skin color), usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae
Plaques formed by coalescence of papules
Loose, slack, or droopy, redundant skin (especially of the neck, axilla, and groin) that occurs with time
Retinal angioid streaks often appearing in the second decade, consisting of broad grayish to reddish-brown irregular lines caused by breaks in Bruch's membrane* that appear to radiate outward from the optic disk or peripapillary region in a pattern that resembles blood vessels; hence the term "angioid"
* Bruch's membrane is the elastin-rich tissue layer of the choroid between the retina and the choriocapillaris.
Note: Fluorescein angiography may be necessary to confirm this retinal finding.
The diagnosis of PXE can be
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 PXE is established in an individual with characteristic skin lesions on the neck, axillae, and/or antecubital fosse and at least one characteristic retinal finding (
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: (1) Presence of the pseudogenes
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 Pseudoxanthoma Elasticum (PXE)
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
Note, MLPA analysis using a widely available commercial kit does not include probes for exons 1, 3, 6, 16, 19-20, 29, and 31.
A deletion of exons 23-29 is common (~11% of alleles in affected individuals) in European populations [
•
• Papules (darker than the skin color), usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae
• Plaques formed by coalescence of papules
• Loose, slack, or droopy, redundant skin (especially of the neck, axilla, and groin) that occurs with time
• Papules (darker than the skin color), usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae
• Plaques formed by coalescence of papules
• Loose, slack, or droopy, redundant skin (especially of the neck, axilla, and groin) that occurs with time
•
• Retinal angioid streaks often appearing in the second decade, consisting of broad grayish to reddish-brown irregular lines caused by breaks in Bruch's membrane* that appear to radiate outward from the optic disk or peripapillary region in a pattern that resembles blood vessels; hence the term "angioid"
• * Bruch's membrane is the elastin-rich tissue layer of the choroid between the retina and the choriocapillaris.
• Note: Fluorescein angiography may be necessary to confirm this retinal finding.
• Retinal angioid streaks often appearing in the second decade, consisting of broad grayish to reddish-brown irregular lines caused by breaks in Bruch's membrane* that appear to radiate outward from the optic disk or peripapillary region in a pattern that resembles blood vessels; hence the term "angioid"
• * Bruch's membrane is the elastin-rich tissue layer of the choroid between the retina and the choriocapillaris.
• Note: Fluorescein angiography may be necessary to confirm this retinal finding.
• Papules (darker than the skin color), usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae
• Plaques formed by coalescence of papules
• Loose, slack, or droopy, redundant skin (especially of the neck, axilla, and groin) that occurs with time
• Retinal angioid streaks often appearing in the second decade, consisting of broad grayish to reddish-brown irregular lines caused by breaks in Bruch's membrane* that appear to radiate outward from the optic disk or peripapillary region in a pattern that resembles blood vessels; hence the term "angioid"
• * Bruch's membrane is the elastin-rich tissue layer of the choroid between the retina and the choriocapillaris.
• Note: Fluorescein angiography may be necessary to confirm this retinal finding.
• Note: (1) Presence of the pseudogenes
• For an introduction to multigene panels click
## Suggestive Findings
PXE
Papules (darker than the skin color), usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae
Plaques formed by coalescence of papules
Loose, slack, or droopy, redundant skin (especially of the neck, axilla, and groin) that occurs with time
Retinal angioid streaks often appearing in the second decade, consisting of broad grayish to reddish-brown irregular lines caused by breaks in Bruch's membrane* that appear to radiate outward from the optic disk or peripapillary region in a pattern that resembles blood vessels; hence the term "angioid"
* Bruch's membrane is the elastin-rich tissue layer of the choroid between the retina and the choriocapillaris.
Note: Fluorescein angiography may be necessary to confirm this retinal finding.
•
• Papules (darker than the skin color), usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae
• Plaques formed by coalescence of papules
• Loose, slack, or droopy, redundant skin (especially of the neck, axilla, and groin) that occurs with time
• Papules (darker than the skin color), usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae
• Plaques formed by coalescence of papules
• Loose, slack, or droopy, redundant skin (especially of the neck, axilla, and groin) that occurs with time
•
• Retinal angioid streaks often appearing in the second decade, consisting of broad grayish to reddish-brown irregular lines caused by breaks in Bruch's membrane* that appear to radiate outward from the optic disk or peripapillary region in a pattern that resembles blood vessels; hence the term "angioid"
• * Bruch's membrane is the elastin-rich tissue layer of the choroid between the retina and the choriocapillaris.
• Note: Fluorescein angiography may be necessary to confirm this retinal finding.
• Retinal angioid streaks often appearing in the second decade, consisting of broad grayish to reddish-brown irregular lines caused by breaks in Bruch's membrane* that appear to radiate outward from the optic disk or peripapillary region in a pattern that resembles blood vessels; hence the term "angioid"
• * Bruch's membrane is the elastin-rich tissue layer of the choroid between the retina and the choriocapillaris.
• Note: Fluorescein angiography may be necessary to confirm this retinal finding.
• Papules (darker than the skin color), usually seen on the lateral aspect of the neck or the flexural creases, such as the antecubital fossae, axillae, groin, or popliteal fossae
• Plaques formed by coalescence of papules
• Loose, slack, or droopy, redundant skin (especially of the neck, axilla, and groin) that occurs with time
• Retinal angioid streaks often appearing in the second decade, consisting of broad grayish to reddish-brown irregular lines caused by breaks in Bruch's membrane* that appear to radiate outward from the optic disk or peripapillary region in a pattern that resembles blood vessels; hence the term "angioid"
• * Bruch's membrane is the elastin-rich tissue layer of the choroid between the retina and the choriocapillaris.
• Note: Fluorescein angiography may be necessary to confirm this retinal finding.
## Establishing the Diagnosis
The diagnosis of PXE can be
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 PXE is established in an individual with characteristic skin lesions on the neck, axillae, and/or antecubital fosse and at least one characteristic retinal finding (
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: (1) Presence of the pseudogenes
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 Pseudoxanthoma Elasticum (PXE)
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
Note, MLPA analysis using a widely available commercial kit does not include probes for exons 1, 3, 6, 16, 19-20, 29, and 31.
A deletion of exons 23-29 is common (~11% of alleles in affected individuals) in European populations [
• Note: (1) Presence of the pseudogenes
• For an introduction to multigene panels click
## Clinical Diagnosis
The diagnosis of PXE is established in an individual with characteristic skin lesions on the neck, axillae, and/or antecubital fosse and at least one characteristic retinal finding (
## Molecular Diagnosis
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: (1) Presence of the pseudogenes
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 Pseudoxanthoma Elasticum (PXE)
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
Note, MLPA analysis using a widely available commercial kit does not include probes for exons 1, 3, 6, 16, 19-20, 29, and 31.
A deletion of exons 23-29 is common (~11% of alleles in affected individuals) in European populations [
• Note: (1) Presence of the pseudogenes
• For an introduction to multigene panels click
## Clinical Characteristics
Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Individuals can present as early as age five years with papules in the skin and/or between ages ten and 30 years with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Manifestations of other vascular involvement include gastrointestinal angina and/or bleeding, intermittent claudication of arm and leg muscles, stroke, and renovascular hypertension, especially at an unexpectedly young age.
Select Features of Pseudoxanthoma Elasticum (PXE)
Based on
GI = gastrointestinal
The papules gradually coalesce to form plaques, and eventually the skin, especially of the neck, axilla, and groin, becomes loose, lax, and redundant.
Mucous membranes can show similar yellowish lesions, most commonly the inner aspect of the lower lip and the vaginal mucosa.
In nearly every person with PXE, angioid streaks develop between the first and second decade.
Neither angioid streaks nor
Although one small series suggested an increased incidence of mitral valve prolapse in individuals with PXE [
No genotype-phenotype correlations for
In addition, the phenotype does not differ between individuals with biallelic
Earlier reports sometimes referred to PXE as Gröndblad-Strandberg syndrome.
Prevalence data are not available.
Common disease-associated variants have been identified in individuals of European descent [
## Clinical Description
Pseudoxanthoma elasticum (PXE) is a systemic disorder that affects the elastic tissue of the skin, the eye, and the cardiovascular and gastrointestinal systems. Individuals can present as early as age five years with papules in the skin and/or between ages ten and 30 years with angioid streaks of the retina found on routine eye examination or associated with retinal hemorrhage. Manifestations of other vascular involvement include gastrointestinal angina and/or bleeding, intermittent claudication of arm and leg muscles, stroke, and renovascular hypertension, especially at an unexpectedly young age.
Select Features of Pseudoxanthoma Elasticum (PXE)
Based on
GI = gastrointestinal
The papules gradually coalesce to form plaques, and eventually the skin, especially of the neck, axilla, and groin, becomes loose, lax, and redundant.
Mucous membranes can show similar yellowish lesions, most commonly the inner aspect of the lower lip and the vaginal mucosa.
In nearly every person with PXE, angioid streaks develop between the first and second decade.
Neither angioid streaks nor
Although one small series suggested an increased incidence of mitral valve prolapse in individuals with PXE [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
In addition, the phenotype does not differ between individuals with biallelic
## Nomenclature
Earlier reports sometimes referred to PXE as Gröndblad-Strandberg syndrome.
## Prevalence
Prevalence data are not available.
Common disease-associated variants have been identified in individuals of European descent [
## Genetically Related (Allelic) Disorders
A few individuals with
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Pseudoxanthoma Elasticum (PXE)
Severe arteriopathy
Children w/GACI may also develop the typical cutaneous & ocular phenotype of PXE.
On skin biopsy, PXE does not have the same extent of abnormal collagen fibers near the calcified elastic fibers.
The skin lesions in BOS do not calcify histopathologically.
No osteopoikilosis in PXE
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Cutis laxa may also be associated with pathogenic variants in
PXE is the most common cause of angioid streaks of the retina.
The skin lesions of pseudoxanthoma elasticum (PXE) are mimicked by those in the following acquired conditions:
White fibrous papulosis of the neck and papillary dermal elastolysis, both signs of intrinsic aging, associated with thinning or loss of elastic fibers and focal thickening of the collagen fiber network (collectively known as fibroelastolytic papulosis)
Solar elastosis, in which yellowish-white papules occur in the skin of the neck and chest as a result of photoaging
Late-onset focal dermal elastosis
Long-term D-penicillamine treatment (used in the treatment of
In high myopia, lacquer cracks may resemble angioid streaks.
Subretinal neovascularization with hemorrhage can be seen in the absence of angioid streaks in age-related macular degeneration, high myopia, and presumed ocular histoplasmosis. Macular atrophy can also be seen in age-related macular degeneration.
PXE should be considered in the differential diagnosis of recurrent gastrointestinal bleeding of unknown cause [
• Severe arteriopathy
• Children w/GACI may also develop the typical cutaneous & ocular phenotype of PXE.
• On skin biopsy, PXE does not have the same extent of abnormal collagen fibers near the calcified elastic fibers.
• The skin lesions in BOS do not calcify histopathologically.
• No osteopoikilosis in PXE
• White fibrous papulosis of the neck and papillary dermal elastolysis, both signs of intrinsic aging, associated with thinning or loss of elastic fibers and focal thickening of the collagen fiber network (collectively known as fibroelastolytic papulosis)
• Solar elastosis, in which yellowish-white papules occur in the skin of the neck and chest as a result of photoaging
• Late-onset focal dermal elastosis
## Hereditary Disorders
Genes of Interest in the Differential Diagnosis of Pseudoxanthoma Elasticum (PXE)
Severe arteriopathy
Children w/GACI may also develop the typical cutaneous & ocular phenotype of PXE.
On skin biopsy, PXE does not have the same extent of abnormal collagen fibers near the calcified elastic fibers.
The skin lesions in BOS do not calcify histopathologically.
No osteopoikilosis in PXE
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Cutis laxa may also be associated with pathogenic variants in
PXE is the most common cause of angioid streaks of the retina.
• Severe arteriopathy
• Children w/GACI may also develop the typical cutaneous & ocular phenotype of PXE.
• On skin biopsy, PXE does not have the same extent of abnormal collagen fibers near the calcified elastic fibers.
• The skin lesions in BOS do not calcify histopathologically.
• No osteopoikilosis in PXE
## Acquired Disorders and Disorders without a Known Genetic Cause
The skin lesions of pseudoxanthoma elasticum (PXE) are mimicked by those in the following acquired conditions:
White fibrous papulosis of the neck and papillary dermal elastolysis, both signs of intrinsic aging, associated with thinning or loss of elastic fibers and focal thickening of the collagen fiber network (collectively known as fibroelastolytic papulosis)
Solar elastosis, in which yellowish-white papules occur in the skin of the neck and chest as a result of photoaging
Late-onset focal dermal elastosis
Long-term D-penicillamine treatment (used in the treatment of
In high myopia, lacquer cracks may resemble angioid streaks.
Subretinal neovascularization with hemorrhage can be seen in the absence of angioid streaks in age-related macular degeneration, high myopia, and presumed ocular histoplasmosis. Macular atrophy can also be seen in age-related macular degeneration.
PXE should be considered in the differential diagnosis of recurrent gastrointestinal bleeding of unknown cause [
• White fibrous papulosis of the neck and papillary dermal elastolysis, both signs of intrinsic aging, associated with thinning or loss of elastic fibers and focal thickening of the collagen fiber network (collectively known as fibroelastolytic papulosis)
• Solar elastosis, in which yellowish-white papules occur in the skin of the neck and chest as a result of photoaging
• Late-onset focal dermal elastosis
## Skin
The skin lesions of pseudoxanthoma elasticum (PXE) are mimicked by those in the following acquired conditions:
White fibrous papulosis of the neck and papillary dermal elastolysis, both signs of intrinsic aging, associated with thinning or loss of elastic fibers and focal thickening of the collagen fiber network (collectively known as fibroelastolytic papulosis)
Solar elastosis, in which yellowish-white papules occur in the skin of the neck and chest as a result of photoaging
Late-onset focal dermal elastosis
Long-term D-penicillamine treatment (used in the treatment of
• White fibrous papulosis of the neck and papillary dermal elastolysis, both signs of intrinsic aging, associated with thinning or loss of elastic fibers and focal thickening of the collagen fiber network (collectively known as fibroelastolytic papulosis)
• Solar elastosis, in which yellowish-white papules occur in the skin of the neck and chest as a result of photoaging
• Late-onset focal dermal elastosis
## Eyes
In high myopia, lacquer cracks may resemble angioid streaks.
Subretinal neovascularization with hemorrhage can be seen in the absence of angioid streaks in age-related macular degeneration, high myopia, and presumed ocular histoplasmosis. Macular atrophy can also be seen in age-related macular degeneration.
## Recurrent Gastrointestinal Bleeding
PXE should be considered in the differential diagnosis of recurrent gastrointestinal bleeding of unknown cause [
## Management
To establish the extent of disease and needs in an individual diagnosed with pseudoxanthoma elasticum (PXE), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Pseudoxanthoma Elasticum (PXE)
OCT = optical coherence tomography
In the US, publicly funded agencies at the state level provide services for the blind or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living.
Low vision aids such as magnifiers and closed-circuit television may provide useful reading vision for individuals with reduced central acuity.
No specific treatment for PXE exists.
Management of PXE requires coordinated input from multidisciplinary specialists (see
Treatment of Manifestations in Individuals with Pseudoxanthoma Elasticum (PXE)
GI = gastrointestinal; MI = myocardial infarction; NSAIDs = nonsteroidal anti-inflammatory drugs
As directed by a dermatologist or plastic surgeon
Bleeding may be difficult to control without surgery [
See
See
Recommended Surveillance for Individuals with Pseudoxanthoma Elasticum (PXE)
MI = myocardial infarction
Racquet and contact sports carry an increased risk for ocular and head trauma, both of which have been reported to precipitate retinal hemorrhage in patients with angioid streaks; participation in such activities should be discouraged.
Individuals with PXE who participate in sports and physical recreation should wear appropriate protective eyewear such as polycarbonate sports goggles and/or protective helmets with eye shields.
Aspirin and nonsteroidal anti-inflammatory medications should be avoided whenever possible to reduce the risk of gastrointestinal bleeding.
Smoking is strongly discouraged because of its vasoconstrictive properties.
It is appropriate to clarify the genetic 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 medical management and preventive measures. In those without a molecular diagnosis, at-risk sibs should be screened by clinical examination, medical history, and detailed review of cardiovascular systems. Evaluations can include:
Retinal examination for
Molecular genetic testing if the
See
Most women with PXE have normal pregnancies; PXE is not associated with markedly increased fetal loss or adverse reproductive outcomes. The incidence of gastrointestinal bleeding and retinal complications (<1%) is lower than previously thought [
In the series of 795 pregnancies examined by
Search
• Retinal examination for
• Molecular genetic testing if the
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with pseudoxanthoma elasticum (PXE), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Pseudoxanthoma Elasticum (PXE)
OCT = optical coherence tomography
In the US, publicly funded agencies at the state level provide services for the blind or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living.
Low vision aids such as magnifiers and closed-circuit television may provide useful reading vision for individuals with reduced central acuity.
## Treatment of Manifestations
No specific treatment for PXE exists.
Management of PXE requires coordinated input from multidisciplinary specialists (see
Treatment of Manifestations in Individuals with Pseudoxanthoma Elasticum (PXE)
GI = gastrointestinal; MI = myocardial infarction; NSAIDs = nonsteroidal anti-inflammatory drugs
As directed by a dermatologist or plastic surgeon
Bleeding may be difficult to control without surgery [
See
See
## Surveillance
Recommended Surveillance for Individuals with Pseudoxanthoma Elasticum (PXE)
MI = myocardial infarction
## Agents/Circumstances to Avoid
Racquet and contact sports carry an increased risk for ocular and head trauma, both of which have been reported to precipitate retinal hemorrhage in patients with angioid streaks; participation in such activities should be discouraged.
Individuals with PXE who participate in sports and physical recreation should wear appropriate protective eyewear such as polycarbonate sports goggles and/or protective helmets with eye shields.
Aspirin and nonsteroidal anti-inflammatory medications should be avoided whenever possible to reduce the risk of gastrointestinal bleeding.
Smoking is strongly discouraged because of its vasoconstrictive properties.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic 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 medical management and preventive measures. In those without a molecular diagnosis, at-risk sibs should be screened by clinical examination, medical history, and detailed review of cardiovascular systems. Evaluations can include:
Retinal examination for
Molecular genetic testing if the
See
• Retinal examination for
• Molecular genetic testing if the
## Pregnancy Management
Most women with PXE have normal pregnancies; PXE is not associated with markedly increased fetal loss or adverse reproductive outcomes. The incidence of gastrointestinal bleeding and retinal complications (<1%) is lower than previously thought [
In the series of 795 pregnancies examined by
## Therapies Under Investigation
Search
## Genetic Counseling
Pseudoxanthoma elasticum (PXE) is inherited in an autosomal recessive manner.
Note: Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) is reported in some families [
If the parents of a proband are clinically unaffected, they are obligate heterozygotes (i.e., presumed to be carriers of one
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that affected children will be born to an affected individual and a carrier (or even to two affected individuals) resulting in pseudodominant inheritance.
In very rare instances, only one parent is a carrier and the proband has PXE as the result of one inherited
Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is 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
Intrafamilial clinical variability in PXE is observed; thus, sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has PXE or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
In populations with a high carrier rate and/or a high rate of consanguinity, the reproductive partner of the proband may have two
Carrier testing for at-risk relatives requires prior identification of the
See Management,
The optimal time for clarification of genetic status, determination of genetic risk, and discussion of the availability of prenatal/preimplantation genetic testing is before 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, particularly if the testing is being considered for the purpose of pregnancy termination rather than early confirmation or exclusion of the diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• If the parents of a proband are clinically unaffected, they are obligate heterozygotes (i.e., presumed to be carriers of one
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that affected children will be born to an affected individual and a carrier (or even to two affected individuals) resulting in pseudodominant inheritance.
• In very rare instances, only one parent is a carrier and the proband has PXE as the result of one inherited
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is 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
• Intrafamilial clinical variability in PXE is observed; thus, sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has PXE or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
• In populations with a high carrier rate and/or a high rate of consanguinity, the reproductive partner of the proband may have two
• The optimal time for clarification of genetic status, determination of genetic risk, and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Pseudoxanthoma elasticum (PXE) is inherited in an autosomal recessive manner.
Note: Pseudodominant inheritance (i.e., an autosomal recessive condition present in individuals in two or more generations) is reported in some families [
## Risk to Family Members
If the parents of a proband are clinically unaffected, they are obligate heterozygotes (i.e., presumed to be carriers of one
In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that affected children will be born to an affected individual and a carrier (or even to two affected individuals) resulting in pseudodominant inheritance.
In very rare instances, only one parent is a carrier and the proband has PXE as the result of one inherited
Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is 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
Intrafamilial clinical variability in PXE is observed; thus, sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Unless an affected individual's reproductive partner also has PXE or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
In populations with a high carrier rate and/or a high rate of consanguinity, the reproductive partner of the proband may have two
• If the parents of a proband are clinically unaffected, they are obligate heterozygotes (i.e., presumed to be carriers of one
• In populations with a high carrier rate and/or a high rate of consanguinity, it is possible that affected children will be born to an affected individual and a carrier (or even to two affected individuals) resulting in pseudodominant inheritance.
• In very rare instances, only one parent is a carrier and the proband has PXE as the result of one inherited
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is 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
• Intrafamilial clinical variability in PXE is observed; thus, sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Unless an affected individual's reproductive partner also has PXE or is a carrier, offspring will be obligate heterozygotes (carriers) for a pathogenic variant in
• In populations with a high carrier rate and/or a high rate of consanguinity, the reproductive partner of the proband may have two
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
The optimal time for clarification of genetic status, determination of genetic risk, and discussion of the availability of prenatal/preimplantation genetic testing is before 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 clarification of genetic status, determination of genetic risk, and discussion of the availability of prenatal/preimplantation genetic testing is before 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, particularly if the testing is being considered for the purpose of pregnancy termination rather than early confirmation or exclusion of the diagnosis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
4301 Connecticut Avenue, NW
Suite 404
Washington DC 20008-2369
•
•
•
• 4301 Connecticut Avenue, NW
• Suite 404
• Washington DC 20008-2369
•
•
•
## Molecular Genetics
Pseudoxanthoma Elasticum: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Pseudoxanthoma Elasticum (
Multiplex ligation-dependent probe amplification (MLPA) analysis to detect intragenic deletions or duplications using a widely available commercial kit does not include probes for exons 1, 3, 6, 16, 19-20, 29, and 31. Therefore, deletion or duplications confined to these exons cannot be detected by this assay. This technical challenge likely contributes to the disease alleles not detected in affected individuals (see
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Multiplex ligation-dependent probe amplification (MLPA) analysis to detect intragenic deletions or duplications using a widely available commercial kit does not include probes for exons 1, 3, 6, 16, 19-20, 29, and 31. Therefore, deletion or duplications confined to these exons cannot be detected by this assay. This technical challenge likely contributes to the disease alleles not detected in affected individuals (see
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Sharon F Terry, MA, is the co-founder of PXE International and co-investigator on more than 30 PXE clinical studies. Her publications exceed 170 peer-reviewed papers. She has given more than 500 presentations at national and international meetings. She manages the International PXE Research Consortium. She is the founder of the PXE BioBank and Registry. She is also the president and CEO of Genetic Alliance.
Dr Jouni Uitto is internationally recognized for his research on connective tissue biochemistry and molecular biology in relation to cutaneous diseases. Dr Uitto's publications include 725 original articles in peer-reviewed journals, 352 textbook chapters and review articles, and 1,048 abstracts on presentations at national and international meetings.
Jouni Uitto, MD (2020-present)Lionel G Bercovitch, MD; Brown University (2001-2020) Charles D Boyd, PhD; University of Hawaii (2001-2006) Sharon F Terry, MA (2001-present)
4 June 2020 (bp) Comprehensive update posted live
14 June 2012 (me) Comprehensive update posted live
2 April 2007 (st) Revision: Molecular Genetic Testing – targeted mutation analysis changed to deletion analysis
11 December 2006 (me) Comprehensive update posted live
5 November 2003 (me) Comprehensive update posted live
14 March 2002 (st) Author revision
5 June 2001 (me) Review posted live
September 2000 (st) Original submission
• 4 June 2020 (bp) Comprehensive update posted live
• 14 June 2012 (me) Comprehensive update posted live
• 2 April 2007 (st) Revision: Molecular Genetic Testing – targeted mutation analysis changed to deletion analysis
• 11 December 2006 (me) Comprehensive update posted live
• 5 November 2003 (me) Comprehensive update posted live
• 14 March 2002 (st) Author revision
• 5 June 2001 (me) Review posted live
• September 2000 (st) Original submission
## Author Notes
Sharon F Terry, MA, is the co-founder of PXE International and co-investigator on more than 30 PXE clinical studies. Her publications exceed 170 peer-reviewed papers. She has given more than 500 presentations at national and international meetings. She manages the International PXE Research Consortium. She is the founder of the PXE BioBank and Registry. She is also the president and CEO of Genetic Alliance.
Dr Jouni Uitto is internationally recognized for his research on connective tissue biochemistry and molecular biology in relation to cutaneous diseases. Dr Uitto's publications include 725 original articles in peer-reviewed journals, 352 textbook chapters and review articles, and 1,048 abstracts on presentations at national and international meetings.
## Author History
Jouni Uitto, MD (2020-present)Lionel G Bercovitch, MD; Brown University (2001-2020) Charles D Boyd, PhD; University of Hawaii (2001-2006) Sharon F Terry, MA (2001-present)
## Revision History
4 June 2020 (bp) Comprehensive update posted live
14 June 2012 (me) Comprehensive update posted live
2 April 2007 (st) Revision: Molecular Genetic Testing – targeted mutation analysis changed to deletion analysis
11 December 2006 (me) Comprehensive update posted live
5 November 2003 (me) Comprehensive update posted live
14 March 2002 (st) Author revision
5 June 2001 (me) Review posted live
September 2000 (st) Original submission
• 4 June 2020 (bp) Comprehensive update posted live
• 14 June 2012 (me) Comprehensive update posted live
• 2 April 2007 (st) Revision: Molecular Genetic Testing – targeted mutation analysis changed to deletion analysis
• 11 December 2006 (me) Comprehensive update posted live
• 5 November 2003 (me) Comprehensive update posted live
• 14 March 2002 (st) Author revision
• 5 June 2001 (me) Review posted live
• September 2000 (st) Original submission
## References
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"JL Anderson, JL Halperin, NM Albert, B Bozkurt, RG Brindis, LH Curtis, D DeMets, RA Guyton, JS Hochman, RJ Kovacs, EM Ohman, SJ Pressler, FW Sellke, WK Shen. Management of patients with peripheral artery disease (compilation of 2005 and 2011 ACCF/AHA guideline recommendations): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines.. Circulation. 2013;127:1425-43",
"M Battaglia Parodi, F Romano, A Marchese, A Arrigo, V Llorenç, MV Cicinelli, F Bandello, A Adán. Anti-VEGF treatment for choroidal neovascularization complicating pattern dystrophy-like deposit associated with pseudoxanthoma elasticum.. Graefes Arch Clin Exp Ophthalmol. 2019;257:273-8",
"C Bécuwe, S Dalle, S Ronger-Savlé, F Skowron, B Balme, J Kanitakis, L Thomas. Elastosis perforans serpiginosa associated with pseudo-pseudoxanthoma elasticum during treatment of Wilson's disease with penicillamine.. Dermatology. 2005;210:60-3",
"L Bercovitch, T Leroux, S Terry, MA Weinstock. Pregnancy and obstetrical outcomes in pseudoxanthoma elasticum.. Br J Dermatol. 2004;151:1011-8",
"AA Bergen. Pseudoxanthoma elasticum: the end of the autosomal dominant segregation myth.. J Invest Dermatol. 2006;126:704-5",
"M Camacho, C Rengel, E López-Herrero, JL Carrillo, AJ Eslava, P Valdivielso. Approach to the management of pregnancy in patients with pseudoxanthoma elasticum: a review.. J Obstet Gynaecol. 2016;36:1061-6",
"N Chassaing, L Martin, S Bourthoumieu, P Calvas, A. Hovnanian. Contribution of ABCC6 genomic rearrangements to the diagnosis of pseudoxanthoma elasticum in French patients.. Hum Mutat. 2007;28:1046",
"I Dalle, K Geboes. Vascular lesions of the gastrointestinal tract.. Acta Gastroenterol Belg. 2002;65:213-9",
"SD Fihn, JC Blankenship, KP Alexander, JA Bittl, JG Byrne, BJ Fletcher, GC Fonarow, RA Lange, GN Levine, TM Maddox, SS Naidu, EM Ohman, PK Smith. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.. J Am Coll Cardiol. 2014;64:1929-49",
"SD Fihn, JM Gardin, J Abrams, K Berra, JC Blankenship, AP Dallas, PS Douglas, JM Foody, TC Gerber, AL Hinderliter, SB King, PD Kligfield, HM Krumholz, RY Kwong, MJ Lim, JA Linderbaum, MJ Mack, MA Munger, RL Prager, JF Sabik, LJ Shaw, JD Sikkema, CR Smith, SC Smith, JA Spertus, SV Williams. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons.. J Am Coll Cardiol. 2012;60:e44-e164",
"M Gliem, PL Müller, J Birtel, D Hendig, FG Holz, P Charbel Issa. Frequency, phenotypic characteristics and progression of atrophy associated with a diseased Bruch's membrane in pseudoxanthoma elasticum.. Invest Ophthalmol Vis Sci. 2016;57:3323-30",
"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",
"A Iwanaga, Y Okubo, M Yozaki, Y Koike, Y Kuwatsuka, S Tomimura, Y Yamamoto, H Tamura, S Ikeda, K Maemura, E Tsuiki, T Kitaoka, Y Endo, H Mishima, KI Yoshiura, T Ogi, H Tanizaki, M Wataya-Kaneda, T Hattori, A Utani. Analysis of clinical symptoms and ABCC6 mutations in 76 Japanese patients with pseudoxanthoma elasticum.. J Dermatol. 2017;44:644-50",
"MK Kringen, C Stormo, JP Berg, SF Terry, CM Vocke, S Rizvi, D Hendig, AP Piehler. Copy number variation in the ATP-binding cassette transporter ABCC6 gene and ABCC6 pseudogenes in patients with pseudoxanthoma elasticum.. Mol Genet Genomic Med. 2015;3:233-7",
"MG Lebwohl, D Distefano, PG Prioleau, M Uram, LA Yannuzzi, R Fleischmajer. Pseudoxanthoma elasticum and mitral-valve prolapse.. N Engl J Med. 1982;307:228-31",
"A Legrand, L Cornez, W Samkari, JM Mazzella, A Venisse, V Boccio, K Auribault, B Keren, K Benistan, DP Germain, M Frank, X Jeunemaitre, J Albuisson. Mutation spectrum in the ABCC6 gene and genotype-phenotype correlations in a French cohort with pseudoxanthoma elasticum.. Genet Med. 2017;19:909-17",
"O Le Saux, K Beck, C Sachsinger, C Treiber, HH Göring, K Curry, EW Johnson, L Bercovitch, AS Marais, SF Terry, DL Viljoen, CD Boyd. Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa.. Hum Genet. 2002;111:331-8",
"S Miksch, A Lumsden, UP Guenther, D Foernzler, S Christen-Zäch, C Daugherty, RK Ramesar, M Lebwohl, D Hohl, KH Neldner, K Lindpaintner, RI Richards, B Struk. Molecular genetics of pseudoxanthoma elasticum: type and frequency of mutations in ABCC6.. Hum Mutat. 2005;26:235-48",
"G Mimoun, JM Ebran, T Grenet, A Donati, SY Cohen, A Ponthieux. Ranibizumab for choroidal neovascularization secondary to pseudoxanthoma elasticum: 4-year results from the PIXEL study in France.. Graefes Arch Clin Exp Ophthalmol. 2017;255:1651-60",
"Y Nitschke, G Baujat, U Botschen, T Wittkampf, M du Moulin, J Stella, M Le Merrer, G Guest, K Lambot, MF Tazarourte-Pinturier, N Chassaing, O Roche, I Feenstra, K Loechner, C Deshpande, SJ Garber, R Chikarmane, B Steinmann, T Shahinyan, L Martorell, J Davies, WE Smith, SG Kahler, M McCulloch, E Wraige, L Loidi, W Höhne, L Martin, S Hadj-Rabia, R Terkeltaub, F Rutsch. Generalized arterial calcification of infancy and pseudoxanthoma elasticum can be caused by mutations in either ENPP1 or ABCC6.. Am J Hum Genet. 2012;90:25-39",
"EG Pfendner, OM Vanakker, SF Terry, S Vourthis, PE McAndrew, MR McClain, S Fratta, AS Marais, S Hariri, PJ Coucke, M Ramsay, D Viljoen, PF Terry, A De Paepe, J Uitto, LG Bercovitch. Mutation detection in the ABCC6 gene and genotype-phenotype analysis in a large international case series affected by pseudoxanthoma elasticum.. J Med Genet. 2007;44:621-8",
"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",
"F Ringpfeil, K McGuigan, L Fuchsel, H Kozic, M Larralde, M Lebwohl, J Uitto. Pseudoxanthoma elasticum is a recessive disease characterized by compound heterozygosity.. J Invest Dermatol. 2006;126:782-6",
"S Risseeuw, J Ossewaarde-van Norel, CCW Klaver, JM Colijn, SM Imhof, R van Leeuwen. Visual acuity in pseudoxanthoma elasticum.. Retina. 2019;39:1580-7",
"J Uitto, Q Jiang, A Varadi, LG Bercovitch, SF Terry. Pseudoxanthoma elasticum: diagnostic features, classification, and treatment options.. Expert Opin Orphan Drugs. 2014;2:567-77"
] |
5/6/2001
|
4/6/2020
|
2/4/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
pycnodys
|
pycnodys
|
[
"Pyknodysostosis",
"Toulouse-Lautrec Syndrome",
"CTSK-Related Pyknodysostosis",
"Pyknodysostosis",
"Toulouse-Lautrec Syndrome",
"CTSK-Related Pyknodysostosis",
"Cathepsin K",
"CTSK",
"Pycnodysostosis"
] |
Pycnodysostosis
|
Shannon LeBlanc, Ravi Savarirayan
|
Summary Pycnodysostosis is characterized by short-limbed short stature, typical facial appearance (convex nasal ridge and small jaw with obtuse mandibular angle), osteosclerosis with increased bone fragility, acroosteolysis of the distal phalanges, delayed closure of the cranial sutures, and dysplasia of the clavicle. In affected individuals, the facial features become more prominent with age, likely due to progressive acroosteolysis of the facial bones, but can usually be appreciated from early childhood, particularly the small jaw and convex nasal ridge. Additional features include dental and nail anomalies. Intelligence is typically normal with mild psychomotor difficulties reported in some individuals. The diagnosis of pycnodysostosis can be established in a proband with characteristic clinical and radiographic features and/or biallelic pathogenic variants in Pycnodysostosis is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
Formal diagnostic criteria for pycnodysostosis have not been established, however the radiographic features of acroosteolysis, osteosclerosis, and loss of the normal angle of the jaw are almost pathognomonic.
Pycnodysostosis
Short-limbed short stature in all individuals (prenatal onset in ~30%)
Brachydactyly
Craniofacial findings
Frontal bossing
Persistently open anterior fontanelle
Prominent nose with convex nasal ridge
Midface retrusion and small jaw due to hypoplasia of the maxilla and mandible
Stridor, laryngomalacia, and obstructive sleep apnea
Prominent eyes with blueish sclera
High arched palate / grooved palate
Dental anomalies (e.g., delayed eruption of deciduous and permanent teeth, persistence of deciduous teeth resulting in a double row of teeth, hypodontia)
Nail anomalies (e.g., dysplastic, grooved, flattened)
Generalized progressive osteosclerosis, particularly of the long bones
Acroosteolysis of the terminal phalanges
Non-pneumatized mastoids
Delayed fusion of the cranial sutures
Obtuse mandibular angle due to loss of the normal mandibular (gonial) angle
Increased incidence of fractures
Clavicular dysplasia, congenital pseudarthrosis of the clavicle
Normal serum calcium, phosphate, vitamin D, and alkaline phosphatase
Growth hormone deficiency
Low IGF-1
No abnormalities of other pituitary hormones
The diagnosis of pycnodysostosis
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 radiographic findings suggest the diagnosis of pycnodysostosis, 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 osteosclerosis and short stature,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Pycnodysostosis
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
Review of approximately 35 pathogenic variants in all available published case literature, ClinVar [
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 301-bp Alu sequence insertion in intron 7 that creates a new potential splice acceptor site [
• Short-limbed short stature in all individuals (prenatal onset in ~30%)
• Brachydactyly
• Craniofacial findings
• Frontal bossing
• Persistently open anterior fontanelle
• Prominent nose with convex nasal ridge
• Midface retrusion and small jaw due to hypoplasia of the maxilla and mandible
• Stridor, laryngomalacia, and obstructive sleep apnea
• Prominent eyes with blueish sclera
• High arched palate / grooved palate
• Craniofacial findings
• Frontal bossing
• Persistently open anterior fontanelle
• Prominent nose with convex nasal ridge
• Midface retrusion and small jaw due to hypoplasia of the maxilla and mandible
• Stridor, laryngomalacia, and obstructive sleep apnea
• Prominent eyes with blueish sclera
• High arched palate / grooved palate
• Dental anomalies (e.g., delayed eruption of deciduous and permanent teeth, persistence of deciduous teeth resulting in a double row of teeth, hypodontia)
• Nail anomalies (e.g., dysplastic, grooved, flattened)
• Craniofacial findings
• Frontal bossing
• Persistently open anterior fontanelle
• Prominent nose with convex nasal ridge
• Midface retrusion and small jaw due to hypoplasia of the maxilla and mandible
• Stridor, laryngomalacia, and obstructive sleep apnea
• Prominent eyes with blueish sclera
• High arched palate / grooved palate
• Generalized progressive osteosclerosis, particularly of the long bones
• Acroosteolysis of the terminal phalanges
• Non-pneumatized mastoids
• Delayed fusion of the cranial sutures
• Obtuse mandibular angle due to loss of the normal mandibular (gonial) angle
• Increased incidence of fractures
• Clavicular dysplasia, congenital pseudarthrosis of the clavicle
• Normal serum calcium, phosphate, vitamin D, and alkaline phosphatase
• Growth hormone deficiency
• Low IGF-1
• No abnormalities of other pituitary hormones
• For an introduction to multigene panels click
## Suggestive Findings
Pycnodysostosis
Short-limbed short stature in all individuals (prenatal onset in ~30%)
Brachydactyly
Craniofacial findings
Frontal bossing
Persistently open anterior fontanelle
Prominent nose with convex nasal ridge
Midface retrusion and small jaw due to hypoplasia of the maxilla and mandible
Stridor, laryngomalacia, and obstructive sleep apnea
Prominent eyes with blueish sclera
High arched palate / grooved palate
Dental anomalies (e.g., delayed eruption of deciduous and permanent teeth, persistence of deciduous teeth resulting in a double row of teeth, hypodontia)
Nail anomalies (e.g., dysplastic, grooved, flattened)
Generalized progressive osteosclerosis, particularly of the long bones
Acroosteolysis of the terminal phalanges
Non-pneumatized mastoids
Delayed fusion of the cranial sutures
Obtuse mandibular angle due to loss of the normal mandibular (gonial) angle
Increased incidence of fractures
Clavicular dysplasia, congenital pseudarthrosis of the clavicle
Normal serum calcium, phosphate, vitamin D, and alkaline phosphatase
Growth hormone deficiency
Low IGF-1
No abnormalities of other pituitary hormones
• Short-limbed short stature in all individuals (prenatal onset in ~30%)
• Brachydactyly
• Craniofacial findings
• Frontal bossing
• Persistently open anterior fontanelle
• Prominent nose with convex nasal ridge
• Midface retrusion and small jaw due to hypoplasia of the maxilla and mandible
• Stridor, laryngomalacia, and obstructive sleep apnea
• Prominent eyes with blueish sclera
• High arched palate / grooved palate
• Craniofacial findings
• Frontal bossing
• Persistently open anterior fontanelle
• Prominent nose with convex nasal ridge
• Midface retrusion and small jaw due to hypoplasia of the maxilla and mandible
• Stridor, laryngomalacia, and obstructive sleep apnea
• Prominent eyes with blueish sclera
• High arched palate / grooved palate
• Dental anomalies (e.g., delayed eruption of deciduous and permanent teeth, persistence of deciduous teeth resulting in a double row of teeth, hypodontia)
• Nail anomalies (e.g., dysplastic, grooved, flattened)
• Craniofacial findings
• Frontal bossing
• Persistently open anterior fontanelle
• Prominent nose with convex nasal ridge
• Midface retrusion and small jaw due to hypoplasia of the maxilla and mandible
• Stridor, laryngomalacia, and obstructive sleep apnea
• Prominent eyes with blueish sclera
• High arched palate / grooved palate
• Generalized progressive osteosclerosis, particularly of the long bones
• Acroosteolysis of the terminal phalanges
• Non-pneumatized mastoids
• Delayed fusion of the cranial sutures
• Obtuse mandibular angle due to loss of the normal mandibular (gonial) angle
• Increased incidence of fractures
• Clavicular dysplasia, congenital pseudarthrosis of the clavicle
• Normal serum calcium, phosphate, vitamin D, and alkaline phosphatase
• Growth hormone deficiency
• Low IGF-1
• No abnormalities of other pituitary hormones
## Establishing the Diagnosis
The diagnosis of pycnodysostosis
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 radiographic findings suggest the diagnosis of pycnodysostosis, 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 osteosclerosis and short stature,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Pycnodysostosis
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
Review of approximately 35 pathogenic variants in all available published case literature, ClinVar [
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 301-bp Alu sequence insertion in intron 7 that creates a new potential splice acceptor site [
• For an introduction to multigene panels click
## Option 1
When the phenotypic and radiographic findings suggest the diagnosis of pycnodysostosis, 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 osteosclerosis and short stature,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Pycnodysostosis
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
Review of approximately 35 pathogenic variants in all available published case literature, ClinVar [
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 301-bp Alu sequence insertion in intron 7 that creates a new potential splice acceptor site [
## Clinical Characteristics
Pycnodysostosis is characterized by short stature, typical facial appearance (small jaw with obtuse mandibular angle and convex nasal ridge), osteosclerosis with increased bone fragility, acroosteolysis of the distal phalanges, delayed closure of the cranial sutures, and dysplasia of the clavicle. In affected individuals, the facial features become more prominent with age, likely due to progressive acroosteolysis of the facial bones, but can usually be appreciated from early childhood, particularly the small jaw and convex nasal ridge [
A comprehensive review of previously published reports [
Pycnodysostosis: Frequency of Select Features
About 50% have growth hormone deficiency but almost all have low IGF-1 levels. Administration of growth hormone has been shown to result in a satisfactory elevation in IGF-1 levels and near-normalization of adult height and skeletal proportions [
Individuals with a growth hormone deficiency often also have pituitary hypoplasia identified on head imaging; no other abnormalities in pituitary hormones or pubertal development have been detected [
Three individuals (2 diagnosed clinically and 1 with a molecular diagnosis) have been reported with taller-than-expected stature including an adult Mexican male of 153 cm (-1.9 SD), an adult Mexican female of 150 cm (-0.6 SD), and a Chinese boy age eleven years with normal height (137cm; -0.9 SD) [
More than 90% of reported individuals have short hands and feet with short digits and progressive acroosteolysis of the terminal phalanges of the fingers and toes. Short metatarsals and metacarpals have not been described.
Other common imaging features include non-pneumatized mastoids (80%) and delayed fusion of the skull sutures (67%). The clavicles may be dysplastic (25%) with acroosteolysis of the acromial end. Less common features include wormian bones (18%), mild scoliosis (12%), leg length discrepancy (8%), spondylolysis, spondylolisthesis, and narrow ilia. Coronal craniosynostosis has been reported in four individuals [
Fracture healing is often delayed with incomplete remodeling. Surgical fixation is often complicated by narrow medullary canals, and sclerotic bone poses an increased risk of intraoperative iatrogenic fracture [
No genotype-phenotype correlations for
The clinical features of pycnodysostosis (Greek:
Pycnodysostosis is also sometimes referred to as "Toulouse-Lautrec syndrome," after the French artist Henri de Toulouse-Lautrec (1864-1901), who was retrospectively thought to have this condition based on several phenotypic features of the disorder including short stature, parental consanguinity, facial dysmorphism, frequent fractures, and large fontanels [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
Approximately 200 affected individuals have been reported in the medical literature. Pycnodysostosis is estimated to affect about 1-1.7 individuals per million.
## Clinical Description
Pycnodysostosis is characterized by short stature, typical facial appearance (small jaw with obtuse mandibular angle and convex nasal ridge), osteosclerosis with increased bone fragility, acroosteolysis of the distal phalanges, delayed closure of the cranial sutures, and dysplasia of the clavicle. In affected individuals, the facial features become more prominent with age, likely due to progressive acroosteolysis of the facial bones, but can usually be appreciated from early childhood, particularly the small jaw and convex nasal ridge [
A comprehensive review of previously published reports [
Pycnodysostosis: Frequency of Select Features
About 50% have growth hormone deficiency but almost all have low IGF-1 levels. Administration of growth hormone has been shown to result in a satisfactory elevation in IGF-1 levels and near-normalization of adult height and skeletal proportions [
Individuals with a growth hormone deficiency often also have pituitary hypoplasia identified on head imaging; no other abnormalities in pituitary hormones or pubertal development have been detected [
Three individuals (2 diagnosed clinically and 1 with a molecular diagnosis) have been reported with taller-than-expected stature including an adult Mexican male of 153 cm (-1.9 SD), an adult Mexican female of 150 cm (-0.6 SD), and a Chinese boy age eleven years with normal height (137cm; -0.9 SD) [
More than 90% of reported individuals have short hands and feet with short digits and progressive acroosteolysis of the terminal phalanges of the fingers and toes. Short metatarsals and metacarpals have not been described.
Other common imaging features include non-pneumatized mastoids (80%) and delayed fusion of the skull sutures (67%). The clavicles may be dysplastic (25%) with acroosteolysis of the acromial end. Less common features include wormian bones (18%), mild scoliosis (12%), leg length discrepancy (8%), spondylolysis, spondylolisthesis, and narrow ilia. Coronal craniosynostosis has been reported in four individuals [
Fracture healing is often delayed with incomplete remodeling. Surgical fixation is often complicated by narrow medullary canals, and sclerotic bone poses an increased risk of intraoperative iatrogenic fracture [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations for
## Nomenclature
The clinical features of pycnodysostosis (Greek:
Pycnodysostosis is also sometimes referred to as "Toulouse-Lautrec syndrome," after the French artist Henri de Toulouse-Lautrec (1864-1901), who was retrospectively thought to have this condition based on several phenotypic features of the disorder including short stature, parental consanguinity, facial dysmorphism, frequent fractures, and large fontanels [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
Approximately 200 affected individuals have been reported in the medical literature. Pycnodysostosis is estimated to affect about 1-1.7 individuals per million.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
It is critical to distinguish pycnodysostosis from other primary sclerosing conditions of bone (see
Disorders Characterized by Osteopetrosis in the Differential Diagnosis of Pycnodysostosis
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
## Management
There are no published treatment or surveillance guidelines for pycnodysostosis or standard guidelines on the best method or surgical intervention for fracture treatment in this condition
To establish the extent of disease and needs in an individual diagnosed with pycnodysostosis, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Pycnodysostosis
Growth assessment
Eval for growth hormone & IGF-1 deficiency as early as practicable
Eval for cleft palate or narrow nasal passages
Baseline audiology eval
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Pycnodysostosis
Referral to endocrinologist
Consideration of growth hormone therapy
Environmental or occupational modifications may be needed (e.g., step stools, lower desks).
Consultation w/OT may be beneficial.
Specialist orthopedic mgmt
Intervention may incl osteosynthesis or immobilization.
At least 35% of persons require orthopedic intervention.
Complications incl non-union have been described following orthopedic surgery.
Referral to pulmonologist & sleep physician
Noninvasive ventilation
Maintenance of oral hygiene
Regular dental care to prevent oral complications
May benefit from orthodontic input
OT = occupational therapist
Recommended Surveillance for Individuals with Pycnodysostosis
Examine for scoliosis & asymmetry.
Assess frequency of fractures.
In the case of general anesthesia, consideration should be given to the possibility of difficult intubation prior to scheduling anesthesia.
Bisphosphonate therapy is contraindicated due to underlying osteoclast dysfunction in pycnodysostosis.
See
In individuals with a small pelvis, delivery by cæsarean section should be considered. However, each individual should be assessed by an obstetrician and anesthetist familiar with skeletal dysplasia [
Search
• Growth assessment
• Eval for growth hormone & IGF-1 deficiency as early as practicable
• Eval for cleft palate or narrow nasal passages
• Baseline audiology eval
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Referral to endocrinologist
• Consideration of growth hormone therapy
• Environmental or occupational modifications may be needed (e.g., step stools, lower desks).
• Consultation w/OT may be beneficial.
• Specialist orthopedic mgmt
• Intervention may incl osteosynthesis or immobilization.
• At least 35% of persons require orthopedic intervention.
• Complications incl non-union have been described following orthopedic surgery.
• Referral to pulmonologist & sleep physician
• Noninvasive ventilation
• Maintenance of oral hygiene
• Regular dental care to prevent oral complications
• May benefit from orthodontic input
• Examine for scoliosis & asymmetry.
• Assess frequency of fractures.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with pycnodysostosis, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Pycnodysostosis
Growth assessment
Eval for growth hormone & IGF-1 deficiency as early as practicable
Eval for cleft palate or narrow nasal passages
Baseline audiology eval
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Growth assessment
• Eval for growth hormone & IGF-1 deficiency as early as practicable
• Eval for cleft palate or narrow nasal passages
• Baseline audiology eval
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Pycnodysostosis
Referral to endocrinologist
Consideration of growth hormone therapy
Environmental or occupational modifications may be needed (e.g., step stools, lower desks).
Consultation w/OT may be beneficial.
Specialist orthopedic mgmt
Intervention may incl osteosynthesis or immobilization.
At least 35% of persons require orthopedic intervention.
Complications incl non-union have been described following orthopedic surgery.
Referral to pulmonologist & sleep physician
Noninvasive ventilation
Maintenance of oral hygiene
Regular dental care to prevent oral complications
May benefit from orthodontic input
OT = occupational therapist
• Referral to endocrinologist
• Consideration of growth hormone therapy
• Environmental or occupational modifications may be needed (e.g., step stools, lower desks).
• Consultation w/OT may be beneficial.
• Specialist orthopedic mgmt
• Intervention may incl osteosynthesis or immobilization.
• At least 35% of persons require orthopedic intervention.
• Complications incl non-union have been described following orthopedic surgery.
• Referral to pulmonologist & sleep physician
• Noninvasive ventilation
• Maintenance of oral hygiene
• Regular dental care to prevent oral complications
• May benefit from orthodontic input
## Surveillance
Recommended Surveillance for Individuals with Pycnodysostosis
Examine for scoliosis & asymmetry.
Assess frequency of fractures.
• Examine for scoliosis & asymmetry.
• Assess frequency of fractures.
## Agents/Circumstances to Avoid
In the case of general anesthesia, consideration should be given to the possibility of difficult intubation prior to scheduling anesthesia.
Bisphosphonate therapy is contraindicated due to underlying osteoclast dysfunction in pycnodysostosis.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
In individuals with a small pelvis, delivery by cæsarean section should be considered. However, each individual should be assessed by an obstetrician and anesthetist familiar with skeletal dysplasia [
## Therapies Under Investigation
Search
## Genetic Counseling
Pycnodysostosis 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 of the parents is recommended to confirm that both parents are heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Intrafamilial clinical variability may be observed in 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
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., presumed to be carriers of one
• If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for a
• Intrafamilial clinical variability may be observed in 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, 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
Pycnodysostosis 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 of the parents is recommended to confirm that both parents are heterozygous for a
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a
Intrafamilial clinical variability may be observed in 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
• If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents is recommended to confirm that both parents are heterozygous for a
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for a
• Intrafamilial clinical variability may be observed in 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
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
Pycnodysostosis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Pycnodysostosis (
Mutational hot spots are residues Arg241 and Ala277 [
Approximately 60
Judicious primer selection will facilitate detection of the intron 7 insertion (see
• Mutational hot spots are residues Arg241 and Ala277 [
• Approximately 60
• Judicious primer selection will facilitate detection of the intron 7 insertion (see
## Molecular Pathogenesis
Mutational hot spots are residues Arg241 and Ala277 [
Approximately 60
Judicious primer selection will facilitate detection of the intron 7 insertion (see
• Mutational hot spots are residues Arg241 and Ala277 [
• Approximately 60
• Judicious primer selection will facilitate detection of the intron 7 insertion (see
## Chapter Notes
6 April 2023 (sw) Revision: "
5 November 2020 (sw) Review posted live
17 August 2020 (rs) Original submission
• 6 April 2023 (sw) Revision: "
• 5 November 2020 (sw) Review posted live
• 17 August 2020 (rs) Original submission
## Revision History
6 April 2023 (sw) Revision: "
5 November 2020 (sw) Review posted live
17 August 2020 (rs) Original submission
• 6 April 2023 (sw) Revision: "
• 5 November 2020 (sw) Review posted live
• 17 August 2020 (rs) Original submission
## References
## Literature Cited
Radiographic features of pycnodysostosis
A. Hand and wrist radiograph in a female age 12 years, showing marked acroosteolysis of the terminal phalanges and generalized increase in bone density.
B. Orthopantomogram in the same individual with mixed dentition present. The mandible is hypoplastic and sclerotic with loss of the gonial angle.
C. Radiographs of the tibia and fibula demonstrating diffuse sclerosis and a transverse midshaft tibial fracture at age ten years.
D. The fracture remains clearly visible three months later with periosteal new bone formation.
Portrait of the painter Henri de Toulouse-Lautrec, considered to have had pycnodysostosis
1898, by Edouard Vuillard (1868-1940)
|
[
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"A Arman, A Bereket, A Coker, P Özlem, S Kiper, T Güran, B Özkan, Z Atay, T Akçay, B Haliloglu, K Boduroglu, Y Alanay, S. Turan. Cathepsin K analysis in a pychnodysostosis cohort: demographic, genotypic and phenotypic features.. Orphanet J Rare Dis. 2014;9:60",
"D Bertola, C Amaral, C Kim, L Albano, M Aguena, M. Passos-Bueno. Craniosynostosis in pycnodysostosis: Broadening the spectrum of the cranial flat bone abnormalities.. Am J Med Genet Part A. 2010;152A:2599-603",
"V Bizaoui, C Michot, G Baujat, C Amouroux, S Baron, Y Capri, M Cohen-Solal, C Collet, A Dieux, D Genevieve, B Isidor, S Monnot, M Rossi, A Rothenbuhler, E Schaefer, V. Cormier-Daire. Pycnodysostosis: Natural history and management guidelines from 27 French cases and a literature review.. Clin Genet. 2019;96:309-16",
"PM Campeau, JT Lu, G Sule, MM Jiang, Y Bae, S Madan, W Högler, NJ Shaw, S Mumm, RA Gibbs, MP Whyte, BH Lee. Whole-exome sequencing identifies mutations in the nucleoside transporter gene SLC29A3 in dysosteosclerosis, a form of osteopetrosis.. Hum Mol Genet. 2012;21:4904-9",
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"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",
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"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",
"A Khoja, M Fida, A Shaikh. Pycnodysostosis with special emphasis on dentofacial characteristics.. Case Rep Dent. 2015;2015",
"MJ Landrum, JM Lee, GR Riley, W Jang, WS Rubinstein, DM Church, DR Maglott. ClinVar: public archive of relationships among sequence variation and human phenotype.. Nucleic Acids Res. 2014;42:D980-5",
"L Li, SS Lv, C Wang, H Yue, ZL Zhang. Novel CLCN7 mutations cause autosomal dominant osteopetrosis type II and intermediate autosomal recessive osteopetrosis.. Mol Med Rep. 2019;19:5030-8",
"GA Otaify, MS Abdel-Hamid, MI Mehrez, E Aboul-Ezz, MS Aglan, SA Temtamy. Genetic study of eight Egyptian patients with pycnodysostosis:identification of novel CTSK mutations and founder effect.. Osteoporos Int. 2018;29:1833-41",
"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 Rothenbühler, C Piquard, I Gueorguieva, N Lahlou, A Linglart, P Bougnéres. Near normalization of adult height and body proportions by growth hormone in pycnodysostosis.. J Clin Endocrinol Metab. 2010;95:2827-31",
"R Savarirayan, JP Rossiter, JE Hoover-Fong. Best practice guidelines regarding prenatal evaluation and delivery of patients with skeletal dysplasia.. Am J Obstet Gynecol. 2018;219:545-62",
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"Z Stark, R. Savarirayan. Osteopetrosis.. Orphanet J Rare Dis. 2009;4:5",
"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",
"E Testani, E Scarano, C Leoni, S Dittoni, A Losurado, S Colicchio, V Gnoni, C Vollono, G Zampino, G Paludetti, G Della Marca. Upper airway surgery of obstructive sleep apnea in pycnodysostosis: Case report and literature review.. Am J Med Genet Part A. 2014;164A:2029-35",
"S. Turan. Current research on pycnodysostosis.. Intractable Rare Dis Res. 2014;3:91-3",
"S Unger, CR Ferreira, GR Mortier, H Ali, DR Bertola, A Calder, DH Cohn, V Cormier-Daire, KM Girisha, C Hall, D Krakow, O Makitie, S Mundlos, G Nishimura, SP Robertson, R Savarirayan, D Sillence, M Simon, VR Sutton, ML Warman, A Superti-Furga. Nosology of genetic skeletal disorders: 2023 revision.. Am J Med Genet A. 2023",
"M Valdes-Flores, A Hidalgo-Bravo, L Casas-Avila, C Chima-Galan, EJ Hazan-Lasri, E Pineda-Gomez, D Lopez-Estrada, JC Xenteno. Molecular and clinical analysis in a series of patients with pyknodysostosis reveals some uncommon phenotypic findings.. Int J Clin Exp Med. 2014;7:3915-23",
"Y Xue, T Cai, S Shi, W Wang, Y Zhang, T Mao, X Duan. Clinical and animal research findings in pycnodysostosis and gene mutations of cathepsin K from 1996 to 2011.. Orphanet J Rare Dis. 2011;6:20",
"JY Xue, Z Wang, S Shinagawa, H Ohashi, N Otomo, NH Elcioglu, T Nakashima, G Nishimura, S Ikegawa, L Guo. TNFRSF11A-associated dysosteosclerosis: a report of the second case and characterization of the phenotypic spectrum.. J Bone Miner Res. 2019;34:1873-9",
"H Zheng, Z Zhang, J He, W Fu, Z. Zhang. A novel mutation (R122Q) in the cathepsin K gene in a Chinese child with pyknodysostosis.. Gene. 2013;521:176-9"
] |
5/11/2020
|
6/4/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
rab18-def
|
rab18-def
|
[
"Martsolf Syndrome",
"Warburg Micro Syndrome",
"Rab3 GTPase-activating protein catalytic subunit",
"Rab3 GTPase-activating protein non-catalytic subunit",
"Ras-related protein Rab-18",
"TBC1 domain family member 20",
"RAB18",
"RAB3GAP1",
"RAB3GAP2",
"TBC1D20",
"RAB18 Deficiency"
] |
RAB18 Deficiency
|
Mark Handley, Eamonn Sheridan
|
Summary RAB18 deficiency is the molecular deficit underlying both Warburg micro syndrome (characterized by eye, nervous system, and endocrine abnormalities) and Martsolf syndrome (characterized by similar – but milder – findings). To date Warburg micro syndrome comprises >96% of reported individuals with genetically defined RAB18 deficiency. The hallmark ophthalmologic findings are bilateral congenital cataracts, usually accompanied by microphthalmia, microcornea (diameter <10), and small atonic pupils. Poor vision despite early cataract surgery likely results from progressive optic atrophy and cortical visual impairment. Individuals with Warburg micro syndrome have severe to profound intellectual disability (ID); those with Martsolf syndrome have mild to moderate ID. Some individuals with RAB18 deficiency also have epilepsy. In Warburg micro syndrome, a progressive ascending spastic paraplegia typically begins with spastic diplegia and contractures during the first year, followed by upper-limb involvement leading to spastic quadriplegia after about age five years, often eventually causing breathing difficulties. In Martsolf syndrome infantile hypotonia is followed primarily by slowly progressive lower-limb spasticity. Hypogonadism – when present – manifests in both syndromes, in males as micropenis and/or cryptorchidism and in females as hypoplastic labia minora, clitoral hypoplasia, and small introitus. The diagnosis of RAB18 deficiency is established in a proband who either has suggestive clinical and neuroimaging findings and biallelic pathogenic variant(s) in RAB18 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
|
Warburg micro syndrome
Martsolf syndrome
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• Warburg micro syndrome
• Martsolf syndrome
## Diagnosis
RAB18 deficiency
Note: Findings indicated with an * are the basis of the diagnosis when molecular genetic testing either has not been performed or has not revealed biallelic pathogenic variants in one of the four known genes.
Hypogenesis of the corpus callosum, particularly the splenium.
Polymicrogyria is bilateral and predominantly frontal, frequently extends to the Sylvian fissure, may extend to the temporal and occipital lobes, and rarely extends over the entire cortex. While polymicrogyria is the most consistently observed cortical abnormality, other described abnormalities include pachygyria and lissencephaly.
Cortical atrophy: Increased subdural spaces are common.
Hypoplasia of the cerebellum and cerebellar vermis are common but not universal. Accompanying abnormalities of the pons, as seen in pontocerebellar hypoplasia, are rare.
The diagnosis of RAB18 deficiency
Has suggestive clinical and neuroimaging findings together with biallelic pathogenic variant(s) in
Meets the clinical diagnostic criteria outlined under
Note that failure to detect biallelic causative pathogenic variant(s) in one of the four genes known to cause RAB18 deficiency does not necessarily exclude a clinical diagnosis of RAB18 deficiency as additional loci may exist.
Molecular testing approaches can include
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Persons with the distinctive findings described in
When the phenotypic and neuroimaging findings suggest the diagnosis of RAB18 deficiency, molecular genetic testing approaches can include
Note: Homozygosity mapping describes a specific type of analysis of a SNP chromosomal microarray that identifies regions of homozygosity in affected individuals.
For an introduction to multigene panels click
When the diagnosis of RAB18 deficiency has not been considered or when gene-targeted testing has not identified pathogenic variant(s),
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Molecularly Confirmed RAB18 Deficiency
Absence of identified biallelic causative pathogenic variant(s) in one of these four genes does not exclude a clinical diagnosis of RAB18 deficiency as additional, as-yet unknown loci may exist.
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 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.
•
• Hypogenesis of the corpus callosum, particularly the splenium.
• Polymicrogyria is bilateral and predominantly frontal, frequently extends to the Sylvian fissure, may extend to the temporal and occipital lobes, and rarely extends over the entire cortex. While polymicrogyria is the most consistently observed cortical abnormality, other described abnormalities include pachygyria and lissencephaly.
• Cortical atrophy: Increased subdural spaces are common.
• Hypoplasia of the cerebellum and cerebellar vermis are common but not universal. Accompanying abnormalities of the pons, as seen in pontocerebellar hypoplasia, are rare.
• Has suggestive clinical and neuroimaging findings together with biallelic pathogenic variant(s) in
• Meets the clinical diagnostic criteria outlined under
• Note: Homozygosity mapping describes a specific type of analysis of a SNP chromosomal microarray that identifies regions of homozygosity in affected individuals.
• For an introduction to multigene panels click
## Suggestive Findings
RAB18 deficiency
Note: Findings indicated with an * are the basis of the diagnosis when molecular genetic testing either has not been performed or has not revealed biallelic pathogenic variants in one of the four known genes.
Hypogenesis of the corpus callosum, particularly the splenium.
Polymicrogyria is bilateral and predominantly frontal, frequently extends to the Sylvian fissure, may extend to the temporal and occipital lobes, and rarely extends over the entire cortex. While polymicrogyria is the most consistently observed cortical abnormality, other described abnormalities include pachygyria and lissencephaly.
Cortical atrophy: Increased subdural spaces are common.
Hypoplasia of the cerebellum and cerebellar vermis are common but not universal. Accompanying abnormalities of the pons, as seen in pontocerebellar hypoplasia, are rare.
•
• Hypogenesis of the corpus callosum, particularly the splenium.
• Polymicrogyria is bilateral and predominantly frontal, frequently extends to the Sylvian fissure, may extend to the temporal and occipital lobes, and rarely extends over the entire cortex. While polymicrogyria is the most consistently observed cortical abnormality, other described abnormalities include pachygyria and lissencephaly.
• Cortical atrophy: Increased subdural spaces are common.
• Hypoplasia of the cerebellum and cerebellar vermis are common but not universal. Accompanying abnormalities of the pons, as seen in pontocerebellar hypoplasia, are rare.
## Clinical Findings
•
## Neuroimaging Findings*
Hypogenesis of the corpus callosum, particularly the splenium.
Polymicrogyria is bilateral and predominantly frontal, frequently extends to the Sylvian fissure, may extend to the temporal and occipital lobes, and rarely extends over the entire cortex. While polymicrogyria is the most consistently observed cortical abnormality, other described abnormalities include pachygyria and lissencephaly.
Cortical atrophy: Increased subdural spaces are common.
Hypoplasia of the cerebellum and cerebellar vermis are common but not universal. Accompanying abnormalities of the pons, as seen in pontocerebellar hypoplasia, are rare.
• Hypogenesis of the corpus callosum, particularly the splenium.
• Polymicrogyria is bilateral and predominantly frontal, frequently extends to the Sylvian fissure, may extend to the temporal and occipital lobes, and rarely extends over the entire cortex. While polymicrogyria is the most consistently observed cortical abnormality, other described abnormalities include pachygyria and lissencephaly.
• Cortical atrophy: Increased subdural spaces are common.
• Hypoplasia of the cerebellum and cerebellar vermis are common but not universal. Accompanying abnormalities of the pons, as seen in pontocerebellar hypoplasia, are rare.
## Establishing the Diagnosis
The diagnosis of RAB18 deficiency
Has suggestive clinical and neuroimaging findings together with biallelic pathogenic variant(s) in
Meets the clinical diagnostic criteria outlined under
Note that failure to detect biallelic causative pathogenic variant(s) in one of the four genes known to cause RAB18 deficiency does not necessarily exclude a clinical diagnosis of RAB18 deficiency as additional loci may exist.
Molecular testing approaches can include
Gene-targeted testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Persons with the distinctive findings described in
When the phenotypic and neuroimaging findings suggest the diagnosis of RAB18 deficiency, molecular genetic testing approaches can include
Note: Homozygosity mapping describes a specific type of analysis of a SNP chromosomal microarray that identifies regions of homozygosity in affected individuals.
For an introduction to multigene panels click
When the diagnosis of RAB18 deficiency has not been considered or when gene-targeted testing has not identified pathogenic variant(s),
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Molecularly Confirmed RAB18 Deficiency
Absence of identified biallelic causative pathogenic variant(s) in one of these four genes does not exclude a clinical diagnosis of RAB18 deficiency as additional, as-yet unknown loci may exist.
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 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.
• Has suggestive clinical and neuroimaging findings together with biallelic pathogenic variant(s) in
• Meets the clinical diagnostic criteria outlined under
• Note: Homozygosity mapping describes a specific type of analysis of a SNP chromosomal microarray that identifies regions of homozygosity in affected individuals.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and neuroimaging findings suggest the diagnosis of RAB18 deficiency, molecular genetic testing approaches can include
Note: Homozygosity mapping describes a specific type of analysis of a SNP chromosomal microarray that identifies regions of homozygosity in affected individuals.
For an introduction to multigene panels click
• Note: Homozygosity mapping describes a specific type of analysis of a SNP chromosomal microarray that identifies regions of homozygosity in affected individuals.
• For an introduction to multigene panels click
## Option 2
When the diagnosis of RAB18 deficiency has not been considered or when gene-targeted testing has not identified pathogenic variant(s),
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Molecularly Confirmed RAB18 Deficiency
Absence of identified biallelic causative pathogenic variant(s) in one of these four genes does not exclude a clinical diagnosis of RAB18 deficiency as additional, as-yet unknown loci may exist.
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 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
RAB18 deficiency describes the molecular deficit underlying Warburg micro syndrome and Martsolf syndrome. Warburg micro syndrome is characterized by eye, nervous system, and endocrine abnormalities [
To date Warburg micro syndrome comprises the majority (>96%) of molecularly confirmed RAB18 deficiency reported [
Genetically defined Martsolf syndrome has been described in only four families (8 individuals), whose countries of origin are Pakistan, Mexico, Gambia, and Egypt [
Eye abnormalities are often the first presenting features of RAB18 deficiency. Both Warburg micro syndrome and Martsolf syndrome are associated with the hallmark finding of bilateral congenital cataracts. Cataracts have been observed prenatally by ultrasound examination in several instances and in one instance as early as the second trimester [
Cataracts are commonly accompanied by microphthalmia and microcornea (diameter <10 mm). Eyes may appear deep set (enophthalmic). Usually the pupils are small and atonic (i.e., unresponsive to light or mydriatic agents). In rare instances, microphthalmia, microcornea, and atonic pupils are absent in Warburg micro syndrome [
Despite early cataract surgery, the vision of individuals with RAB18 deficiency remains poor, likely due to progressive optic atrophy and cortical visual impairment, both of which are more severe in Warburg micro syndrome than in Martsolf syndrome. The following electrophysiologic findings support the presence of cortical visual impairment:
Normal electroretinograms (ERGs)
Visually evoked potentials (VEPs), which are nearly absent in Warburg micro syndrome but may be present in Martsolf syndrome [
EEG findings, which may be normal or abnormal in affected individuals, do not appear to demonstrate a consistent pattern.
Warburg micro syndrome is associated with progressive ascending spastic paraplegia. Affected infants are usually hypotonic with poor postural and head control; however, they may roll and sit with support. Increased deep tendon reflexes in the lower limbs may progress to hyperreflexia and then contractures and spastic diplegia from approximately 8 to 12 months. Involvement of the upper limbs leading to spastic quadriplegia occurs (variably) from about age five years. Later progression may lead to breathing difficulties. It is likely that paraplegia results from impaired motor neuron function.
Clinical findings of a motor and sensory peripheral neuropathy have been reported [
Martsolf syndrome is associated with hypotonia and primarily lower-limb spasticity, which progresses more slowly than that of Warburg micro syndrome [
Both Warburg micro syndrome and Martsolf syndrome are frequently associated with hypogonadism. Clinical findings are consistent with hypogonadotropic hypogonadism of hypothalamic origin [
In affected males it manifests as micropenis and/or cryptorchidism [
Untreated hypogonadism may be associated with delayed-onset puberty or lack of puberty.
RAB18 deficiency is often – but not always – associated with short stature (height <-2 SD).
Dysmorphic features associated with RAB18 deficiency are mild but form a recognizable pattern, including deep-set eyes, a wide nasal bridge and prominent nasal root, relatively narrow mouth, and proportionately large anteverted ears (
Mild micrognathia, a high-arched palate, and delayed dentition may also be seen [
Mild hypertrichosis has been reported; see for example
Osteopenia has been reported as potentially a primary manifestation of Warburg micro syndrome in one family [
Although secondary complications from RAB18 deficiency can be life-threatening, RAB18 deficiency is not known to directly affect life expectancy.
Clinical observations cannot be used to distinguish the genetic basis of RAB18 deficiency.
The strongest suggestion of phenotype correlation by gene comes from comparative analysis of brain MRIs in which it appears that biallelic loss-of-function
Of note, several individuals with biallelic loss-of-function pathogenic variants in
RAB18 deficiency results from biallelic pathogenic variants in
RAB18 deficiency usually results from pathogenic variants likely to completely nullify gene expression (nonsense, frameshift, intragenic deletion or consensus splice sites). The clinical presentation in these individuals is highly consistent, in keeping with the likelihood that the clinical consequences of these loss-of-function variants are equivalent.
Other variants associated with Warburg micro syndrome that are likely to abrogate the function of the encoded protein (see
The homozygous missense variant
The homozygous missense variant
Although the following naming system has been used – in some instances – to designate the causative gene for Warburg micro syndrome, no clinical purpose is served by this naming system as the causative gene does not influence phenotype.
Warburg micro syndrome type 1:
Warburg micro syndrome type 2:
Warburg micro syndrome type 3:
Warburg micro syndrome type 4:
Data on the prevalence of RAB18 deficiency are limited.
As expected for an autosomal recessive disorder, incidence is known to be higher in isolated communities and in communities with a high rate of consanguinity [
Incidence may be higher in populations in which pathogenic founder variants are present at a high frequency. Notably, loss of function of an essential splice site variant in
• Normal electroretinograms (ERGs)
• Visually evoked potentials (VEPs), which are nearly absent in Warburg micro syndrome but may be present in Martsolf syndrome [
• RAB18 deficiency usually results from pathogenic variants likely to completely nullify gene expression (nonsense, frameshift, intragenic deletion or consensus splice sites). The clinical presentation in these individuals is highly consistent, in keeping with the likelihood that the clinical consequences of these loss-of-function variants are equivalent.
• Other variants associated with Warburg micro syndrome that are likely to abrogate the function of the encoded protein (see
•
• The homozygous missense variant
• The homozygous missense variant
• The homozygous missense variant
• The homozygous missense variant
• The homozygous missense variant
• The homozygous missense variant
• Warburg micro syndrome type 1:
• Warburg micro syndrome type 2:
• Warburg micro syndrome type 3:
• Warburg micro syndrome type 4:
## Clinical Description
RAB18 deficiency describes the molecular deficit underlying Warburg micro syndrome and Martsolf syndrome. Warburg micro syndrome is characterized by eye, nervous system, and endocrine abnormalities [
To date Warburg micro syndrome comprises the majority (>96%) of molecularly confirmed RAB18 deficiency reported [
Genetically defined Martsolf syndrome has been described in only four families (8 individuals), whose countries of origin are Pakistan, Mexico, Gambia, and Egypt [
Eye abnormalities are often the first presenting features of RAB18 deficiency. Both Warburg micro syndrome and Martsolf syndrome are associated with the hallmark finding of bilateral congenital cataracts. Cataracts have been observed prenatally by ultrasound examination in several instances and in one instance as early as the second trimester [
Cataracts are commonly accompanied by microphthalmia and microcornea (diameter <10 mm). Eyes may appear deep set (enophthalmic). Usually the pupils are small and atonic (i.e., unresponsive to light or mydriatic agents). In rare instances, microphthalmia, microcornea, and atonic pupils are absent in Warburg micro syndrome [
Despite early cataract surgery, the vision of individuals with RAB18 deficiency remains poor, likely due to progressive optic atrophy and cortical visual impairment, both of which are more severe in Warburg micro syndrome than in Martsolf syndrome. The following electrophysiologic findings support the presence of cortical visual impairment:
Normal electroretinograms (ERGs)
Visually evoked potentials (VEPs), which are nearly absent in Warburg micro syndrome but may be present in Martsolf syndrome [
EEG findings, which may be normal or abnormal in affected individuals, do not appear to demonstrate a consistent pattern.
Warburg micro syndrome is associated with progressive ascending spastic paraplegia. Affected infants are usually hypotonic with poor postural and head control; however, they may roll and sit with support. Increased deep tendon reflexes in the lower limbs may progress to hyperreflexia and then contractures and spastic diplegia from approximately 8 to 12 months. Involvement of the upper limbs leading to spastic quadriplegia occurs (variably) from about age five years. Later progression may lead to breathing difficulties. It is likely that paraplegia results from impaired motor neuron function.
Clinical findings of a motor and sensory peripheral neuropathy have been reported [
Martsolf syndrome is associated with hypotonia and primarily lower-limb spasticity, which progresses more slowly than that of Warburg micro syndrome [
Both Warburg micro syndrome and Martsolf syndrome are frequently associated with hypogonadism. Clinical findings are consistent with hypogonadotropic hypogonadism of hypothalamic origin [
In affected males it manifests as micropenis and/or cryptorchidism [
Untreated hypogonadism may be associated with delayed-onset puberty or lack of puberty.
RAB18 deficiency is often – but not always – associated with short stature (height <-2 SD).
Dysmorphic features associated with RAB18 deficiency are mild but form a recognizable pattern, including deep-set eyes, a wide nasal bridge and prominent nasal root, relatively narrow mouth, and proportionately large anteverted ears (
Mild micrognathia, a high-arched palate, and delayed dentition may also be seen [
Mild hypertrichosis has been reported; see for example
Osteopenia has been reported as potentially a primary manifestation of Warburg micro syndrome in one family [
Although secondary complications from RAB18 deficiency can be life-threatening, RAB18 deficiency is not known to directly affect life expectancy.
• Normal electroretinograms (ERGs)
• Visually evoked potentials (VEPs), which are nearly absent in Warburg micro syndrome but may be present in Martsolf syndrome [
## Eye Findings
Eye abnormalities are often the first presenting features of RAB18 deficiency. Both Warburg micro syndrome and Martsolf syndrome are associated with the hallmark finding of bilateral congenital cataracts. Cataracts have been observed prenatally by ultrasound examination in several instances and in one instance as early as the second trimester [
Cataracts are commonly accompanied by microphthalmia and microcornea (diameter <10 mm). Eyes may appear deep set (enophthalmic). Usually the pupils are small and atonic (i.e., unresponsive to light or mydriatic agents). In rare instances, microphthalmia, microcornea, and atonic pupils are absent in Warburg micro syndrome [
Despite early cataract surgery, the vision of individuals with RAB18 deficiency remains poor, likely due to progressive optic atrophy and cortical visual impairment, both of which are more severe in Warburg micro syndrome than in Martsolf syndrome. The following electrophysiologic findings support the presence of cortical visual impairment:
Normal electroretinograms (ERGs)
Visually evoked potentials (VEPs), which are nearly absent in Warburg micro syndrome but may be present in Martsolf syndrome [
• Normal electroretinograms (ERGs)
• Visually evoked potentials (VEPs), which are nearly absent in Warburg micro syndrome but may be present in Martsolf syndrome [
## Neurologic Findings
EEG findings, which may be normal or abnormal in affected individuals, do not appear to demonstrate a consistent pattern.
## Motor Dysfunction
Warburg micro syndrome is associated with progressive ascending spastic paraplegia. Affected infants are usually hypotonic with poor postural and head control; however, they may roll and sit with support. Increased deep tendon reflexes in the lower limbs may progress to hyperreflexia and then contractures and spastic diplegia from approximately 8 to 12 months. Involvement of the upper limbs leading to spastic quadriplegia occurs (variably) from about age five years. Later progression may lead to breathing difficulties. It is likely that paraplegia results from impaired motor neuron function.
Clinical findings of a motor and sensory peripheral neuropathy have been reported [
Martsolf syndrome is associated with hypotonia and primarily lower-limb spasticity, which progresses more slowly than that of Warburg micro syndrome [
## Hypogonadism
Both Warburg micro syndrome and Martsolf syndrome are frequently associated with hypogonadism. Clinical findings are consistent with hypogonadotropic hypogonadism of hypothalamic origin [
In affected males it manifests as micropenis and/or cryptorchidism [
Untreated hypogonadism may be associated with delayed-onset puberty or lack of puberty.
## Other
RAB18 deficiency is often – but not always – associated with short stature (height <-2 SD).
Dysmorphic features associated with RAB18 deficiency are mild but form a recognizable pattern, including deep-set eyes, a wide nasal bridge and prominent nasal root, relatively narrow mouth, and proportionately large anteverted ears (
Mild micrognathia, a high-arched palate, and delayed dentition may also be seen [
Mild hypertrichosis has been reported; see for example
Osteopenia has been reported as potentially a primary manifestation of Warburg micro syndrome in one family [
Although secondary complications from RAB18 deficiency can be life-threatening, RAB18 deficiency is not known to directly affect life expectancy.
## Phenotype Correlations by Gene
Clinical observations cannot be used to distinguish the genetic basis of RAB18 deficiency.
The strongest suggestion of phenotype correlation by gene comes from comparative analysis of brain MRIs in which it appears that biallelic loss-of-function
Of note, several individuals with biallelic loss-of-function pathogenic variants in
## Genotype-Phenotype Correlations
RAB18 deficiency results from biallelic pathogenic variants in
RAB18 deficiency usually results from pathogenic variants likely to completely nullify gene expression (nonsense, frameshift, intragenic deletion or consensus splice sites). The clinical presentation in these individuals is highly consistent, in keeping with the likelihood that the clinical consequences of these loss-of-function variants are equivalent.
Other variants associated with Warburg micro syndrome that are likely to abrogate the function of the encoded protein (see
The homozygous missense variant
The homozygous missense variant
• RAB18 deficiency usually results from pathogenic variants likely to completely nullify gene expression (nonsense, frameshift, intragenic deletion or consensus splice sites). The clinical presentation in these individuals is highly consistent, in keeping with the likelihood that the clinical consequences of these loss-of-function variants are equivalent.
• Other variants associated with Warburg micro syndrome that are likely to abrogate the function of the encoded protein (see
•
• The homozygous missense variant
• The homozygous missense variant
• The homozygous missense variant
• The homozygous missense variant
• The homozygous missense variant
• The homozygous missense variant
## Nomenclature
Although the following naming system has been used – in some instances – to designate the causative gene for Warburg micro syndrome, no clinical purpose is served by this naming system as the causative gene does not influence phenotype.
Warburg micro syndrome type 1:
Warburg micro syndrome type 2:
Warburg micro syndrome type 3:
Warburg micro syndrome type 4:
• Warburg micro syndrome type 1:
• Warburg micro syndrome type 2:
• Warburg micro syndrome type 3:
• Warburg micro syndrome type 4:
## Prevalence
Data on the prevalence of RAB18 deficiency are limited.
As expected for an autosomal recessive disorder, incidence is known to be higher in isolated communities and in communities with a high rate of consanguinity [
Incidence may be higher in populations in which pathogenic founder variants are present at a high frequency. Notably, loss of function of an essential splice site variant in
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Array CGH may be useful in identifying pathogenic copy number variants associated with clinical findings similar to those in RAB18 deficiency [
Note that in RAB18 deficiency, prenatal onset of cataracts appears to be a consistent feature, a finding in contrast to other inherited conditions in which cataracts are a more variable manifestation or can arise postnatally (
Differential diagnosis therefore includes some other syndromes with congenital cataracts.
Disorders to Consider in the Differential Diagnosis of RAB18 Deficiency
AD = autosomal dominant; AR = autosomal recessive; CC = congenital cataracts; DD = developmental delay; FTT = failure to thrive; ID = intellectual disability; MOI = mode of inheritance; NA = not applicable; SNHL = sensorineural hearing loss; XL = X-linked
## Management
To establish the extent of disease and needs in an individual diagnosed with RAB18 deficiency, the evaluations in
Recommended Evaluations Following Initial Diagnosis of RAB18 Deficiency
OFC = occipitofrontal circumference
Treatment is symptomatic and supportive. It is best approached through collaborative care involving medical specialists, and is best coordinated by a pediatrician who is aware of the child's general health and development. Psychosocial support for families is an important component of effective care.
Treatment of Manifestations in Individuals with RAB18 Deficiency
CPAP = continuous positive airway pressure; 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.
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.
No formal surveillance guidelines exist for RAB18 deficiency. Suggested surveillance includes routine follow up with
An ophthalmologist
A neurologist
A developmental specialist, such as a developmental pediatrician
A feeding team and nutritionist
An endocrinologist, especially in infancy to assess degree of hypogonadism and at the age that puberty typically would occur
Hearing tests
See
Search
• 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 ophthalmologist
• A neurologist
• A developmental specialist, such as a developmental pediatrician
• A feeding team and nutritionist
• An endocrinologist, especially in infancy to assess degree of hypogonadism and at the age that puberty typically would occur
• Hearing tests
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with RAB18 deficiency, the evaluations in
Recommended Evaluations Following Initial Diagnosis of RAB18 Deficiency
OFC = occipitofrontal circumference
## Treatment of Manifestations
Treatment is symptomatic and supportive. It is best approached through collaborative care involving medical specialists, and is best coordinated by a pediatrician who is aware of the child's general health and development. Psychosocial support for families is an important component of effective care.
Treatment of Manifestations in Individuals with RAB18 Deficiency
CPAP = continuous positive airway pressure; 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.
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.
## 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
## Prevention of Secondary Complications
## Surveillance
No formal surveillance guidelines exist for RAB18 deficiency. Suggested surveillance includes routine follow up with
An ophthalmologist
A neurologist
A developmental specialist, such as a developmental pediatrician
A feeding team and nutritionist
An endocrinologist, especially in infancy to assess degree of hypogonadism and at the age that puberty typically would occur
Hearing tests
• An ophthalmologist
• A neurologist
• A developmental specialist, such as a developmental pediatrician
• A feeding team and nutritionist
• An endocrinologist, especially in infancy to assess degree of hypogonadism and at the age that puberty typically would occur
• Hearing tests
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
RAB18 deficiency 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 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, 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 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 carriers or are at risk of being carriers.
## Mode of Inheritance
RAB18 deficiency 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 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 (Heterozygote) 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, 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
No specific resources for RAB18 Deficiency have been identified by
## Molecular Genetics
RAB18 Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for RAB18 Deficiency (
The molecular pathology of Warburg micro syndrome and Martsolf syndrome arises either from the absence of Ras-related protein Rab-18 (RAB18) protein or from its functional absence as a result of dysregulation. Because RAB3GAP1, RAB3GAP2, and TBC1D20 are each essential for the regulation of RAB18, biallelic loss-of-function variants in the genes that encode these proteins lead to clinically indistinguishable phenotypes.
In common with other small GTPases, RAB proteins function as "molecular switches." They can bind to GDP or GTP and adopt different conformations according to which nucleotide is bound. These different conformations are in turn associated with altered protein-binding characteristics that affect interactions with regulators and with the mediators of their downstream cellular functions. Switching between GDP- and GTP-bound conformations is tightly regulated by two classes of protein, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs mediate the exchange of bound GDP for GTP. GAPs stimulate the intrinsic GTPase activity of the RAB proteins, thereby mediating hydrolysis of bound GTP into GDP.
An additional in-frame microexon of 21 nucleotides constitutes exon 24 that is incorporated into the 25-exon alternative transcript,
Homozygous pathogenic variants were identified in 67 families: 19 were splice site, 18 nonsense, 20 frameshift, six missense, and four intragenic deletions [
Compound heterozygous pathogenic variants were identified in ten families: 12 were nonsense, three splice site, three frameshift, one missense, and one was unidentified [
Pathogenic variants identified in
In individuals of Turkish ethnic origin: the splice site variant c.748+1G>A [
In individuals of Pakistani ethnic origin: the splice site variant c.649-2A>G and a missense variant, c.52A>C [
Recurrent pathogenic variants identified in individuals with different ethnic backgrounds include c.899+1G>A, c.1039C>T, and c.2801delC.
The apparent frameshift variant c.9delC was identified in sibs with Martsolf syndrome [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
See
See
Two of three pathogenic missense variants in
A third pathogenic missense variant, c.560G>C, p.Arg187Pro, has not been characterized at a molecular level [
The location of the loss-of-function missense variants in
Two of the pathogenic variants in
Nonsense variants were identified in five families, frameshift variants in two families, and missense variants in two families. An in-frame deletion and a variant affecting splicing were each identified in single families. One pathogenic missense
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
An in-frame deletion associated with Warburg micro syndrome, c.499_507del, removes conserved residues Phe167, Tyr168, and Thr169 from the protein, suggesting that these residues are also functionally important [
A pathogenic founder variant,
Variants listed in the table have been provided by the authors.
An extension variant with a sequence change in the translation termination (stop or Ter) codon 207 that extends the normal translational reading frame adding new amino acids and ending at new stop codon at position 20.
In vitro analyses of recombinant RAB18 p.Leu24Gln and p.Arg93del proteins shows that these variants completely abolish nucleotide binding [
A c.284C>G, p.Thr95Arg variant has not been functionally characterized, but the proximity of Thr95 to Arg93 suggests that this substitution has a similar effect [
A disease-associated extension variant, c.619T>C, is unlikely to impair nucleotide binding but is likely to compromise the post-translational modification of RAB18 and its association with membranes [
Together, these data suggest that both nucleotide binding and post-translational modification are essential for RAB18 to function.
A pathogenic variant identified in the mutated mouse model,
• Homozygous pathogenic variants were identified in 67 families: 19 were splice site, 18 nonsense, 20 frameshift, six missense, and four intragenic deletions [
• Compound heterozygous pathogenic variants were identified in ten families: 12 were nonsense, three splice site, three frameshift, one missense, and one was unidentified [
• In individuals of Turkish ethnic origin: the splice site variant c.748+1G>A [
• In individuals of Pakistani ethnic origin: the splice site variant c.649-2A>G and a missense variant, c.52A>C [
## Molecular Pathogenesis
The molecular pathology of Warburg micro syndrome and Martsolf syndrome arises either from the absence of Ras-related protein Rab-18 (RAB18) protein or from its functional absence as a result of dysregulation. Because RAB3GAP1, RAB3GAP2, and TBC1D20 are each essential for the regulation of RAB18, biallelic loss-of-function variants in the genes that encode these proteins lead to clinically indistinguishable phenotypes.
In common with other small GTPases, RAB proteins function as "molecular switches." They can bind to GDP or GTP and adopt different conformations according to which nucleotide is bound. These different conformations are in turn associated with altered protein-binding characteristics that affect interactions with regulators and with the mediators of their downstream cellular functions. Switching between GDP- and GTP-bound conformations is tightly regulated by two classes of protein, guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs). GEFs mediate the exchange of bound GDP for GTP. GAPs stimulate the intrinsic GTPase activity of the RAB proteins, thereby mediating hydrolysis of bound GTP into GDP.
An additional in-frame microexon of 21 nucleotides constitutes exon 24 that is incorporated into the 25-exon alternative transcript,
Homozygous pathogenic variants were identified in 67 families: 19 were splice site, 18 nonsense, 20 frameshift, six missense, and four intragenic deletions [
Compound heterozygous pathogenic variants were identified in ten families: 12 were nonsense, three splice site, three frameshift, one missense, and one was unidentified [
Pathogenic variants identified in
In individuals of Turkish ethnic origin: the splice site variant c.748+1G>A [
In individuals of Pakistani ethnic origin: the splice site variant c.649-2A>G and a missense variant, c.52A>C [
Recurrent pathogenic variants identified in individuals with different ethnic backgrounds include c.899+1G>A, c.1039C>T, and c.2801delC.
The apparent frameshift variant c.9delC was identified in sibs with Martsolf syndrome [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
See
See
Two of three pathogenic missense variants in
A third pathogenic missense variant, c.560G>C, p.Arg187Pro, has not been characterized at a molecular level [
The location of the loss-of-function missense variants in
Two of the pathogenic variants in
Nonsense variants were identified in five families, frameshift variants in two families, and missense variants in two families. An in-frame deletion and a variant affecting splicing were each identified in single families. One pathogenic missense
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
An in-frame deletion associated with Warburg micro syndrome, c.499_507del, removes conserved residues Phe167, Tyr168, and Thr169 from the protein, suggesting that these residues are also functionally important [
A pathogenic founder variant,
Variants listed in the table have been provided by the authors.
An extension variant with a sequence change in the translation termination (stop or Ter) codon 207 that extends the normal translational reading frame adding new amino acids and ending at new stop codon at position 20.
In vitro analyses of recombinant RAB18 p.Leu24Gln and p.Arg93del proteins shows that these variants completely abolish nucleotide binding [
A c.284C>G, p.Thr95Arg variant has not been functionally characterized, but the proximity of Thr95 to Arg93 suggests that this substitution has a similar effect [
A disease-associated extension variant, c.619T>C, is unlikely to impair nucleotide binding but is likely to compromise the post-translational modification of RAB18 and its association with membranes [
Together, these data suggest that both nucleotide binding and post-translational modification are essential for RAB18 to function.
A pathogenic variant identified in the mutated mouse model,
• Homozygous pathogenic variants were identified in 67 families: 19 were splice site, 18 nonsense, 20 frameshift, six missense, and four intragenic deletions [
• Compound heterozygous pathogenic variants were identified in ten families: 12 were nonsense, three splice site, three frameshift, one missense, and one was unidentified [
• In individuals of Turkish ethnic origin: the splice site variant c.748+1G>A [
• In individuals of Pakistani ethnic origin: the splice site variant c.649-2A>G and a missense variant, c.52A>C [
##
An additional in-frame microexon of 21 nucleotides constitutes exon 24 that is incorporated into the 25-exon alternative transcript,
Homozygous pathogenic variants were identified in 67 families: 19 were splice site, 18 nonsense, 20 frameshift, six missense, and four intragenic deletions [
Compound heterozygous pathogenic variants were identified in ten families: 12 were nonsense, three splice site, three frameshift, one missense, and one was unidentified [
Pathogenic variants identified in
In individuals of Turkish ethnic origin: the splice site variant c.748+1G>A [
In individuals of Pakistani ethnic origin: the splice site variant c.649-2A>G and a missense variant, c.52A>C [
Recurrent pathogenic variants identified in individuals with different ethnic backgrounds include c.899+1G>A, c.1039C>T, and c.2801delC.
The apparent frameshift variant c.9delC was identified in sibs with Martsolf syndrome [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
See
See
Two of three pathogenic missense variants in
A third pathogenic missense variant, c.560G>C, p.Arg187Pro, has not been characterized at a molecular level [
The location of the loss-of-function missense variants in
Two of the pathogenic variants in
• Homozygous pathogenic variants were identified in 67 families: 19 were splice site, 18 nonsense, 20 frameshift, six missense, and four intragenic deletions [
• Compound heterozygous pathogenic variants were identified in ten families: 12 were nonsense, three splice site, three frameshift, one missense, and one was unidentified [
• In individuals of Turkish ethnic origin: the splice site variant c.748+1G>A [
• In individuals of Pakistani ethnic origin: the splice site variant c.649-2A>G and a missense variant, c.52A>C [
##
Nonsense variants were identified in five families, frameshift variants in two families, and missense variants in two families. An in-frame deletion and a variant affecting splicing were each identified in single families. One pathogenic missense
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
An in-frame deletion associated with Warburg micro syndrome, c.499_507del, removes conserved residues Phe167, Tyr168, and Thr169 from the protein, suggesting that these residues are also functionally important [
##
A pathogenic founder variant,
Variants listed in the table have been provided by the authors.
An extension variant with a sequence change in the translation termination (stop or Ter) codon 207 that extends the normal translational reading frame adding new amino acids and ending at new stop codon at position 20.
In vitro analyses of recombinant RAB18 p.Leu24Gln and p.Arg93del proteins shows that these variants completely abolish nucleotide binding [
A c.284C>G, p.Thr95Arg variant has not been functionally characterized, but the proximity of Thr95 to Arg93 suggests that this substitution has a similar effect [
A disease-associated extension variant, c.619T>C, is unlikely to impair nucleotide binding but is likely to compromise the post-translational modification of RAB18 and its association with membranes [
Together, these data suggest that both nucleotide binding and post-translational modification are essential for RAB18 to function.
##
A pathogenic variant identified in the mutated mouse model,
## References
## Literature Cited
## Chapter Notes
We thank the patients, their families, and clinicians for their collaboration and contribution to our knowledge about Warburg micro syndrome and Martsolf syndrome.
4 January 2018 (bp) Review posted live
2 May 2017 (mh) Original submission
• 4 January 2018 (bp) Review posted live
• 2 May 2017 (mh) Original submission
## Acknowledgments
We thank the patients, their families, and clinicians for their collaboration and contribution to our knowledge about Warburg micro syndrome and Martsolf syndrome.
## Revision History
4 January 2018 (bp) Review posted live
2 May 2017 (mh) Original submission
• 4 January 2018 (bp) Review posted live
• 2 May 2017 (mh) Original submission
Photographs of individuals with Warburg micro and Martsolf syndromes
Brothers K2.1 (age 15 years) and K2.2 (age 13 years) with Warburg micro syndrome are homozygous for the
The girl K6.1 (age 13 years) and her brother K6.2 (age 6 years) with Warburg micro syndrome are homozygous for the
The boy K48 (age 4 months; age 3 years) with Warburg micro syndrome is homozygous for the
The girl K7.1 (age 8 years) and her brother K7.2 (age 4 years) with Martsolf syndrome are homozygous for the p.Asp4ThrTer31 variant.
Sisters K44.1 (age 17 years) and K44.2 (age 14 years) with Martsolf syndrome are homozygous for the
The boy K52 with Warburg micro syndrome is homozygous for the
Reused with permission from
|
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] |
4/1/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
rapid-odp
|
rapid-odp
|
[
"Alternating Hemiplegia of Childhood (AHC)",
"Cerebellar Ataxia, Areflexia, Pes Cavus, Optic Atrophy, and Sensorineural Hearing Loss (CAPOS) Syndrome",
"Rapid-Onset Dystonia-Parkinsonism (RDP)",
"Relapsing Encephalopathy with Cerebellar Ataxia (RECA) / Fever-Induced Paroxysmal Weakness and Encephalopathy (FIPWE)",
"Sodium/potassium-transporting ATPase subunit alpha-3",
"ATP1A3",
"ATP1A3-Related Disorder"
] |
Allison Brashear, Kathleen J Sweadner, Ihtsham Haq, Eleonora Napoli, Laurie Ozelius
|
Summary AHC is characterized by onset prior to age 18 months of paroxysmal hemiplegic episodes, predominately involving the limbs and/or the whole body, lasting from minutes to hours to days (and sometimes weeks) with remission only during sleep, only to resume after awakening. Although paroxysmal episodic neurologic dysfunction predominates early in the disease course, with age increasingly persistent neurologic dysfunction predominates, including oculomotor apraxia and strabismus, dysarthria, speech and language delay, developmental delay, and impairment in social skills. Other system involvement may include cardiovascular (cardiac conduction abnormalities) and gastrointestinal (constipation, vomiting, anorexia, diarrhea, nausea, and abdominal pain) manifestations. CAPOS syndrome presents in infancy or childhood (usually ages 6 months to 5 years) with cerebellar ataxia during or after a fever. The acute febrile encephalopathy may include hypotonia, flaccidity, nystagmus, strabismus, dysarthria/anarthria, lethargy, loss of consciousness, and even coma. Usually, considerable recovery occurs within days to weeks; however, persistence of some degree of ataxia and other manifestations is typical. RECA/FIPWE primarily presents with fever-induced episodes (infancy to age 5 years); however, first episodes can occur occasionally in young adults during illnesses such as mononucleosis. Recurrent fever-induced episodes may be ataxia-dominated RECA-like motor manifestations or FIPWE-like non-motor manifestations (encephalopathy) and can vary among affected individuals. Notably, RECA-like and FIPWE-like manifestations can occur in the same individual in different episodes. In some individuals episodes seem to decrease in frequency and severity over time, whereas others might experience worsening of manifestations. RDP presents in individuals ages 18 months to 60 years and older with dystonia that is typically of abrupt onset over hours to several weeks, though some individuals report gradual onset over the course of months. A stress-related trigger is identifiable in up to 75% of individuals. Dystonia rarely improves significantly after onset; some individuals report mild improvement over time, whereas others can experience subsequent episodes of abrupt worsening months to years after onset. Limbs are usually the first to be affected, although by the time of diagnosis – typically many years after onset – individuals most commonly display a bulbar-predominant generalized dystonia. Exceptions are common and a rostrocaudal gradient is rare rather than typical. Migraines and seizures are also observed. The diagnosis of There is no cure for
|
Alternating hemiplegia of childhood (AHC)
Cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS) syndrome
Relapsing encephalopathy with cerebellar ataxia (RECA) / fever-induced paroxysmal weakness and encephalopathy (FIPWE)
Rapid-onset dystonia-parkinsonism (RDP)
For synonyms and outdated names, see
Severe perinatal phenotypes including
• Alternating hemiplegia of childhood (AHC)
• Cerebellar ataxia, areflexia, pes cavus, optic atrophy, sensorineural hearing loss (CAPOS) syndrome
• Relapsing encephalopathy with cerebellar ataxia (RECA) / fever-induced paroxysmal weakness and encephalopathy (FIPWE)
• Rapid-onset dystonia-parkinsonism (RDP)
## Diagnosis
No consensus diagnostic criteria for
Hemiplegic events
Dystonic episodes, usually with no or minimal response to an adequate trial of levodopa therapy [
Seizures
Abnormal eye movements
Apnea
Autonomic episodes
Dystonia and/or chorea
Ataxia
Behavioral difficulties
Attention-deficit/hyperactivity disorder
Autism spectrum disorder
Childhood-onset schizophrenia [
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
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
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 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. These methods 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.
•
• Hemiplegic events
• Dystonic episodes, usually with no or minimal response to an adequate trial of levodopa therapy [
• Seizures
• Abnormal eye movements
• Apnea
• Autonomic episodes
• Hemiplegic events
• Dystonic episodes, usually with no or minimal response to an adequate trial of levodopa therapy [
• Seizures
• Abnormal eye movements
• Apnea
• Autonomic episodes
•
• Dystonia and/or chorea
• Ataxia
• Dystonia and/or chorea
• Ataxia
•
• Behavioral difficulties
• Attention-deficit/hyperactivity disorder
• Autism spectrum disorder
• Childhood-onset schizophrenia [
• Behavioral difficulties
• Attention-deficit/hyperactivity disorder
• Autism spectrum disorder
• Childhood-onset schizophrenia [
• Hemiplegic events
• Dystonic episodes, usually with no or minimal response to an adequate trial of levodopa therapy [
• Seizures
• Abnormal eye movements
• Apnea
• Autonomic episodes
• Dystonia and/or chorea
• Ataxia
• Behavioral difficulties
• Attention-deficit/hyperactivity disorder
• Autism spectrum disorder
• Childhood-onset schizophrenia [
• For an introduction to comprehensive genomic testing click
• For an introduction to multigene panels click
## Suggestive Findings
Hemiplegic events
Dystonic episodes, usually with no or minimal response to an adequate trial of levodopa therapy [
Seizures
Abnormal eye movements
Apnea
Autonomic episodes
Dystonia and/or chorea
Ataxia
Behavioral difficulties
Attention-deficit/hyperactivity disorder
Autism spectrum disorder
Childhood-onset schizophrenia [
•
• Hemiplegic events
• Dystonic episodes, usually with no or minimal response to an adequate trial of levodopa therapy [
• Seizures
• Abnormal eye movements
• Apnea
• Autonomic episodes
• Hemiplegic events
• Dystonic episodes, usually with no or minimal response to an adequate trial of levodopa therapy [
• Seizures
• Abnormal eye movements
• Apnea
• Autonomic episodes
•
• Dystonia and/or chorea
• Ataxia
• Dystonia and/or chorea
• Ataxia
•
• Behavioral difficulties
• Attention-deficit/hyperactivity disorder
• Autism spectrum disorder
• Childhood-onset schizophrenia [
• Behavioral difficulties
• Attention-deficit/hyperactivity disorder
• Autism spectrum disorder
• Childhood-onset schizophrenia [
• Hemiplegic events
• Dystonic episodes, usually with no or minimal response to an adequate trial of levodopa therapy [
• Seizures
• Abnormal eye movements
• Apnea
• Autonomic episodes
• Dystonia and/or chorea
• Ataxia
• Behavioral difficulties
• Attention-deficit/hyperactivity disorder
• Autism spectrum disorder
• Childhood-onset schizophrenia [
## 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
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
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 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. These methods 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
Following the initial description of rapid-onset dystonia-parkinsonism (RDP) by
The overlapping clinical findings in the most common historically defined phenotypes of
Adapted with permission from
Criteria have been proposed whereby a diagnosis of AHC can be established in an individual with two mandatory features in addition to either three major features or two major and three minor features [
Alternating Hemiplegia of Childhood: Diagnostic Criteria
Paroxysmal episodes of hemiplegia alternating between right & left side &/or of quadriplegia
Evidence of background abnormal neurologic development
Presence of
Onset before age 18 months
Dystonia episodes
Different types of episodes occurring independently or simultaneously w/evolution from one or more manifestations to different ones during the same episode
Paroxysmal episodes of nystagmus
Sleep-dependent spell improvement
Occurrence of epileptic seizures
Episodes of altered consciousness
Abnormal motor function
Episodes of autonomic dysfunction
Other paroxysmal neurologic manifestations can include the following:
Oculomotor abnormalities (usually the earliest abnormalities seen), including monocular or binocular nystagmus, intermittent eso- or exotropia, skew deviation, ocular bobbing, and ocular flutter
Tonic or dystonic episodes (in one or more limbs either unilaterally or generalized)
Status dystonicus (sustained contractions of the limbs and potentially the axial musculature, which can be a medical emergency) [
More complex dyskinesias, such as chorea of the limbs
Episodes of quadriparesis or hemi- or quadriplegia (separate attacks or result from generalization of a hemiplegic episode
Seizures and status epilepticus (i.e., a seizure with ≥5 minutes of continuous clinical and/or electrographic activity, or two or more seizures within a 5-minute period without recovery) [
Seizure-like episodes without EEG correlation, including status dystonicus and psychogenic non-epileptic seizure (PNES)
Autonomic phenomena either during hemiplegic episodes or independently, such as unilateral or bilateral pupillary dilatation, flushing, pallor affecting one limb or hemibody (i.e., either right or left half of the body)
Impairment of speech and/or swallowing
Respiratory distress with oxygen desaturation during episodes of neurologic dysfunction [
Headache
Non-motor interictal neurobehavioral/psychiatric manifestations including behavioral outbursts, impulsivity, aggression, and mood disorders [
Developmental delay or other persistent neurologic disability, including speech and language delay [
By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
Oculomotor apraxia and strabismus can be present.
Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
Hypotonia, flaccidity, hyporeflexia, areflexia, pes cavus
Dystonia and choreiform movements
Abnormal eye movements (nystagmus, strabismus)
Progressive optic nerve atrophy and vision loss
Progressive sensorineural hearing loss
Brief generalized tonic-clonic seizures
Dysarthria/anarthria
Dysphagia
Cognitive dysfunction, including lethargy, loss of consciousness, and coma
Neurobehavioral/psychiatric manifestations
Triggering fevers usually accompany typical childhood illnesses, with or without identified infections; rarely, episodes occur during infections without fever.
Many episodes involve generalized weakness, usually bilateral hypotonia but sometimes unilateral.
Some episodes involve acute cerebellar ataxia, possibly with choreoathetosis or pyramidal signs.
Manifestations can involve bulbar function, including dysarthria, dysphagia, difficulty swallowing, and/or drooling.
Encephalopathy during fever in some individuals can manifest as impaired consciousness ranging from drowsiness to transient loss of consciousness to coma in rare instances. Other individuals have no alteration of consciousness.
Mutism can be a principal manifestation during the febrile phase.
Other manifestations that sometimes appear in the acute phase are brief dystonic episodes or paroxysmal stiffness, abnormal ocular movements, suspected seizure, areflexia, or facial grimaces.
While acute manifestations resolve gradually after the fever resolves, some manifestations persist, especially apraxia and ataxia [
During recovery from acute fever, motor manifestations that can also emerge include the following:
Cerebellar ataxia (often the most prominent feature during recovery) rather than weakness (Of note, while ataxia can be present during acute illness, it may not be obvious because of hypotonia.)
Ocular movement abnormalities
Dystonia and muscle rigidity
Choreiform movements
Areflexia
Dysarthria, including speech difficulty (Severity varies widely between individuals.)
Seizures (However, epilepsy is not a major feature.)
Sustained reduced responsiveness, bradykinesia, and paraparesis (rare)
After the acute phase, some manifestations may gradually worsen, including the following:
Persistent motor deficits (particularly ataxia, dysarthria, and dystonia)
Inability to walk independently
Areflexia (In one individual, electromyogram indicated some distal denervation accompanying areflexia [
While frank impairment of cognition is not common, cognitive delays and challenges with memory or concentration have been observed. Psychomotor delay prior to episodes has been reported.
Neurobehavioral/psychiatric manifestations, such as irritability, mood fluctuations, and anger outbursts have been reported but are not universal.
The RDP phenotype was initially named because its delayed and rapid onset was thought to be distinctive; however, over time it became apparent that dystonia and bradykinesia, its predominant manifestations, are common in the other ATP1A3-related phenotypes [
Primary onset occurs between ages four and 55 years (range: 9 months to >60 years) with dystonia characterized by the following (see
Typically, onset is paroxysmal, or abrupt, over hours to several weeks. Although the arms and hands are usually affected first, most individuals – when first examined by a neurologist – have multifocal or generalized paroxysmal spells that can be difficult to distinguish from seizures, especially given that seizures are more common (31%) than paroxysmal events (7%) [
Prominent bulbar findings include impairment of speech, voice, and swallowing [
There is minimal or no tremor at onset.
Onset often follows a physiologic stressor, such as physical activity, childbirth, infection, alcohol binge, or psychological stress [
Progression typically stops at or before one month after onset with little subsequent improvement.
Preliminary analysis of 14 individuals with longitudinal follow up suggests severity of dystonia can vary over time, with most experiencing stability or mild worsening [Haq et al, unpublished data]. When present, bradykinesia is directly proportional to the severity of the dystonia and appears to be a function of the dystonia, without other parkinsonian features such as pill-rolling tremor and diurnal fluctuation, and with minimal or no response to standard medications for parkinsonism.
Both interfamilial variability (i.e., wide variability of clinical presentation in individuals from unrelated families who have the same
Although
Phenotypes associated with certain pathogenic variants in multiple individuals include the following:
Individuals with the recurrent pathogenic variant p.Glu815Lys may have earlier onset of manifestations, more seizures, greater motor and cognitive impairment, and more rapid progression, including status epilepticus and respiratory paralysis, especially when compared to individuals with the other most common AHC pathogenic variant, p.Asp801Asn [
The prevalence of
• Paroxysmal episodes of hemiplegia alternating between right & left side &/or of quadriplegia
• Evidence of background abnormal neurologic development
• Presence of
• Onset before age 18 months
• Dystonia episodes
• Different types of episodes occurring independently or simultaneously w/evolution from one or more manifestations to different ones during the same episode
• Paroxysmal episodes of nystagmus
• Sleep-dependent spell improvement
• Occurrence of epileptic seizures
• Episodes of altered consciousness
• Abnormal motor function
• Episodes of autonomic dysfunction
• Oculomotor abnormalities (usually the earliest abnormalities seen), including monocular or binocular nystagmus, intermittent eso- or exotropia, skew deviation, ocular bobbing, and ocular flutter
• Tonic or dystonic episodes (in one or more limbs either unilaterally or generalized)
• Status dystonicus (sustained contractions of the limbs and potentially the axial musculature, which can be a medical emergency) [
• More complex dyskinesias, such as chorea of the limbs
• Episodes of quadriparesis or hemi- or quadriplegia (separate attacks or result from generalization of a hemiplegic episode
• Seizures and status epilepticus (i.e., a seizure with ≥5 minutes of continuous clinical and/or electrographic activity, or two or more seizures within a 5-minute period without recovery) [
• Seizure-like episodes without EEG correlation, including status dystonicus and psychogenic non-epileptic seizure (PNES)
• Autonomic phenomena either during hemiplegic episodes or independently, such as unilateral or bilateral pupillary dilatation, flushing, pallor affecting one limb or hemibody (i.e., either right or left half of the body)
• Impairment of speech and/or swallowing
• Respiratory distress with oxygen desaturation during episodes of neurologic dysfunction [
• Headache
• Non-motor interictal neurobehavioral/psychiatric manifestations including behavioral outbursts, impulsivity, aggression, and mood disorders [
• Developmental delay or other persistent neurologic disability, including speech and language delay [
• By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
• Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
• Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
• Oculomotor apraxia and strabismus can be present.
• Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
• Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
• Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
• Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
• By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
• Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
• Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
• Oculomotor apraxia and strabismus can be present.
• Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
• Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
• Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
• Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
• By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
• Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
• Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
• Oculomotor apraxia and strabismus can be present.
• Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
• Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
• Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
• Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
• Hypotonia, flaccidity, hyporeflexia, areflexia, pes cavus
• Dystonia and choreiform movements
• Abnormal eye movements (nystagmus, strabismus)
• Progressive optic nerve atrophy and vision loss
• Progressive sensorineural hearing loss
• Brief generalized tonic-clonic seizures
• Dysarthria/anarthria
• Dysphagia
• Cognitive dysfunction, including lethargy, loss of consciousness, and coma
• Neurobehavioral/psychiatric manifestations
• Triggering fevers usually accompany typical childhood illnesses, with or without identified infections; rarely, episodes occur during infections without fever.
• Many episodes involve generalized weakness, usually bilateral hypotonia but sometimes unilateral.
• Some episodes involve acute cerebellar ataxia, possibly with choreoathetosis or pyramidal signs.
• Manifestations can involve bulbar function, including dysarthria, dysphagia, difficulty swallowing, and/or drooling.
• Encephalopathy during fever in some individuals can manifest as impaired consciousness ranging from drowsiness to transient loss of consciousness to coma in rare instances. Other individuals have no alteration of consciousness.
• Mutism can be a principal manifestation during the febrile phase.
• Other manifestations that sometimes appear in the acute phase are brief dystonic episodes or paroxysmal stiffness, abnormal ocular movements, suspected seizure, areflexia, or facial grimaces.
• Cerebellar ataxia (often the most prominent feature during recovery) rather than weakness (Of note, while ataxia can be present during acute illness, it may not be obvious because of hypotonia.)
• Ocular movement abnormalities
• Dystonia and muscle rigidity
• Choreiform movements
• Areflexia
• Dysarthria, including speech difficulty (Severity varies widely between individuals.)
• Seizures (However, epilepsy is not a major feature.)
• Sustained reduced responsiveness, bradykinesia, and paraparesis (rare)
• Persistent motor deficits (particularly ataxia, dysarthria, and dystonia)
• Inability to walk independently
• Areflexia (In one individual, electromyogram indicated some distal denervation accompanying areflexia [
• Typically, onset is paroxysmal, or abrupt, over hours to several weeks. Although the arms and hands are usually affected first, most individuals – when first examined by a neurologist – have multifocal or generalized paroxysmal spells that can be difficult to distinguish from seizures, especially given that seizures are more common (31%) than paroxysmal events (7%) [
• Prominent bulbar findings include impairment of speech, voice, and swallowing [
• There is minimal or no tremor at onset.
• Onset often follows a physiologic stressor, such as physical activity, childbirth, infection, alcohol binge, or psychological stress [
• Preliminary analysis of 14 individuals with longitudinal follow up suggests severity of dystonia can vary over time, with most experiencing stability or mild worsening [Haq et al, unpublished data]. When present, bradykinesia is directly proportional to the severity of the dystonia and appears to be a function of the dystonia, without other parkinsonian features such as pill-rolling tremor and diurnal fluctuation, and with minimal or no response to standard medications for parkinsonism.
• Individuals with the recurrent pathogenic variant p.Glu815Lys may have earlier onset of manifestations, more seizures, greater motor and cognitive impairment, and more rapid progression, including status epilepticus and respiratory paralysis, especially when compared to individuals with the other most common AHC pathogenic variant, p.Asp801Asn [
## Clinical Description
Following the initial description of rapid-onset dystonia-parkinsonism (RDP) by
The overlapping clinical findings in the most common historically defined phenotypes of
Adapted with permission from
Criteria have been proposed whereby a diagnosis of AHC can be established in an individual with two mandatory features in addition to either three major features or two major and three minor features [
Alternating Hemiplegia of Childhood: Diagnostic Criteria
Paroxysmal episodes of hemiplegia alternating between right & left side &/or of quadriplegia
Evidence of background abnormal neurologic development
Presence of
Onset before age 18 months
Dystonia episodes
Different types of episodes occurring independently or simultaneously w/evolution from one or more manifestations to different ones during the same episode
Paroxysmal episodes of nystagmus
Sleep-dependent spell improvement
Occurrence of epileptic seizures
Episodes of altered consciousness
Abnormal motor function
Episodes of autonomic dysfunction
Other paroxysmal neurologic manifestations can include the following:
Oculomotor abnormalities (usually the earliest abnormalities seen), including monocular or binocular nystagmus, intermittent eso- or exotropia, skew deviation, ocular bobbing, and ocular flutter
Tonic or dystonic episodes (in one or more limbs either unilaterally or generalized)
Status dystonicus (sustained contractions of the limbs and potentially the axial musculature, which can be a medical emergency) [
More complex dyskinesias, such as chorea of the limbs
Episodes of quadriparesis or hemi- or quadriplegia (separate attacks or result from generalization of a hemiplegic episode
Seizures and status epilepticus (i.e., a seizure with ≥5 minutes of continuous clinical and/or electrographic activity, or two or more seizures within a 5-minute period without recovery) [
Seizure-like episodes without EEG correlation, including status dystonicus and psychogenic non-epileptic seizure (PNES)
Autonomic phenomena either during hemiplegic episodes or independently, such as unilateral or bilateral pupillary dilatation, flushing, pallor affecting one limb or hemibody (i.e., either right or left half of the body)
Impairment of speech and/or swallowing
Respiratory distress with oxygen desaturation during episodes of neurologic dysfunction [
Headache
Non-motor interictal neurobehavioral/psychiatric manifestations including behavioral outbursts, impulsivity, aggression, and mood disorders [
Developmental delay or other persistent neurologic disability, including speech and language delay [
By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
Oculomotor apraxia and strabismus can be present.
Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
Hypotonia, flaccidity, hyporeflexia, areflexia, pes cavus
Dystonia and choreiform movements
Abnormal eye movements (nystagmus, strabismus)
Progressive optic nerve atrophy and vision loss
Progressive sensorineural hearing loss
Brief generalized tonic-clonic seizures
Dysarthria/anarthria
Dysphagia
Cognitive dysfunction, including lethargy, loss of consciousness, and coma
Neurobehavioral/psychiatric manifestations
Triggering fevers usually accompany typical childhood illnesses, with or without identified infections; rarely, episodes occur during infections without fever.
Many episodes involve generalized weakness, usually bilateral hypotonia but sometimes unilateral.
Some episodes involve acute cerebellar ataxia, possibly with choreoathetosis or pyramidal signs.
Manifestations can involve bulbar function, including dysarthria, dysphagia, difficulty swallowing, and/or drooling.
Encephalopathy during fever in some individuals can manifest as impaired consciousness ranging from drowsiness to transient loss of consciousness to coma in rare instances. Other individuals have no alteration of consciousness.
Mutism can be a principal manifestation during the febrile phase.
Other manifestations that sometimes appear in the acute phase are brief dystonic episodes or paroxysmal stiffness, abnormal ocular movements, suspected seizure, areflexia, or facial grimaces.
While acute manifestations resolve gradually after the fever resolves, some manifestations persist, especially apraxia and ataxia [
During recovery from acute fever, motor manifestations that can also emerge include the following:
Cerebellar ataxia (often the most prominent feature during recovery) rather than weakness (Of note, while ataxia can be present during acute illness, it may not be obvious because of hypotonia.)
Ocular movement abnormalities
Dystonia and muscle rigidity
Choreiform movements
Areflexia
Dysarthria, including speech difficulty (Severity varies widely between individuals.)
Seizures (However, epilepsy is not a major feature.)
Sustained reduced responsiveness, bradykinesia, and paraparesis (rare)
After the acute phase, some manifestations may gradually worsen, including the following:
Persistent motor deficits (particularly ataxia, dysarthria, and dystonia)
Inability to walk independently
Areflexia (In one individual, electromyogram indicated some distal denervation accompanying areflexia [
While frank impairment of cognition is not common, cognitive delays and challenges with memory or concentration have been observed. Psychomotor delay prior to episodes has been reported.
Neurobehavioral/psychiatric manifestations, such as irritability, mood fluctuations, and anger outbursts have been reported but are not universal.
The RDP phenotype was initially named because its delayed and rapid onset was thought to be distinctive; however, over time it became apparent that dystonia and bradykinesia, its predominant manifestations, are common in the other ATP1A3-related phenotypes [
Primary onset occurs between ages four and 55 years (range: 9 months to >60 years) with dystonia characterized by the following (see
Typically, onset is paroxysmal, or abrupt, over hours to several weeks. Although the arms and hands are usually affected first, most individuals – when first examined by a neurologist – have multifocal or generalized paroxysmal spells that can be difficult to distinguish from seizures, especially given that seizures are more common (31%) than paroxysmal events (7%) [
Prominent bulbar findings include impairment of speech, voice, and swallowing [
There is minimal or no tremor at onset.
Onset often follows a physiologic stressor, such as physical activity, childbirth, infection, alcohol binge, or psychological stress [
Progression typically stops at or before one month after onset with little subsequent improvement.
Preliminary analysis of 14 individuals with longitudinal follow up suggests severity of dystonia can vary over time, with most experiencing stability or mild worsening [Haq et al, unpublished data]. When present, bradykinesia is directly proportional to the severity of the dystonia and appears to be a function of the dystonia, without other parkinsonian features such as pill-rolling tremor and diurnal fluctuation, and with minimal or no response to standard medications for parkinsonism.
Both interfamilial variability (i.e., wide variability of clinical presentation in individuals from unrelated families who have the same
• Paroxysmal episodes of hemiplegia alternating between right & left side &/or of quadriplegia
• Evidence of background abnormal neurologic development
• Presence of
• Onset before age 18 months
• Dystonia episodes
• Different types of episodes occurring independently or simultaneously w/evolution from one or more manifestations to different ones during the same episode
• Paroxysmal episodes of nystagmus
• Sleep-dependent spell improvement
• Occurrence of epileptic seizures
• Episodes of altered consciousness
• Abnormal motor function
• Episodes of autonomic dysfunction
• Oculomotor abnormalities (usually the earliest abnormalities seen), including monocular or binocular nystagmus, intermittent eso- or exotropia, skew deviation, ocular bobbing, and ocular flutter
• Tonic or dystonic episodes (in one or more limbs either unilaterally or generalized)
• Status dystonicus (sustained contractions of the limbs and potentially the axial musculature, which can be a medical emergency) [
• More complex dyskinesias, such as chorea of the limbs
• Episodes of quadriparesis or hemi- or quadriplegia (separate attacks or result from generalization of a hemiplegic episode
• Seizures and status epilepticus (i.e., a seizure with ≥5 minutes of continuous clinical and/or electrographic activity, or two or more seizures within a 5-minute period without recovery) [
• Seizure-like episodes without EEG correlation, including status dystonicus and psychogenic non-epileptic seizure (PNES)
• Autonomic phenomena either during hemiplegic episodes or independently, such as unilateral or bilateral pupillary dilatation, flushing, pallor affecting one limb or hemibody (i.e., either right or left half of the body)
• Impairment of speech and/or swallowing
• Respiratory distress with oxygen desaturation during episodes of neurologic dysfunction [
• Headache
• Non-motor interictal neurobehavioral/psychiatric manifestations including behavioral outbursts, impulsivity, aggression, and mood disorders [
• Developmental delay or other persistent neurologic disability, including speech and language delay [
• By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
• Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
• Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
• Oculomotor apraxia and strabismus can be present.
• Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
• Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
• Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
• Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
• By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
• Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
• Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
• Oculomotor apraxia and strabismus can be present.
• Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
• Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
• Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
• Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
• By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
• Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
• Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
• Oculomotor apraxia and strabismus can be present.
• Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
• Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
• Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
• Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
• Hypotonia, flaccidity, hyporeflexia, areflexia, pes cavus
• Dystonia and choreiform movements
• Abnormal eye movements (nystagmus, strabismus)
• Progressive optic nerve atrophy and vision loss
• Progressive sensorineural hearing loss
• Brief generalized tonic-clonic seizures
• Dysarthria/anarthria
• Dysphagia
• Cognitive dysfunction, including lethargy, loss of consciousness, and coma
• Neurobehavioral/psychiatric manifestations
• Triggering fevers usually accompany typical childhood illnesses, with or without identified infections; rarely, episodes occur during infections without fever.
• Many episodes involve generalized weakness, usually bilateral hypotonia but sometimes unilateral.
• Some episodes involve acute cerebellar ataxia, possibly with choreoathetosis or pyramidal signs.
• Manifestations can involve bulbar function, including dysarthria, dysphagia, difficulty swallowing, and/or drooling.
• Encephalopathy during fever in some individuals can manifest as impaired consciousness ranging from drowsiness to transient loss of consciousness to coma in rare instances. Other individuals have no alteration of consciousness.
• Mutism can be a principal manifestation during the febrile phase.
• Other manifestations that sometimes appear in the acute phase are brief dystonic episodes or paroxysmal stiffness, abnormal ocular movements, suspected seizure, areflexia, or facial grimaces.
• Cerebellar ataxia (often the most prominent feature during recovery) rather than weakness (Of note, while ataxia can be present during acute illness, it may not be obvious because of hypotonia.)
• Ocular movement abnormalities
• Dystonia and muscle rigidity
• Choreiform movements
• Areflexia
• Dysarthria, including speech difficulty (Severity varies widely between individuals.)
• Seizures (However, epilepsy is not a major feature.)
• Sustained reduced responsiveness, bradykinesia, and paraparesis (rare)
• Persistent motor deficits (particularly ataxia, dysarthria, and dystonia)
• Inability to walk independently
• Areflexia (In one individual, electromyogram indicated some distal denervation accompanying areflexia [
• Typically, onset is paroxysmal, or abrupt, over hours to several weeks. Although the arms and hands are usually affected first, most individuals – when first examined by a neurologist – have multifocal or generalized paroxysmal spells that can be difficult to distinguish from seizures, especially given that seizures are more common (31%) than paroxysmal events (7%) [
• Prominent bulbar findings include impairment of speech, voice, and swallowing [
• There is minimal or no tremor at onset.
• Onset often follows a physiologic stressor, such as physical activity, childbirth, infection, alcohol binge, or psychological stress [
• Preliminary analysis of 14 individuals with longitudinal follow up suggests severity of dystonia can vary over time, with most experiencing stability or mild worsening [Haq et al, unpublished data]. When present, bradykinesia is directly proportional to the severity of the dystonia and appears to be a function of the dystonia, without other parkinsonian features such as pill-rolling tremor and diurnal fluctuation, and with minimal or no response to standard medications for parkinsonism.
## AHC
Criteria have been proposed whereby a diagnosis of AHC can be established in an individual with two mandatory features in addition to either three major features or two major and three minor features [
Alternating Hemiplegia of Childhood: Diagnostic Criteria
Paroxysmal episodes of hemiplegia alternating between right & left side &/or of quadriplegia
Evidence of background abnormal neurologic development
Presence of
Onset before age 18 months
Dystonia episodes
Different types of episodes occurring independently or simultaneously w/evolution from one or more manifestations to different ones during the same episode
Paroxysmal episodes of nystagmus
Sleep-dependent spell improvement
Occurrence of epileptic seizures
Episodes of altered consciousness
Abnormal motor function
Episodes of autonomic dysfunction
Other paroxysmal neurologic manifestations can include the following:
Oculomotor abnormalities (usually the earliest abnormalities seen), including monocular or binocular nystagmus, intermittent eso- or exotropia, skew deviation, ocular bobbing, and ocular flutter
Tonic or dystonic episodes (in one or more limbs either unilaterally or generalized)
Status dystonicus (sustained contractions of the limbs and potentially the axial musculature, which can be a medical emergency) [
More complex dyskinesias, such as chorea of the limbs
Episodes of quadriparesis or hemi- or quadriplegia (separate attacks or result from generalization of a hemiplegic episode
Seizures and status epilepticus (i.e., a seizure with ≥5 minutes of continuous clinical and/or electrographic activity, or two or more seizures within a 5-minute period without recovery) [
Seizure-like episodes without EEG correlation, including status dystonicus and psychogenic non-epileptic seizure (PNES)
Autonomic phenomena either during hemiplegic episodes or independently, such as unilateral or bilateral pupillary dilatation, flushing, pallor affecting one limb or hemibody (i.e., either right or left half of the body)
Impairment of speech and/or swallowing
Respiratory distress with oxygen desaturation during episodes of neurologic dysfunction [
Headache
Non-motor interictal neurobehavioral/psychiatric manifestations including behavioral outbursts, impulsivity, aggression, and mood disorders [
Developmental delay or other persistent neurologic disability, including speech and language delay [
By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
Oculomotor apraxia and strabismus can be present.
Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
• Paroxysmal episodes of hemiplegia alternating between right & left side &/or of quadriplegia
• Evidence of background abnormal neurologic development
• Presence of
• Onset before age 18 months
• Dystonia episodes
• Different types of episodes occurring independently or simultaneously w/evolution from one or more manifestations to different ones during the same episode
• Paroxysmal episodes of nystagmus
• Sleep-dependent spell improvement
• Occurrence of epileptic seizures
• Episodes of altered consciousness
• Abnormal motor function
• Episodes of autonomic dysfunction
• Oculomotor abnormalities (usually the earliest abnormalities seen), including monocular or binocular nystagmus, intermittent eso- or exotropia, skew deviation, ocular bobbing, and ocular flutter
• Tonic or dystonic episodes (in one or more limbs either unilaterally or generalized)
• Status dystonicus (sustained contractions of the limbs and potentially the axial musculature, which can be a medical emergency) [
• More complex dyskinesias, such as chorea of the limbs
• Episodes of quadriparesis or hemi- or quadriplegia (separate attacks or result from generalization of a hemiplegic episode
• Seizures and status epilepticus (i.e., a seizure with ≥5 minutes of continuous clinical and/or electrographic activity, or two or more seizures within a 5-minute period without recovery) [
• Seizure-like episodes without EEG correlation, including status dystonicus and psychogenic non-epileptic seizure (PNES)
• Autonomic phenomena either during hemiplegic episodes or independently, such as unilateral or bilateral pupillary dilatation, flushing, pallor affecting one limb or hemibody (i.e., either right or left half of the body)
• Impairment of speech and/or swallowing
• Respiratory distress with oxygen desaturation during episodes of neurologic dysfunction [
• Headache
• Non-motor interictal neurobehavioral/psychiatric manifestations including behavioral outbursts, impulsivity, aggression, and mood disorders [
• Developmental delay or other persistent neurologic disability, including speech and language delay [
• By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
• Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
• Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
• Oculomotor apraxia and strabismus can be present.
• Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
• Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
• Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
• Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
• By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
• Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
• Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
• Oculomotor apraxia and strabismus can be present.
• Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
• Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
• Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
• Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
• By early childhood, more than 50% of children with AHC have clinical seizure activity, including focal, partial, or generalized tonic-clonic movements [
• Persistent motor abnormalities include ataxia, generalized or focal dystonia, choreoathetosis, and/or parkinsonism with tremor/bradykinesia/rigidity.
• Areflexia or hyperreflexia. Tone may be increased or decreased; thus, at different times affected individuals may find limb movement is either easier or more difficult.
• Oculomotor apraxia and strabismus can be present.
• Dysarthria can manifest as difficulty with subtle pronunciation of words or articulation more broadly.
• Dysphagia typically manifests initially as difficulty swallowing liquids compared with eating solid food, and is sometimes accompanied by drooling.
• Cognitive deficits include speech and language delay and developmental delay. Impairment of social skills can be in multiple domains [
• Neurobehavioral/psychiatric manifestations can include behavioral outbursts, impulsivity and aggression, and mood disorder [
## CAPOS Syndrome
Hypotonia, flaccidity, hyporeflexia, areflexia, pes cavus
Dystonia and choreiform movements
Abnormal eye movements (nystagmus, strabismus)
Progressive optic nerve atrophy and vision loss
Progressive sensorineural hearing loss
Brief generalized tonic-clonic seizures
Dysarthria/anarthria
Dysphagia
Cognitive dysfunction, including lethargy, loss of consciousness, and coma
Neurobehavioral/psychiatric manifestations
• Hypotonia, flaccidity, hyporeflexia, areflexia, pes cavus
• Dystonia and choreiform movements
• Abnormal eye movements (nystagmus, strabismus)
• Progressive optic nerve atrophy and vision loss
• Progressive sensorineural hearing loss
• Brief generalized tonic-clonic seizures
• Dysarthria/anarthria
• Dysphagia
• Cognitive dysfunction, including lethargy, loss of consciousness, and coma
• Neurobehavioral/psychiatric manifestations
## RECA/FIPWE
Triggering fevers usually accompany typical childhood illnesses, with or without identified infections; rarely, episodes occur during infections without fever.
Many episodes involve generalized weakness, usually bilateral hypotonia but sometimes unilateral.
Some episodes involve acute cerebellar ataxia, possibly with choreoathetosis or pyramidal signs.
Manifestations can involve bulbar function, including dysarthria, dysphagia, difficulty swallowing, and/or drooling.
Encephalopathy during fever in some individuals can manifest as impaired consciousness ranging from drowsiness to transient loss of consciousness to coma in rare instances. Other individuals have no alteration of consciousness.
Mutism can be a principal manifestation during the febrile phase.
Other manifestations that sometimes appear in the acute phase are brief dystonic episodes or paroxysmal stiffness, abnormal ocular movements, suspected seizure, areflexia, or facial grimaces.
While acute manifestations resolve gradually after the fever resolves, some manifestations persist, especially apraxia and ataxia [
During recovery from acute fever, motor manifestations that can also emerge include the following:
Cerebellar ataxia (often the most prominent feature during recovery) rather than weakness (Of note, while ataxia can be present during acute illness, it may not be obvious because of hypotonia.)
Ocular movement abnormalities
Dystonia and muscle rigidity
Choreiform movements
Areflexia
Dysarthria, including speech difficulty (Severity varies widely between individuals.)
Seizures (However, epilepsy is not a major feature.)
Sustained reduced responsiveness, bradykinesia, and paraparesis (rare)
After the acute phase, some manifestations may gradually worsen, including the following:
Persistent motor deficits (particularly ataxia, dysarthria, and dystonia)
Inability to walk independently
Areflexia (In one individual, electromyogram indicated some distal denervation accompanying areflexia [
While frank impairment of cognition is not common, cognitive delays and challenges with memory or concentration have been observed. Psychomotor delay prior to episodes has been reported.
Neurobehavioral/psychiatric manifestations, such as irritability, mood fluctuations, and anger outbursts have been reported but are not universal.
• Triggering fevers usually accompany typical childhood illnesses, with or without identified infections; rarely, episodes occur during infections without fever.
• Many episodes involve generalized weakness, usually bilateral hypotonia but sometimes unilateral.
• Some episodes involve acute cerebellar ataxia, possibly with choreoathetosis or pyramidal signs.
• Manifestations can involve bulbar function, including dysarthria, dysphagia, difficulty swallowing, and/or drooling.
• Encephalopathy during fever in some individuals can manifest as impaired consciousness ranging from drowsiness to transient loss of consciousness to coma in rare instances. Other individuals have no alteration of consciousness.
• Mutism can be a principal manifestation during the febrile phase.
• Other manifestations that sometimes appear in the acute phase are brief dystonic episodes or paroxysmal stiffness, abnormal ocular movements, suspected seizure, areflexia, or facial grimaces.
• Cerebellar ataxia (often the most prominent feature during recovery) rather than weakness (Of note, while ataxia can be present during acute illness, it may not be obvious because of hypotonia.)
• Ocular movement abnormalities
• Dystonia and muscle rigidity
• Choreiform movements
• Areflexia
• Dysarthria, including speech difficulty (Severity varies widely between individuals.)
• Seizures (However, epilepsy is not a major feature.)
• Sustained reduced responsiveness, bradykinesia, and paraparesis (rare)
• Persistent motor deficits (particularly ataxia, dysarthria, and dystonia)
• Inability to walk independently
• Areflexia (In one individual, electromyogram indicated some distal denervation accompanying areflexia [
## RDP
The RDP phenotype was initially named because its delayed and rapid onset was thought to be distinctive; however, over time it became apparent that dystonia and bradykinesia, its predominant manifestations, are common in the other ATP1A3-related phenotypes [
Primary onset occurs between ages four and 55 years (range: 9 months to >60 years) with dystonia characterized by the following (see
Typically, onset is paroxysmal, or abrupt, over hours to several weeks. Although the arms and hands are usually affected first, most individuals – when first examined by a neurologist – have multifocal or generalized paroxysmal spells that can be difficult to distinguish from seizures, especially given that seizures are more common (31%) than paroxysmal events (7%) [
Prominent bulbar findings include impairment of speech, voice, and swallowing [
There is minimal or no tremor at onset.
Onset often follows a physiologic stressor, such as physical activity, childbirth, infection, alcohol binge, or psychological stress [
Progression typically stops at or before one month after onset with little subsequent improvement.
Preliminary analysis of 14 individuals with longitudinal follow up suggests severity of dystonia can vary over time, with most experiencing stability or mild worsening [Haq et al, unpublished data]. When present, bradykinesia is directly proportional to the severity of the dystonia and appears to be a function of the dystonia, without other parkinsonian features such as pill-rolling tremor and diurnal fluctuation, and with minimal or no response to standard medications for parkinsonism.
• Typically, onset is paroxysmal, or abrupt, over hours to several weeks. Although the arms and hands are usually affected first, most individuals – when first examined by a neurologist – have multifocal or generalized paroxysmal spells that can be difficult to distinguish from seizures, especially given that seizures are more common (31%) than paroxysmal events (7%) [
• Prominent bulbar findings include impairment of speech, voice, and swallowing [
• There is minimal or no tremor at onset.
• Onset often follows a physiologic stressor, such as physical activity, childbirth, infection, alcohol binge, or psychological stress [
• Preliminary analysis of 14 individuals with longitudinal follow up suggests severity of dystonia can vary over time, with most experiencing stability or mild worsening [Haq et al, unpublished data]. When present, bradykinesia is directly proportional to the severity of the dystonia and appears to be a function of the dystonia, without other parkinsonian features such as pill-rolling tremor and diurnal fluctuation, and with minimal or no response to standard medications for parkinsonism.
## Interfamilial and Intrafamilial Variability
Both interfamilial variability (i.e., wide variability of clinical presentation in individuals from unrelated families who have the same
## Genotype-Phenotype Correlations
Although
Phenotypes associated with certain pathogenic variants in multiple individuals include the following:
Individuals with the recurrent pathogenic variant p.Glu815Lys may have earlier onset of manifestations, more seizures, greater motor and cognitive impairment, and more rapid progression, including status epilepticus and respiratory paralysis, especially when compared to individuals with the other most common AHC pathogenic variant, p.Asp801Asn [
• Individuals with the recurrent pathogenic variant p.Glu815Lys may have earlier onset of manifestations, more seizures, greater motor and cognitive impairment, and more rapid progression, including status epilepticus and respiratory paralysis, especially when compared to individuals with the other most common AHC pathogenic variant, p.Asp801Asn [
## Penetrance
## Nomenclature
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
Severe perinatal phenotypes associated with an
AHC = alternating hemiplegia of childhood; DD = developmental delay; ID = intellectual disability
## Differential Diagnosis
Given the early onset and protean neurologic manifestations in affected infants and young children, the differential diagnosis of alternating hemiplegia of childhood (AHC) is unavoidably broad. It is particularly important early in the diagnostic evaluation of an individual suspected of having AHC to exclude metabolic disorders or vascular syndromes that could benefit from specific therapeutic approaches, including moyamoya disease (OMIM
The often prolonged episodes of hemiparesis, dystonia, or quadriplegia observed early in the course of AHC are typically not associated with epileptiform activity on EEG, a finding that can help to distinguish AHC from early-infantile developmental and epileptic encephalopathy (OMIM
Specific disorders and alternative genetic etiologies to consider include those listed in
Selected Genes of Interest in the Differential Diagnosis of Alternating Hemiplegia of Childhood
AHC = alternating hemiplegia of childhood; AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; XL = X-linked
Despite the related genes and manifestations of hemiplegia and seizure,
The combination of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss is unique to CAPOS syndrome. However, an individual with the CAPOS syndrome-related
The differential diagnosis of fever-induced manifestations such as weakness and ataxia is broad and includes the episodic ataxias (see
Forms of dystonia-parkinsonism that are more common than rapid-onset dystonia-parkinsonism (RDP) (see
The differential diagnosis of RDP includes the genes listed in
Selected Genes of Interest in the Differential Diagnosis of Rapid-Onset Dystonia-Parkinsonism
Combined dystonia (dystonia + parkinsonism)
Dopa responsive
Differs from RDP in response to levodopa, which is minimal in those w/RDP,
AD = autosomal dominant; AR = autosomal recessive; DYT = dystonia; MOI = mode of inheritance; PARK = parkinsonism; RDP = rapid-onset dystonia-parkinsonism
• Combined dystonia (dystonia + parkinsonism)
• Dopa responsive
• Differs from RDP in response to levodopa, which is minimal in those w/RDP,
## Alternating Hemiplegia of Childhood
Given the early onset and protean neurologic manifestations in affected infants and young children, the differential diagnosis of alternating hemiplegia of childhood (AHC) is unavoidably broad. It is particularly important early in the diagnostic evaluation of an individual suspected of having AHC to exclude metabolic disorders or vascular syndromes that could benefit from specific therapeutic approaches, including moyamoya disease (OMIM
The often prolonged episodes of hemiparesis, dystonia, or quadriplegia observed early in the course of AHC are typically not associated with epileptiform activity on EEG, a finding that can help to distinguish AHC from early-infantile developmental and epileptic encephalopathy (OMIM
Specific disorders and alternative genetic etiologies to consider include those listed in
Selected Genes of Interest in the Differential Diagnosis of Alternating Hemiplegia of Childhood
AHC = alternating hemiplegia of childhood; AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance; XL = X-linked
Despite the related genes and manifestations of hemiplegia and seizure,
## CAPOS Syndrome
The combination of cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss is unique to CAPOS syndrome. However, an individual with the CAPOS syndrome-related
## RECA/FIPWE
The differential diagnosis of fever-induced manifestations such as weakness and ataxia is broad and includes the episodic ataxias (see
## Rapid-Onset Dystonia-Parkinsonism
Forms of dystonia-parkinsonism that are more common than rapid-onset dystonia-parkinsonism (RDP) (see
The differential diagnosis of RDP includes the genes listed in
Selected Genes of Interest in the Differential Diagnosis of Rapid-Onset Dystonia-Parkinsonism
Combined dystonia (dystonia + parkinsonism)
Dopa responsive
Differs from RDP in response to levodopa, which is minimal in those w/RDP,
AD = autosomal dominant; AR = autosomal recessive; DYT = dystonia; MOI = mode of inheritance; PARK = parkinsonism; RDP = rapid-onset dystonia-parkinsonism
• Combined dystonia (dystonia + parkinsonism)
• Dopa responsive
• Differs from RDP in response to levodopa, which is minimal in those w/RDP,
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Episodic or persistent weakness;
Movement disorders (e.g., dystonia, chorea, ataxia);
Dysfunctions of speech & swallowing;
Hypo- or hypertonia;
Cognitive manifestations (e.g., apraxia, frontal lobe dysfunction).
Seizures;
Headaches.
Gross motor & fine motor skills;
Contractures, pes cavus, kyphoscoliosis;
Mobility, ADL, need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement when aspiration risk is ↑.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / need for IEP services &/or 504 plan
Determine cognitive deficits or impairments.
Refer for guidance on interventions & support.
To assess for mood disorder (depression, anxiety, psychosis, OCD)
To assess for cognitive dysfunction, particularly language (esp fluency), executive function
Evaluate for cardiac conduction abnormalities.
Consider referral to cardiologist.
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; IEP= individualized education plan; MOI = mode of inheritance; OCD = obsessive-compulsive disorder; OT = occupational therapy; PT = physical therapy
In the US, a 504 plan involves legally required classroom accommodations or modifications (e.g., front-of-class seating, assistive technology devices, modified assignments).
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Some studies have suggested that flunarizine may be particularly efficacious in persons w/p.Glu815Lys variant.
Abrupt withdrawal of flunarizine has been assoc w/deterioration in clinical status.
In RDP, there is no known way to prevent abrupt onset of dystonia.
Caution is advised re side effects of sedation & mood/impulsivity as for persons w/movement disorders in general.
Benzodiazepines are used as rescue drugs in persons w/AHC.
Trial high-dose benzodiazepines in persons w/RDP.
Adult: place in quiet, dark room.
Child: put down for a nap.
For those w/dystonia: PT to prevent contractures in hands & feet
For all: consider need for positioning & mobility devices, disability parking placard.
Neurodevelopmental specialist;
PT, OT, speech therapist, &/or cognitive therapist.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / 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
ADL = activities of daily living; AHC = alternating hemiplegia of childhood; ASM = anti-seizure medication; OT = occupational therapy/therapist; PT = physical therapy/therapist
Pallidal deep brain stimulation has not been effective [
Flunarizine has remained the most prescribed therapy for prophylaxis of episodic neurologic dysfunction in AHC for more than two decades.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Per treating speech-language pathologist
Consider need for alternative means of communication (e.g.,
ADL = activities of daily living
To the extent possible, individuals who are heterozygous for an
Physical, psychological (e.g., missed meals, sleep deprivation), and emotional stress (e.g., excitement, fear)
Environmental stress (e.g., bright sunlight or fluorescent lighting, heat/cold, excessive noise, crowds)
Excessive or atypically strenuous exercise (e.g., walking farther than usual)
Alcohol binges
Illness, infections, and fever are common triggers. While practical preventive strategies are lacking, unnecessary exposure should be avoided.
Helmets and protective devices to prevent head injuries should be worn when participating in activities with risk of fall.
There is no known reason to avoid vaccinations.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with
See
It is recommended that during pregnancy a woman with
In principle, abortion or cesarean section could be sufficiently stressful to trigger an episode.
In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place before conception. Transitioning to a lower-risk ASM before pregnancy may be possible [
See
A clinical trial studying the variable phenotypic presentations of
Search
• Episodic or persistent weakness;
• Movement disorders (e.g., dystonia, chorea, ataxia);
• Dysfunctions of speech & swallowing;
• Hypo- or hypertonia;
• Cognitive manifestations (e.g., apraxia, frontal lobe dysfunction).
• Seizures;
• Headaches.
• Gross motor & fine motor skills;
• Contractures, pes cavus, kyphoscoliosis;
• Mobility, ADL, need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement when aspiration risk is ↑.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / need for IEP services &/or 504 plan
• Determine cognitive deficits or impairments.
• Refer for guidance on interventions & support.
• To assess for mood disorder (depression, anxiety, psychosis, OCD)
• To assess for cognitive dysfunction, particularly language (esp fluency), executive function
• Evaluate for cardiac conduction abnormalities.
• Consider referral to cardiologist.
• Community or
• Social work involvement for parental support
• Home nursing referral
• Some studies have suggested that flunarizine may be particularly efficacious in persons w/p.Glu815Lys variant.
• Abrupt withdrawal of flunarizine has been assoc w/deterioration in clinical status.
• In RDP, there is no known way to prevent abrupt onset of dystonia.
• Caution is advised re side effects of sedation & mood/impulsivity as for persons w/movement disorders in general.
• Benzodiazepines are used as rescue drugs in persons w/AHC.
• Trial high-dose benzodiazepines in persons w/RDP.
• Adult: place in quiet, dark room.
• Child: put down for a nap.
• For those w/dystonia: PT to prevent contractures in hands & feet
• For all: consider need for positioning & mobility devices, disability parking placard.
• Neurodevelopmental specialist;
• PT, OT, speech therapist, &/or cognitive therapist.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / 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
• Per treating speech-language pathologist
• Consider need for alternative means of communication (e.g.,
• Physical, psychological (e.g., missed meals, sleep deprivation), and emotional stress (e.g., excitement, fear)
• Environmental stress (e.g., bright sunlight or fluorescent lighting, heat/cold, excessive noise, crowds)
• Excessive or atypically strenuous exercise (e.g., walking farther than usual)
• Alcohol binges
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Episodic or persistent weakness;
Movement disorders (e.g., dystonia, chorea, ataxia);
Dysfunctions of speech & swallowing;
Hypo- or hypertonia;
Cognitive manifestations (e.g., apraxia, frontal lobe dysfunction).
Seizures;
Headaches.
Gross motor & fine motor skills;
Contractures, pes cavus, kyphoscoliosis;
Mobility, ADL, need for adaptive devices;
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement when aspiration risk is ↑.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / need for IEP services &/or 504 plan
Determine cognitive deficits or impairments.
Refer for guidance on interventions & support.
To assess for mood disorder (depression, anxiety, psychosis, OCD)
To assess for cognitive dysfunction, particularly language (esp fluency), executive function
Evaluate for cardiac conduction abnormalities.
Consider referral to cardiologist.
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; IEP= individualized education plan; MOI = mode of inheritance; OCD = obsessive-compulsive disorder; OT = occupational therapy; PT = physical therapy
In the US, a 504 plan involves legally required classroom accommodations or modifications (e.g., front-of-class seating, assistive technology devices, modified assignments).
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Episodic or persistent weakness;
• Movement disorders (e.g., dystonia, chorea, ataxia);
• Dysfunctions of speech & swallowing;
• Hypo- or hypertonia;
• Cognitive manifestations (e.g., apraxia, frontal lobe dysfunction).
• Seizures;
• Headaches.
• Gross motor & fine motor skills;
• Contractures, pes cavus, kyphoscoliosis;
• Mobility, ADL, need for adaptive devices;
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills).
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement when aspiration risk is ↑.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / need for IEP services &/or 504 plan
• Determine cognitive deficits or impairments.
• Refer for guidance on interventions & support.
• To assess for mood disorder (depression, anxiety, psychosis, OCD)
• To assess for cognitive dysfunction, particularly language (esp fluency), executive function
• Evaluate for cardiac conduction abnormalities.
• Consider referral to cardiologist.
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for
Some studies have suggested that flunarizine may be particularly efficacious in persons w/p.Glu815Lys variant.
Abrupt withdrawal of flunarizine has been assoc w/deterioration in clinical status.
In RDP, there is no known way to prevent abrupt onset of dystonia.
Caution is advised re side effects of sedation & mood/impulsivity as for persons w/movement disorders in general.
Benzodiazepines are used as rescue drugs in persons w/AHC.
Trial high-dose benzodiazepines in persons w/RDP.
Adult: place in quiet, dark room.
Child: put down for a nap.
For those w/dystonia: PT to prevent contractures in hands & feet
For all: consider need for positioning & mobility devices, disability parking placard.
Neurodevelopmental specialist;
PT, OT, speech therapist, &/or cognitive therapist.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / 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
ADL = activities of daily living; AHC = alternating hemiplegia of childhood; ASM = anti-seizure medication; OT = occupational therapy/therapist; PT = physical therapy/therapist
Pallidal deep brain stimulation has not been effective [
Flunarizine has remained the most prescribed therapy for prophylaxis of episodic neurologic dysfunction in AHC for more than two decades.
• Some studies have suggested that flunarizine may be particularly efficacious in persons w/p.Glu815Lys variant.
• Abrupt withdrawal of flunarizine has been assoc w/deterioration in clinical status.
• In RDP, there is no known way to prevent abrupt onset of dystonia.
• Caution is advised re side effects of sedation & mood/impulsivity as for persons w/movement disorders in general.
• Benzodiazepines are used as rescue drugs in persons w/AHC.
• Trial high-dose benzodiazepines in persons w/RDP.
• Adult: place in quiet, dark room.
• Child: put down for a nap.
• For those w/dystonia: PT to prevent contractures in hands & feet
• For all: consider need for positioning & mobility devices, disability parking placard.
• Neurodevelopmental specialist;
• PT, OT, speech therapist, &/or cognitive therapist.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / 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
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Per treating speech-language pathologist
Consider need for alternative means of communication (e.g.,
ADL = activities of daily living
• Per treating speech-language pathologist
• Consider need for alternative means of communication (e.g.,
## Agents/Circumstances to Avoid
To the extent possible, individuals who are heterozygous for an
Physical, psychological (e.g., missed meals, sleep deprivation), and emotional stress (e.g., excitement, fear)
Environmental stress (e.g., bright sunlight or fluorescent lighting, heat/cold, excessive noise, crowds)
Excessive or atypically strenuous exercise (e.g., walking farther than usual)
Alcohol binges
Illness, infections, and fever are common triggers. While practical preventive strategies are lacking, unnecessary exposure should be avoided.
Helmets and protective devices to prevent head injuries should be worn when participating in activities with risk of fall.
There is no known reason to avoid vaccinations.
• Physical, psychological (e.g., missed meals, sleep deprivation), and emotional stress (e.g., excitement, fear)
• Environmental stress (e.g., bright sunlight or fluorescent lighting, heat/cold, excessive noise, crowds)
• Excessive or atypically strenuous exercise (e.g., walking farther than usual)
• Alcohol binges
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk relatives of an individual with
See
## Pregnancy Management
It is recommended that during pregnancy a woman with
In principle, abortion or cesarean section could be sufficiently stressful to trigger an episode.
In general, women with epilepsy or a seizure disorder from any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place before conception. Transitioning to a lower-risk ASM before pregnancy may be possible [
See
## Therapies Under Investigation
A clinical trial studying the variable phenotypic presentations of
Search
## Genetic Counseling
Individuals with
Very rarely, individuals with a more severe
About half of individuals diagnosed with a relatively less severe
Some individuals with RDP have the disorder as the result of an
Individuals with
Most individuals with AHC have the disorder as the result of a
About half of individuals reported to date with CAPOS syndrome (53 individuals from 40 families) [
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
The proband has a
The proband inherited an
* A parent with somatic and gonadal mosaicism for an
The family history of some individuals diagnosed with
If a parent of a proband is affected and/or is known to have an
Sibs who inherit an
If the
If the parents have not been tested for the
See Management,
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.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
• Individuals with
• Very rarely, individuals with a more severe
• About half of individuals diagnosed with a relatively less severe
• Some individuals with RDP have the disorder as the result of an
• Very rarely, individuals with a more severe
• About half of individuals diagnosed with a relatively less severe
• Some individuals with RDP have the disorder as the result of an
• Individuals with
• Most individuals with AHC have the disorder as the result of a
• About half of individuals reported to date with CAPOS syndrome (53 individuals from 40 families) [
• Most individuals with AHC have the disorder as the result of a
• About half of individuals reported to date with CAPOS syndrome (53 individuals from 40 families) [
• 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
• The proband has a
• The proband inherited an
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited an
• * A parent with somatic and gonadal mosaicism for an
• The family history of some individuals diagnosed with
• Very rarely, individuals with a more severe
• About half of individuals diagnosed with a relatively less severe
• Some individuals with RDP have the disorder as the result of an
• Most individuals with AHC have the disorder as the result of a
• About half of individuals reported to date with CAPOS syndrome (53 individuals from 40 families) [
• The proband has a
• The proband inherited an
• * A parent with somatic and gonadal mosaicism for an
• If a parent of a proband is affected and/or is known to have an
• Sibs who inherit an
• 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Individuals with
Very rarely, individuals with a more severe
About half of individuals diagnosed with a relatively less severe
Some individuals with RDP have the disorder as the result of an
Individuals with
Most individuals with AHC have the disorder as the result of a
About half of individuals reported to date with CAPOS syndrome (53 individuals from 40 families) [
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
The proband has a
The proband inherited an
* A parent with somatic and gonadal mosaicism for an
The family history of some individuals diagnosed with
If a parent of a proband is affected and/or is known to have an
Sibs who inherit an
If the
If the parents have not been tested for the
• Individuals with
• Very rarely, individuals with a more severe
• About half of individuals diagnosed with a relatively less severe
• Some individuals with RDP have the disorder as the result of an
• Very rarely, individuals with a more severe
• About half of individuals diagnosed with a relatively less severe
• Some individuals with RDP have the disorder as the result of an
• Individuals with
• Most individuals with AHC have the disorder as the result of a
• About half of individuals reported to date with CAPOS syndrome (53 individuals from 40 families) [
• Most individuals with AHC have the disorder as the result of a
• About half of individuals reported to date with CAPOS syndrome (53 individuals from 40 families) [
• 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
• The proband has a
• The proband inherited an
• * A parent with somatic and gonadal mosaicism for an
• The proband has a
• The proband inherited an
• * A parent with somatic and gonadal mosaicism for an
• The family history of some individuals diagnosed with
• Very rarely, individuals with a more severe
• About half of individuals diagnosed with a relatively less severe
• Some individuals with RDP have the disorder as the result of an
• Most individuals with AHC have the disorder as the result of a
• About half of individuals reported to date with CAPOS syndrome (53 individuals from 40 families) [
• The proband has a
• The proband inherited an
• * A parent with somatic and gonadal mosaicism for an
• If a parent of a proband is affected and/or is known to have an
• Sibs who inherit an
• If the
• If the parents have not been tested for the
## Related Genetic Counseling Issues
See Management,
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.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Dystonia Medical Research Foundation
•
•
•
•
•
•
•
•
•
•
•
•
•
• Dystonia Medical Research Foundation
•
## Molecular Genetics
ATP1A3-Related Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for ATP1A3-Related Disorder (
The Na
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The Na
Variants listed in the table have been provided by the authors.
## Chapter Notes
Drs Brashear and Haq are actively involved in clinical research regarding individuals with
Contact Drs Sweadner and Ozelius to inquire about review of
The authors would like to thank Dr William B Dobyns and Dr Vicki Wheelock for their contributions to this research and all the families and patients who participated in this research.
Allison Brashear, MD (2008-present)Jared F Cook, MA; Wake Forest University School of Medicine (2014-2024)Ihtsham Haq, MD (2024-present)Eleonora Napoli, PhD (2024-present)Laurie Ozelius, PhD (2008-present)Kathleen J Sweadner, PhD (2008-present)Kathryn J Swoboda, MD; Massachusetts General Hospital (2014-2024)
5 December 2024 (bp) Comprehensive update posted live; title changed
22 February 2018 (ma) Comprehensive update posted live
6 November 2014 (me) Comprehensive update posted live; title changed
25 August 2011 (me) Comprehensive update posted live
7 February 2008 (me) Review posted live
5 October 2007 (ab) Original submission
• 5 December 2024 (bp) Comprehensive update posted live; title changed
• 22 February 2018 (ma) Comprehensive update posted live
• 6 November 2014 (me) Comprehensive update posted live; title changed
• 25 August 2011 (me) Comprehensive update posted live
• 7 February 2008 (me) Review posted live
• 5 October 2007 (ab) Original submission
## Author Notes
Drs Brashear and Haq are actively involved in clinical research regarding individuals with
Contact Drs Sweadner and Ozelius to inquire about review of
## Acknowledgments
The authors would like to thank Dr William B Dobyns and Dr Vicki Wheelock for their contributions to this research and all the families and patients who participated in this research.
## Author History
Allison Brashear, MD (2008-present)Jared F Cook, MA; Wake Forest University School of Medicine (2014-2024)Ihtsham Haq, MD (2024-present)Eleonora Napoli, PhD (2024-present)Laurie Ozelius, PhD (2008-present)Kathleen J Sweadner, PhD (2008-present)Kathryn J Swoboda, MD; Massachusetts General Hospital (2014-2024)
## Revision History
5 December 2024 (bp) Comprehensive update posted live; title changed
22 February 2018 (ma) Comprehensive update posted live
6 November 2014 (me) Comprehensive update posted live; title changed
25 August 2011 (me) Comprehensive update posted live
7 February 2008 (me) Review posted live
5 October 2007 (ab) Original submission
• 5 December 2024 (bp) Comprehensive update posted live; title changed
• 22 February 2018 (ma) Comprehensive update posted live
• 6 November 2014 (me) Comprehensive update posted live; title changed
• 25 August 2011 (me) Comprehensive update posted live
• 7 February 2008 (me) Review posted live
• 5 October 2007 (ab) Original submission
## References
## Literature Cited
In a cohort of individuals with
Reproduced with permission from
|
[] |
7/2/2008
|
5/12/2024
|
13/9/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
rasa1-rel-dis
|
rasa1-rel-dis
|
[
"CM-AVM Syndrome",
"CM-AVM Syndrome",
"RASA1 Parkes Weber Syndrome",
"Ephrin type-B receptor 4",
"Ras GTPase-activating protein 1",
"EPHB4",
"RASA1",
"Capillary Malformation-Arteriovenous Malformation Syndrome"
] |
Capillary Malformation-Arteriovenous Malformation Syndrome
|
Pinar Bayrak-Toydemir, David A Stevenson
|
Summary Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is characterized by the presence of multiple small (1-2 cm in diameter) capillary malformations mostly localized on the face and limbs. Some affected individuals also have associated arteriovenous malformations (AVMs) and/or arteriovenous fistulas (AFVs), fast-flow vascular anomalies that typically arise in the skin, muscle, bone, spine, and brain; life-threatening complications of these lesions can include bleeding, congestive heart failure, and/or neurologic consequences. Symptoms from intracranial AVMs/AVFs appear to occur early in life. Several individuals have Parkes Weber syndrome (multiple micro-AVFs associated with a cutaneous capillary stain and excessive soft-tissue and skeletal growth of an affected limb). The diagnosis of CM-AVM syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in CM-AVM syndrome is inherited in an autosomal dominant manner. For
|
For synonyms and outdated names see
For other genetic causes of this phenotype see
## Diagnosis
Diagnostic criteria for capillary malformation-arteriovenous malformation (CM-AVM) syndrome have been proposed but not systematically evaluated [
CM-AVM syndrome
Multifocal, atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo;
Composed of dilated capillaries in the papillary dermis [
Mostly localized on the face and limbs;
Seen in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVF), but may be the only finding [
The diagnosis of a CM-AVM syndrome
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 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 CM-AVM syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of CM-AVM syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
Note: (1) In
When the phenotype is indistinguishable from many other inherited disorders characterized by capillary malformations and/or arteriovenous malformations,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Capillary Malformation-Arteriovenous Malformation (CM-AVM) 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.
• Multifocal, atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo;
• Composed of dilated capillaries in the papillary dermis [
• Mostly localized on the face and limbs;
• Seen in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVF), but may be the only finding [
• Multifocal, atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo;
• Composed of dilated capillaries in the papillary dermis [
• Mostly localized on the face and limbs;
• Seen in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVF), but may be the only finding [
• Multifocal, atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo;
• Composed of dilated capillaries in the papillary dermis [
• Mostly localized on the face and limbs;
• Seen in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVF), but may be the only finding [
## Suggestive Findings
CM-AVM syndrome
Multifocal, atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo;
Composed of dilated capillaries in the papillary dermis [
Mostly localized on the face and limbs;
Seen in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVF), but may be the only finding [
• Multifocal, atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo;
• Composed of dilated capillaries in the papillary dermis [
• Mostly localized on the face and limbs;
• Seen in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVF), but may be the only finding [
• Multifocal, atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo;
• Composed of dilated capillaries in the papillary dermis [
• Mostly localized on the face and limbs;
• Seen in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVF), but may be the only finding [
• Multifocal, atypical pink-to-reddish brown, multiple, small (1-2 cm in diameter), round-to-oval lesions sometimes with a white halo;
• Composed of dilated capillaries in the papillary dermis [
• Mostly localized on the face and limbs;
• Seen in combination with arteriovenous malformations (AVMs) or arteriovenous fistulas (AVF), but may be the only finding [
## Establishing the Diagnosis
The diagnosis of a CM-AVM syndrome
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 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 CM-AVM syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of CM-AVM syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
Note: (1) In
When the phenotype is indistinguishable from many other inherited disorders characterized by capillary malformations and/or arteriovenous malformations,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Capillary Malformation-Arteriovenous Malformation (CM-AVM) 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.
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of CM-AVM syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
Note: (1) In
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by capillary malformations and/or arteriovenous malformations,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Capillary Malformation-Arteriovenous Malformation (CM-AVM) 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.
## Clinical Characteristics
The clinical manifestations of
The clinical manifestations of
Significant intra- and interfamilial variability in the existence and location of vascular malformations has been described.
Features of Capillary Malformation-Arteriovenous Malformation
13% extra-CNS
10% intra-CNS
Mostly AVM & extracranial
1% vein of Galen aneurysmal malformation
An ascertainment bias exists for the two studies included. In the first large study individuals were ascertained for CM-AVM syndrome [
Not all individuals with CM-AVM syndrome are likely to have had comprehensive imaging studies; therefore, the frequency of AVMs/AVFs is difficult to determine.
CMs are multiple round or oval pink lesions often with a blanched halo. CMs can be present at birth and tend to increase in number over time.
Arterial flow with Doppler ultrasound has been reported over the CMs [
Current data on long-term development of AVMs/AVFs after initial screening are insufficient. Although it has been hypothesized that AVMs/AVFs may develop over time [
Although approximately 50% of AVMs/AVFs have been reported to be in the head/neck region [
Symptomatic intraspinal AVMs resulting in neurologic deficits have been reported; MRI has identified intraspinous lesions requiring endovascular/surgical treatment [
AVMs/AVFs have not been commonly reported in viscera [
Limb overgrowth has been reported in both the upper and lower extremities in individuals with CM-AVM syndrome. The overgrowth is typically noticeable in infancy and can range in severity. Most individuals with limb overgrowth fulfill the findings of Parkes Weber syndrome, defined by
In particular, one third of individuals with
One infant with
One woman with
Nonimmune hydrops fetalis due to an AVM has been reported in
Congenital heart defects have been reported in a few individuals with
Studies to date are insufficient to identify genotype-phenotype correlations.
Prevalence of CM-AVM syndrome is estimated at 1:100,000 in northern Europeans [
• 13% extra-CNS
• 10% intra-CNS
• Mostly AVM & extracranial
• 1% vein of Galen aneurysmal malformation
## Clinical Description
The clinical manifestations of
The clinical manifestations of
Significant intra- and interfamilial variability in the existence and location of vascular malformations has been described.
Features of Capillary Malformation-Arteriovenous Malformation
13% extra-CNS
10% intra-CNS
Mostly AVM & extracranial
1% vein of Galen aneurysmal malformation
An ascertainment bias exists for the two studies included. In the first large study individuals were ascertained for CM-AVM syndrome [
Not all individuals with CM-AVM syndrome are likely to have had comprehensive imaging studies; therefore, the frequency of AVMs/AVFs is difficult to determine.
CMs are multiple round or oval pink lesions often with a blanched halo. CMs can be present at birth and tend to increase in number over time.
Arterial flow with Doppler ultrasound has been reported over the CMs [
Current data on long-term development of AVMs/AVFs after initial screening are insufficient. Although it has been hypothesized that AVMs/AVFs may develop over time [
Although approximately 50% of AVMs/AVFs have been reported to be in the head/neck region [
Symptomatic intraspinal AVMs resulting in neurologic deficits have been reported; MRI has identified intraspinous lesions requiring endovascular/surgical treatment [
AVMs/AVFs have not been commonly reported in viscera [
Limb overgrowth has been reported in both the upper and lower extremities in individuals with CM-AVM syndrome. The overgrowth is typically noticeable in infancy and can range in severity. Most individuals with limb overgrowth fulfill the findings of Parkes Weber syndrome, defined by
In particular, one third of individuals with
One infant with
One woman with
Nonimmune hydrops fetalis due to an AVM has been reported in
Congenital heart defects have been reported in a few individuals with
• 13% extra-CNS
• 10% intra-CNS
• Mostly AVM & extracranial
• 1% vein of Galen aneurysmal malformation
## Capillary Malformations (CMs)
CMs are multiple round or oval pink lesions often with a blanched halo. CMs can be present at birth and tend to increase in number over time.
Arterial flow with Doppler ultrasound has been reported over the CMs [
## Arteriovenous Malformations / Arteriovenous Fistulas (AVMs/AVFs)
Current data on long-term development of AVMs/AVFs after initial screening are insufficient. Although it has been hypothesized that AVMs/AVFs may develop over time [
Although approximately 50% of AVMs/AVFs have been reported to be in the head/neck region [
Symptomatic intraspinal AVMs resulting in neurologic deficits have been reported; MRI has identified intraspinous lesions requiring endovascular/surgical treatment [
AVMs/AVFs have not been commonly reported in viscera [
## Parkes Weber Syndrome
Limb overgrowth has been reported in both the upper and lower extremities in individuals with CM-AVM syndrome. The overgrowth is typically noticeable in infancy and can range in severity. Most individuals with limb overgrowth fulfill the findings of Parkes Weber syndrome, defined by
## Other
In particular, one third of individuals with
One infant with
One woman with
Nonimmune hydrops fetalis due to an AVM has been reported in
Congenital heart defects have been reported in a few individuals with
## Genotype-Phenotype Correlations
Studies to date are insufficient to identify genotype-phenotype correlations.
## Penetrance
## Nomenclature
## Prevalence
Prevalence of CM-AVM syndrome is estimated at 1:100,000 in northern Europeans [
## Genetically Related (Allelic) Disorders
Developmental delay and severe neurologic findings were reported in individuals with deletions encompassing
## Differential Diagnosis
Other Genes of Interest in the Differential Diagnosis of Capillary Malformation-Arteriovenous Malformation (CV-AVM) Syndrome
Spontaneous & recurrent nosebleeds (epistaxis) are more common.
Telangiectases generally only on lips, nose, & hands
~25% may have GI bleeding later in life.
Large capillary malformations are not typical.
Vascular anomalies are usually intramuscular, assoc w/ectopic fat, & severely disrupt tissue architecture.
Tumor predisposition is more prominent.
Small, multifocal bluish cutaneous &/or mucosal VMs, usually present at birth. New lesions appear w/time.
Small lesions are usually asymptomatic; larger lesions can invade subcutaneous muscle & cause pain.
Clinically GVM can look like any VM, but GVMs are more painful on palpation, only partially compressible, & usually not found in mucosa.
Lesions consist of glomus cells.
Familial aggregation is generally more common in hereditary GVM than in VMs.
AD = autosomal dominant; AVM = arteriovenous malformation; CM = capillary malformation; MOI = mode of inheritance; VM = venous malformation
The known hereditary hemorrhagic telangiectasia-related genes are involved in the TGF-β/BMP signaling cascade.
Somatic mosaic mutation of
Leptomeningeal angiomatosis most often involves the occipital and posterior parietal lobes.
No
Also referred to as Klippel-Trenaunay syndrome (KTS)
Mosaic variants in
Diagnostic criteria for KTS have been proposed [
Hereditary GVMs have a cobblestone appearance with a consistency harder than that of venous malformations. Histologically, glomuvenous malformations are distinguishable by the presence of pathognomonic rounded cells (glomus cells) around the distended vein-like channels [
• Spontaneous & recurrent nosebleeds (epistaxis) are more common.
• Telangiectases generally only on lips, nose, & hands
• ~25% may have GI bleeding later in life.
• Large capillary malformations are not typical.
• Vascular anomalies are usually intramuscular, assoc w/ectopic fat, & severely disrupt tissue architecture.
• Tumor predisposition is more prominent.
• Small, multifocal bluish cutaneous &/or mucosal VMs, usually present at birth. New lesions appear w/time.
• Small lesions are usually asymptomatic; larger lesions can invade subcutaneous muscle & cause pain.
• Clinically GVM can look like any VM, but GVMs are more painful on palpation, only partially compressible, & usually not found in mucosa.
• Lesions consist of glomus cells.
• Familial aggregation is generally more common in hereditary GVM than in VMs.
## Management
To establish the extent of disease and needs of an individual diagnosed with capillary malformation-arteriovenous malformation (CM-AVM) syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Medical history and physical examination with a focus on symptoms and findings secondary to arteriovenous malformations/arteriovenous fistulas (AVMs/AVFs)
Brain imaging – if not already performed – to identify AVMs/AVFs (e.g., vein of Galen aneurysms and other intracranial AVMs) to allow early identification of macrofistulas that can be treated prior to the development of symptoms [
Consideration of spine imaging to identify and characterize AVMs/AVFs. Currently no consensus protocols for radiographic evaluation of individuals with CM-AVM syndrome have been developed; therefore, discussion with a radiologist is recommended in order to develop an appropriate plan for imaging based on the patient's age and the capabilities and experience of the imaging facility.
Consideration of further imaging in individuals with evidence of cardiac overload, to look for causative AVMs/AVFs
Evaluation for evidence of epistaxis (nosebleeds), and if present, referral to otolaryngologist as appropriate. If epistaxis is present, consider complete blood count for evaluation of anemia.
Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations in Individuals with CM-AVM Syndrome
To determine treatment (e.g., embolization vs surgery)
Risks & benefits of intervention for AVMs & AVFs must be considered.
Lymphangiography to evaluate for lymphatic malformations;
Compression stockings for those w/evidence of lymphedema.
The clinician should have a low threshold to repeat imaging studies if clinical signs/symptoms of AVMs/AVFs become evident over time.
Although no agents/circumstances resulting in complications of CM-AVM syndrome have been reported, a theoretic consideration is avoidance of routine use of anticoagulants unless indicated for treatment of a different medical condition.
Clarification of the genetic status of at-risk relatives is appropriate in order to allow early diagnosis and treatment of AVMs/AVFs to reduce/avoid secondary adverse outcomes. In particular, at-risk infants are candidates for prompt diagnosis given the possible early presentation of neurologic complications from intracranial AVMs/AVFs [
Evaluations can include:
Molecular genetic testing if the
Physical evaluation of the skin to look for capillary malformations if the pathogenic variant in the family is not known.
See
Search
• Medical history and physical examination with a focus on symptoms and findings secondary to arteriovenous malformations/arteriovenous fistulas (AVMs/AVFs)
• Brain imaging – if not already performed – to identify AVMs/AVFs (e.g., vein of Galen aneurysms and other intracranial AVMs) to allow early identification of macrofistulas that can be treated prior to the development of symptoms [
• Consideration of spine imaging to identify and characterize AVMs/AVFs. Currently no consensus protocols for radiographic evaluation of individuals with CM-AVM syndrome have been developed; therefore, discussion with a radiologist is recommended in order to develop an appropriate plan for imaging based on the patient's age and the capabilities and experience of the imaging facility.
• Consideration of further imaging in individuals with evidence of cardiac overload, to look for causative AVMs/AVFs
• Evaluation for evidence of epistaxis (nosebleeds), and if present, referral to otolaryngologist as appropriate. If epistaxis is present, consider complete blood count for evaluation of anemia.
• Consultation with a clinical geneticist and/or genetic counselor
• To determine treatment (e.g., embolization vs surgery)
• Risks & benefits of intervention for AVMs & AVFs must be considered.
• Lymphangiography to evaluate for lymphatic malformations;
• Compression stockings for those w/evidence of lymphedema.
• Molecular genetic testing if the
• Physical evaluation of the skin to look for capillary malformations if the pathogenic variant in the family is not known.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with capillary malformation-arteriovenous malformation (CM-AVM) syndrome, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Medical history and physical examination with a focus on symptoms and findings secondary to arteriovenous malformations/arteriovenous fistulas (AVMs/AVFs)
Brain imaging – if not already performed – to identify AVMs/AVFs (e.g., vein of Galen aneurysms and other intracranial AVMs) to allow early identification of macrofistulas that can be treated prior to the development of symptoms [
Consideration of spine imaging to identify and characterize AVMs/AVFs. Currently no consensus protocols for radiographic evaluation of individuals with CM-AVM syndrome have been developed; therefore, discussion with a radiologist is recommended in order to develop an appropriate plan for imaging based on the patient's age and the capabilities and experience of the imaging facility.
Consideration of further imaging in individuals with evidence of cardiac overload, to look for causative AVMs/AVFs
Evaluation for evidence of epistaxis (nosebleeds), and if present, referral to otolaryngologist as appropriate. If epistaxis is present, consider complete blood count for evaluation of anemia.
Consultation with a clinical geneticist and/or genetic counselor
• Medical history and physical examination with a focus on symptoms and findings secondary to arteriovenous malformations/arteriovenous fistulas (AVMs/AVFs)
• Brain imaging – if not already performed – to identify AVMs/AVFs (e.g., vein of Galen aneurysms and other intracranial AVMs) to allow early identification of macrofistulas that can be treated prior to the development of symptoms [
• Consideration of spine imaging to identify and characterize AVMs/AVFs. Currently no consensus protocols for radiographic evaluation of individuals with CM-AVM syndrome have been developed; therefore, discussion with a radiologist is recommended in order to develop an appropriate plan for imaging based on the patient's age and the capabilities and experience of the imaging facility.
• Consideration of further imaging in individuals with evidence of cardiac overload, to look for causative AVMs/AVFs
• Evaluation for evidence of epistaxis (nosebleeds), and if present, referral to otolaryngologist as appropriate. If epistaxis is present, consider complete blood count for evaluation of anemia.
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Treatment of Manifestations in Individuals with CM-AVM Syndrome
To determine treatment (e.g., embolization vs surgery)
Risks & benefits of intervention for AVMs & AVFs must be considered.
Lymphangiography to evaluate for lymphatic malformations;
Compression stockings for those w/evidence of lymphedema.
• To determine treatment (e.g., embolization vs surgery)
• Risks & benefits of intervention for AVMs & AVFs must be considered.
• Lymphangiography to evaluate for lymphatic malformations;
• Compression stockings for those w/evidence of lymphedema.
## Surveillance
The clinician should have a low threshold to repeat imaging studies if clinical signs/symptoms of AVMs/AVFs become evident over time.
## Agents/Circumstances to Avoid
Although no agents/circumstances resulting in complications of CM-AVM syndrome have been reported, a theoretic consideration is avoidance of routine use of anticoagulants unless indicated for treatment of a different medical condition.
## Evaluation of Relatives at Risk
Clarification of the genetic status of at-risk relatives is appropriate in order to allow early diagnosis and treatment of AVMs/AVFs to reduce/avoid secondary adverse outcomes. In particular, at-risk infants are candidates for prompt diagnosis given the possible early presentation of neurologic complications from intracranial AVMs/AVFs [
Evaluations can include:
Molecular genetic testing if the
Physical evaluation of the skin to look for capillary malformations if the pathogenic variant in the family is not known.
See
• Molecular genetic testing if the
• Physical evaluation of the skin to look for capillary malformations if the pathogenic variant in the family is not known.
## Therapies Under Investigation
Search
## Genetic Counseling
Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is inherited in an autosomal dominant manner.
About 70% of individuals diagnosed with
A proband with CM-AVM syndrome 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 an individual diagnosed with CV-AVM syndrome 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband has 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 parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for CV-AVM syndrome because of the possibility of reduced penetrance in a 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 CV-AVM syndrome causative 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 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 70% of individuals diagnosed with
• A proband with CM-AVM syndrome 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 an individual diagnosed with CV-AVM syndrome 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband has 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 parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for CV-AVM syndrome because of the possibility of reduced penetrance in a 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
Capillary malformation-arteriovenous malformation (CM-AVM) syndrome is inherited in an autosomal dominant manner.
## Risk to Family Members
About 70% of individuals diagnosed with
A proband with CM-AVM syndrome 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 an individual diagnosed with CV-AVM syndrome 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband has 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 parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for CV-AVM syndrome because of the possibility of reduced penetrance in a parent.
• About 70% of individuals diagnosed with
• A proband with CM-AVM syndrome 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 an individual diagnosed with CV-AVM syndrome 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband has 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 parents have not been tested for the pathogenic variant but are clinically unaffected, the risk to the sibs of a proband appears to be low. However, the sibs of a proband with clinically unaffected parents are still at increased risk for CV-AVM syndrome because of the possibility of reduced penetrance in a 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 CV-AVM syndrome causative 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 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
No specific resources for Capillary Malformation-Arteriovenous Malformation Syndrome have been identified by
## Molecular Genetics
Capillary Malformation-Arteriovenous Malformation Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Capillary Malformation-Arteriovenous Malformation Syndrome (
The protein RASA1 switches the active GTP-bound Ras to the inactive GDP-bound form. It is a negative regulator of the Ras/MAPK-signaling pathway, which mediates cellular growth, differentiation, and proliferation from various protein kinases on cell surfaces.
Germline heterozygous
EPHB4 and its ligand, EphrinB2, are transmembrane proteins, receptor and ligand, respectively. These two proteins act in concert with Notch signaling to control arterial-venous differentiation. EphrinB2-EPHB4 interactions suppress RAS-MAPK-ERK1/2 and P13K-AKT-MTORC1 pathways [
Loss of function of
## Molecular Pathogenesis
The protein RASA1 switches the active GTP-bound Ras to the inactive GDP-bound form. It is a negative regulator of the Ras/MAPK-signaling pathway, which mediates cellular growth, differentiation, and proliferation from various protein kinases on cell surfaces.
Germline heterozygous
EPHB4 and its ligand, EphrinB2, are transmembrane proteins, receptor and ligand, respectively. These two proteins act in concert with Notch signaling to control arterial-venous differentiation. EphrinB2-EPHB4 interactions suppress RAS-MAPK-ERK1/2 and P13K-AKT-MTORC1 pathways [
Loss of function of
## Chapter Notes
We acknowledge Dr Johannes Fredrik Grimmer for his insights.
12 September 2019 (sw) Comprehensive update posted live
6 October 2016 (bp) Comprehensive update posted live
19 December 2013 (me) Comprehensive update posted live
22 February 2011 (me) Review posted live
6 December 2010 (pbt) Original submission
• 12 September 2019 (sw) Comprehensive update posted live
• 6 October 2016 (bp) Comprehensive update posted live
• 19 December 2013 (me) Comprehensive update posted live
• 22 February 2011 (me) Review posted live
• 6 December 2010 (pbt) Original submission
## Acknowledgments
We acknowledge Dr Johannes Fredrik Grimmer for his insights.
## Revision History
12 September 2019 (sw) Comprehensive update posted live
6 October 2016 (bp) Comprehensive update posted live
19 December 2013 (me) Comprehensive update posted live
22 February 2011 (me) Review posted live
6 December 2010 (pbt) Original submission
• 12 September 2019 (sw) Comprehensive update posted live
• 6 October 2016 (bp) Comprehensive update posted live
• 19 December 2013 (me) Comprehensive update posted live
• 22 February 2011 (me) Review posted live
• 6 December 2010 (pbt) Original submission
## References
## Literature Cited
|
[] |
22/2/2011
|
12/9/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
rbs
|
rbs
|
[
"Roberts Syndrome",
"SC Phocomelia Syndrome",
"N-acetyltransferase ESCO2",
"ESCO2",
"ESCO2 Spectrum Disorder"
] |
Hugo Vega, Miriam Gordillo, Ethylin Wang Jabs
|
Summary The diagnosis of
|
Roberts syndrome
SC phocomelia syndrome
For synonyms and outdated names see
• Roberts syndrome
• SC phocomelia syndrome
## Diagnosis
The diagnosis
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 [
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 subscription-based professional version 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.
Standard cytogenetic preparations stained with Giemsa or C-banding techniques show the characteristic chromosome abnormality of PCS and separation of the heterochromatic regions (heterochromatin repulsion; HR) in most chromosomes in all metaphases (see
Note: The centromere and the heterochromatin are affected in
Many chromosomes display a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers.
The heterochromatic region of the long arm of the Y chromosome is often widely separated in metaphase spreads.
Note: PCS/HR is different from premature sister chromatid separation (PSCS) described in
Aneuploidy, micronucleation, and multilobulated nuclei are also common findings in Roberts syndrome cell cultures.
•
•
• Many chromosomes display a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers.
• The heterochromatic region of the long arm of the Y chromosome is often widely separated in metaphase spreads.
## Suggestive Findings
•
•
## Establishing the Diagnosis
The diagnosis
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 [
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 subscription-based professional version 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.
Standard cytogenetic preparations stained with Giemsa or C-banding techniques show the characteristic chromosome abnormality of PCS and separation of the heterochromatic regions (heterochromatin repulsion; HR) in most chromosomes in all metaphases (see
Note: The centromere and the heterochromatin are affected in
Many chromosomes display a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers.
The heterochromatic region of the long arm of the Y chromosome is often widely separated in metaphase spreads.
Note: PCS/HR is different from premature sister chromatid separation (PSCS) described in
Aneuploidy, micronucleation, and multilobulated nuclei are also common findings in Roberts syndrome cell cultures.
• Many chromosomes display a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers.
• The heterochromatic region of the long arm of the Y chromosome is often widely separated in metaphase spreads.
## 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 subscription-based professional version 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.
## Cytogenetic Testing
Standard cytogenetic preparations stained with Giemsa or C-banding techniques show the characteristic chromosome abnormality of PCS and separation of the heterochromatic regions (heterochromatin repulsion; HR) in most chromosomes in all metaphases (see
Note: The centromere and the heterochromatin are affected in
Many chromosomes display a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers.
The heterochromatic region of the long arm of the Y chromosome is often widely separated in metaphase spreads.
Note: PCS/HR is different from premature sister chromatid separation (PSCS) described in
Aneuploidy, micronucleation, and multilobulated nuclei are also common findings in Roberts syndrome cell cultures.
• Many chromosomes display a "railroad track" appearance as a result of the absence of the primary constriction and presence of "puffing" or "repulsion" at the heterochromatic regions around the centromeres and nucleolar organizers.
• The heterochromatic region of the long arm of the Y chromosome is often widely separated in metaphase spreads.
## Clinical Characteristics
Upper limbs only (21%)
Upper & lower limbs (79%)
Knees, ankles, wrists, elbows, talipes equinovarus
Syndactyly (18%)
Flexion contractures (16%)
Enlarged phallus/clitoris (20%)
Cryptorchidism (13%)
ASD = atrial septal defect; PDA = persistent ductus arteriosus; VSD = ventricular septal defect
Upper limbs: radii, ulnae, and humeri;
Lower limbs: fibulae, tibiae, and femurs.
The degree of limb abnormality follows a cephalocaudal pattern: the upper limbs are more severely affected than the lower, with several individuals with upper limb-only malformations.
Mildly affected individuals have no palate abnormalities or only a high-arched palate. The most severely affected individuals have fronto-ethmoid-nasal-maxillary encephalocele.
Correlation between the degree of limb and facial involvement is observed; individuals with mild limb abnormalities also have mild craniofacial malformations, whereas those with severely affected limbs have extensive craniofacial abnormalities.
The cause of death has not been reported for most affected individuals. Reported causes are infection (5 individuals), aneurysm/hemorrhage (3 individuals), and malignancy (3 individuals) [
To date, correlation of
The term SC syndrome is based on the initials of the surnames of the two families described by
Other terms used for Roberts syndrome in the past include Appelt-Gerken-Lenz syndrome, hypomelia-hypotrichosis-facial hemangioma syndrome, tetraphocomelia-cleft palate syndrome, and pseudothalidomide syndrome.
Recurrent variants, including c.1131+1G>A and c.760dupA, have been identified in multiple unrelated individuals. In addition, founder variants c.505C>T and c.751dupG have been reported in individuals of Colombian ancestry, and the recurrent variant c.879_880delAG has been reported in individuals of Turkish and Pakistani ancestry. Pathogenic variant c.1132-7A>G has been identified in four unrelated individuals, always in compound heterozygous form (see
Parental consanguinity is common.
• Upper limbs only (21%)
• Upper & lower limbs (79%)
• Knees, ankles, wrists, elbows, talipes equinovarus
• Syndactyly (18%)
• Flexion contractures (16%)
• Enlarged phallus/clitoris (20%)
• Cryptorchidism (13%)
• Upper limbs: radii, ulnae, and humeri;
• Lower limbs: fibulae, tibiae, and femurs.
## Clinical Description
Upper limbs only (21%)
Upper & lower limbs (79%)
Knees, ankles, wrists, elbows, talipes equinovarus
Syndactyly (18%)
Flexion contractures (16%)
Enlarged phallus/clitoris (20%)
Cryptorchidism (13%)
ASD = atrial septal defect; PDA = persistent ductus arteriosus; VSD = ventricular septal defect
Upper limbs: radii, ulnae, and humeri;
Lower limbs: fibulae, tibiae, and femurs.
The degree of limb abnormality follows a cephalocaudal pattern: the upper limbs are more severely affected than the lower, with several individuals with upper limb-only malformations.
Mildly affected individuals have no palate abnormalities or only a high-arched palate. The most severely affected individuals have fronto-ethmoid-nasal-maxillary encephalocele.
Correlation between the degree of limb and facial involvement is observed; individuals with mild limb abnormalities also have mild craniofacial malformations, whereas those with severely affected limbs have extensive craniofacial abnormalities.
The cause of death has not been reported for most affected individuals. Reported causes are infection (5 individuals), aneurysm/hemorrhage (3 individuals), and malignancy (3 individuals) [
• Upper limbs only (21%)
• Upper & lower limbs (79%)
• Knees, ankles, wrists, elbows, talipes equinovarus
• Syndactyly (18%)
• Flexion contractures (16%)
• Enlarged phallus/clitoris (20%)
• Cryptorchidism (13%)
• Upper limbs: radii, ulnae, and humeri;
• Lower limbs: fibulae, tibiae, and femurs.
## Genotype-Phenotype Correlations
To date, correlation of
## Nomenclature
The term SC syndrome is based on the initials of the surnames of the two families described by
Other terms used for Roberts syndrome in the past include Appelt-Gerken-Lenz syndrome, hypomelia-hypotrichosis-facial hemangioma syndrome, tetraphocomelia-cleft palate syndrome, and pseudothalidomide syndrome.
## Prevalence
Recurrent variants, including c.1131+1G>A and c.760dupA, have been identified in multiple unrelated individuals. In addition, founder variants c.505C>T and c.751dupG have been reported in individuals of Colombian ancestry, and the recurrent variant c.879_880delAG has been reported in individuals of Turkish and Pakistani ancestry. Pathogenic variant c.1132-7A>G has been identified in four unrelated individuals, always in compound heterozygous form (see
Parental consanguinity is common.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
While some syndromes share some of the clinical features of
Genes of Interest in the Differential Diagnosis of
Bone marrow failure, ↑ risk for malignancy
Physical abnormalities (e.g., short stature, abnormal skin pigmentation, microcephaly, & ophthalmic & genitourinary tract anomalies)
Severe microcephaly, growth restriction, ID
Childhood cancer predisposition
Constitutional mosaicism for chromosome gains & losses
Cytogenetic findings: PCS/HR in
Generally transient thrombocytopenia (<50 platelets/nL)
Anomalies of vertebrae, heart, & genitourinary system
Disorder to consider in persons w/severe manifestations
Cleft lip & palate assoc w/skeletal changes such as absent radius suggests
Radial ray defect manifesting as oligodactyly; aplasia or hypoplasia of thumb &/or of radius
Patellar hypo- or aplasia becomes apparent in childhood.
Disorder to consider in persons w/severe manifestations
HOS can be excluded in persons w/congenital malformations of ulnar ray only, kidney, vertebra, craniofacies, auditory system (hearing loss or ear malformations), lower limb, anus, or eye.
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; ID = intellectual disability; MOI = mode of inheritance; PCD = premature centromere division; PCS/HR = premature centromere separation / heterochromatin repulsion; PSCS = premature sister chromatid separation; XL = X-linked
Fanconi anemia (FA) is inherited in an autosomal recessive manner, an autosomal dominant manner (
Craniofacial features include synophrys, arched eyebrows, long eyelashes, small nose with anteverted nares, small, widely spaced teeth, and microcephaly.
Phenotypic overlap of Baller-Gerold syndrome and Roberts syndrome was noted in an individual with bicoronal synostosis and bilateral radial hypoplasia, initially diagnosed with Baller-Gerold syndrome and later found to have premature centromere separation [
First introduced as a sedative agent, thalidomide was also used to treat morning sickness. It was withdrawn from the market in the 1960s because of reports of teratogenicity. Currently, thalidomide is used to treat various cancers and dermatologic, neurologic, and inflammatory diseases [
To reduce the risk of fetal exposure, the marketing and use of thalidomide in the United States is restricted through the mandatory System for Thalidomide Education and Prescribing Safety program [
• Bone marrow failure, ↑ risk for malignancy
• Physical abnormalities (e.g., short stature, abnormal skin pigmentation, microcephaly, & ophthalmic & genitourinary tract anomalies)
• Severe microcephaly, growth restriction, ID
• Childhood cancer predisposition
• Constitutional mosaicism for chromosome gains & losses
• Cytogenetic findings: PCS/HR in
• Generally transient thrombocytopenia (<50 platelets/nL)
• Anomalies of vertebrae, heart, & genitourinary system
• Disorder to consider in persons w/severe manifestations
• Cleft lip & palate assoc w/skeletal changes such as absent radius suggests
• Radial ray defect manifesting as oligodactyly; aplasia or hypoplasia of thumb &/or of radius
• Patellar hypo- or aplasia becomes apparent in childhood.
• Disorder to consider in persons w/severe manifestations
• HOS can be excluded in persons w/congenital malformations of ulnar ray only, kidney, vertebra, craniofacies, auditory system (hearing loss or ear malformations), lower limb, anus, or eye.
• First introduced as a sedative agent, thalidomide was also used to treat morning sickness. It was withdrawn from the market in the 1960s because of reports of teratogenicity. Currently, thalidomide is used to treat various cancers and dermatologic, neurologic, and inflammatory diseases [
• To reduce the risk of fetal exposure, the marketing and use of thalidomide in the United States is restricted through the mandatory System for Thalidomide Education and Prescribing Safety program [
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Gross motor & fine motor skills, contractures;
Need for adaptive devices to improve fine motor & gross motor skills;
Possible need for surgery to improve prehensile hand grasp &/or prostheses.
Effect of lip & palatal anomalies on feeding & speech development;
Need for surgical interventions.
Newborn: corneal opacities
Adolescence & early adulthood: cranial nerve III cavernous angioma
Motor, speech-language eval, & general cognitive skills
Eval for early intervention / special education
Full skin exam by dermatologist for risk of melanoma
Physical exam incl assessment of cranial nerves & musculoskeletal system for masses/pain & for other signs/symptoms of malignancy
Community or
Social work involvement for parental support
Home nursing referral
DD = developmental delay; ID = intellectual disability; Ig = immunoglobulin; MOI = mode of inheritance; OT = occupational therapist; PDA = patent ductus arteriosus; PT = physical therapist
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment is based on the affected individual's specific needs and may include the issues in
Assessment of caloric intake
High-calorie foods/formulas &/or supplementation via nasogastric or enteral feeding may be necessary.
Consider PT to improve range of motion & stretching, night splints, serial casts, surgery.
Avoid periods of prolonged immobilization (e.g., following surgery).
Specialized cleft bottles
Timing & type of surgical repair is determined by craniofacial team.
The earliest surgeries are surgical cleft lip/palate repairs, which are initially performed at age 10 wks; cleft palate is usually repaired at age 6-12 mos. The optimal age range for surgery for cleft palate is 18-24 mos.
Postoperative speech therapy is highly recommended.
Affected persons usually present w/fragile health that is occasionally accompanied by cardiac & kidney dysfunction; every anesthesia exposure & surgery may be life threatening.
If micrognathia is also present, may be evaluated for Pierre Robin sequence.
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; ID = intellectual disability; OT = occupational therapy/therapist; PT = physical therapy/therapist; SLP = speech-language pathologist
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.
As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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).
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Assess equipment & techniques for feeding infants w/cleft palate.
Determine surgical repair timing & type of procedure.
Audiologic eval as needed
In infants: visit frequency determined by feeding & respiratory issues
In children: varies depending on comorbidities; at least annually
Monitor developmental progress & educational needs, mobility, & self-care needs.
Assess for household barriers to mobility/self-help.
Speech assessment by SLP familiar w/cleft palate & neuromuscular contributors to speech issues
Consider speech therapy, surgical interventions, & augmentative communication devices.
ID = intellectual disability; Ig = immunoglobulin; OT = occupational therapist; PT = physical therapist; SLP = speech-language pathologist
See
Search
• Gross motor & fine motor skills, contractures;
• Need for adaptive devices to improve fine motor & gross motor skills;
• Possible need for surgery to improve prehensile hand grasp &/or prostheses.
• Effect of lip & palatal anomalies on feeding & speech development;
• Need for surgical interventions.
• Newborn: corneal opacities
• Adolescence & early adulthood: cranial nerve III cavernous angioma
• Motor, speech-language eval, & general cognitive skills
• Eval for early intervention / special education
• Full skin exam by dermatologist for risk of melanoma
• Physical exam incl assessment of cranial nerves & musculoskeletal system for masses/pain & for other signs/symptoms of malignancy
• Community or
• Social work involvement for parental support
• Home nursing referral
• Assessment of caloric intake
• High-calorie foods/formulas &/or supplementation via nasogastric or enteral feeding may be necessary.
• Consider PT to improve range of motion & stretching, night splints, serial casts, surgery.
• Avoid periods of prolonged immobilization (e.g., following surgery).
• Specialized cleft bottles
• Timing & type of surgical repair is determined by craniofacial team.
• The earliest surgeries are surgical cleft lip/palate repairs, which are initially performed at age 10 wks; cleft palate is usually repaired at age 6-12 mos. The optimal age range for surgery for cleft palate is 18-24 mos.
• Postoperative speech therapy is highly recommended.
• Affected persons usually present w/fragile health that is occasionally accompanied by cardiac & kidney dysfunction; every anesthesia exposure & surgery may be life threatening.
• If micrognathia is also present, may be evaluated for Pierre Robin sequence.
• 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.
• As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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.
• As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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.
• As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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).
• Assess equipment & techniques for feeding infants w/cleft palate.
• Determine surgical repair timing & type of procedure.
• Audiologic eval as needed
• In infants: visit frequency determined by feeding & respiratory issues
• In children: varies depending on comorbidities; at least annually
• Monitor developmental progress & educational needs, mobility, & self-care needs.
• Assess for household barriers to mobility/self-help.
• Speech assessment by SLP familiar w/cleft palate & neuromuscular contributors to speech issues
• Consider speech therapy, surgical interventions, & augmentative communication devices.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Gross motor & fine motor skills, contractures;
Need for adaptive devices to improve fine motor & gross motor skills;
Possible need for surgery to improve prehensile hand grasp &/or prostheses.
Effect of lip & palatal anomalies on feeding & speech development;
Need for surgical interventions.
Newborn: corneal opacities
Adolescence & early adulthood: cranial nerve III cavernous angioma
Motor, speech-language eval, & general cognitive skills
Eval for early intervention / special education
Full skin exam by dermatologist for risk of melanoma
Physical exam incl assessment of cranial nerves & musculoskeletal system for masses/pain & for other signs/symptoms of malignancy
Community or
Social work involvement for parental support
Home nursing referral
DD = developmental delay; ID = intellectual disability; Ig = immunoglobulin; MOI = mode of inheritance; OT = occupational therapist; PDA = patent ductus arteriosus; PT = physical therapist
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Gross motor & fine motor skills, contractures;
• Need for adaptive devices to improve fine motor & gross motor skills;
• Possible need for surgery to improve prehensile hand grasp &/or prostheses.
• Effect of lip & palatal anomalies on feeding & speech development;
• Need for surgical interventions.
• Newborn: corneal opacities
• Adolescence & early adulthood: cranial nerve III cavernous angioma
• Motor, speech-language eval, & general cognitive skills
• Eval for early intervention / special education
• Full skin exam by dermatologist for risk of melanoma
• Physical exam incl assessment of cranial nerves & musculoskeletal system for masses/pain & for other signs/symptoms of malignancy
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
Treatment is based on the affected individual's specific needs and may include the issues in
Assessment of caloric intake
High-calorie foods/formulas &/or supplementation via nasogastric or enteral feeding may be necessary.
Consider PT to improve range of motion & stretching, night splints, serial casts, surgery.
Avoid periods of prolonged immobilization (e.g., following surgery).
Specialized cleft bottles
Timing & type of surgical repair is determined by craniofacial team.
The earliest surgeries are surgical cleft lip/palate repairs, which are initially performed at age 10 wks; cleft palate is usually repaired at age 6-12 mos. The optimal age range for surgery for cleft palate is 18-24 mos.
Postoperative speech therapy is highly recommended.
Affected persons usually present w/fragile health that is occasionally accompanied by cardiac & kidney dysfunction; every anesthesia exposure & surgery may be life threatening.
If micrognathia is also present, may be evaluated for Pierre Robin sequence.
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; ID = intellectual disability; OT = occupational therapy/therapist; PT = physical therapy/therapist; SLP = speech-language pathologist
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.
As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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).
• Assessment of caloric intake
• High-calorie foods/formulas &/or supplementation via nasogastric or enteral feeding may be necessary.
• Consider PT to improve range of motion & stretching, night splints, serial casts, surgery.
• Avoid periods of prolonged immobilization (e.g., following surgery).
• Specialized cleft bottles
• Timing & type of surgical repair is determined by craniofacial team.
• The earliest surgeries are surgical cleft lip/palate repairs, which are initially performed at age 10 wks; cleft palate is usually repaired at age 6-12 mos. The optimal age range for surgery for cleft palate is 18-24 mos.
• Postoperative speech therapy is highly recommended.
• Affected persons usually present w/fragile health that is occasionally accompanied by cardiac & kidney dysfunction; every anesthesia exposure & surgery may be life threatening.
• If micrognathia is also present, may be evaluated for Pierre Robin sequence.
• 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.
• As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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.
• As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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.
• As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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.
As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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.
• As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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.
• As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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.
• As required by special education law, children should be in the least restrictive 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 the teen years, a transition plan should 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).
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Assess equipment & techniques for feeding infants w/cleft palate.
Determine surgical repair timing & type of procedure.
Audiologic eval as needed
In infants: visit frequency determined by feeding & respiratory issues
In children: varies depending on comorbidities; at least annually
Monitor developmental progress & educational needs, mobility, & self-care needs.
Assess for household barriers to mobility/self-help.
Speech assessment by SLP familiar w/cleft palate & neuromuscular contributors to speech issues
Consider speech therapy, surgical interventions, & augmentative communication devices.
ID = intellectual disability; Ig = immunoglobulin; OT = occupational therapist; PT = physical therapist; SLP = speech-language pathologist
• Assess equipment & techniques for feeding infants w/cleft palate.
• Determine surgical repair timing & type of procedure.
• Audiologic eval as needed
• In infants: visit frequency determined by feeding & respiratory issues
• In children: varies depending on comorbidities; at least annually
• Monitor developmental progress & educational needs, mobility, & self-care needs.
• Assess for household barriers to mobility/self-help.
• Speech assessment by SLP familiar w/cleft palate & neuromuscular contributors to speech issues
• Consider speech therapy, surgical interventions, & augmentative communication devices.
## Evaluation of Relatives at Risk
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
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Pregnancies in individuals with an
The offspring of an individual with an
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 the parents of affected children and 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 be heterozygous for an
Note: The sensitivity of prenatal ultrasound examination for ESCO2 spectrum disorder is 41%-65% [
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.
• Pregnancies in individuals with an
• The offspring of an individual with 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 the parents of affected children and 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 be heterozygous for an
• Note: The sensitivity of prenatal ultrasound examination for ESCO2 spectrum disorder is 41%-65% [
## 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
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Pregnancies in individuals with an
The offspring of an individual with an
• 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.
• Pregnancies in individuals with an
• The offspring of an individual with an
## 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 the parents of affected children and 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 be 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 the parents of affected children and 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 be heterozygous for an
## Prenatal Testing and Preimplantation Genetic Testing
Note: The sensitivity of prenatal ultrasound examination for ESCO2 spectrum disorder is 41%-65% [
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.
• Note: The sensitivity of prenatal ultrasound examination for ESCO2 spectrum disorder is 41%-65% [
## Resources
United Kingdom
United Kingdom
•
•
•
• United Kingdom
•
•
•
• United Kingdom
•
## Molecular Genetics
ESCO2 Spectrum Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for ESCO2 Spectrum Disorder (
Without ESCO2, metaphase chromosomes lack primary constrictions and show impaired centromeric cohesion; however, the sister chromatids are held together by arm cohesion, allowing their metaphase alignment. Cells proceed to anaphase despite the lack of centromeric cohesion [
There is evidence that cohesin binding contributes to the formation of DNA loops, allowing the physical association of distant promoters or enhancers that affect gene transcription. Although cells in
To date, 35 different
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
Without ESCO2, metaphase chromosomes lack primary constrictions and show impaired centromeric cohesion; however, the sister chromatids are held together by arm cohesion, allowing their metaphase alignment. Cells proceed to anaphase despite the lack of centromeric cohesion [
There is evidence that cohesin binding contributes to the formation of DNA loops, allowing the physical association of distant promoters or enhancers that affect gene transcription. Although cells in
To date, 35 different
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
Hugo Vega (
14 August 2025 (sw) Comprehensive update posted live
26 March 2020 (bp) Comprehensive update posted live
14 November 2013 (me) Comprehensive update posted live
2 October 2008 (me) Comprehensive update posted live
18 April 2006 (me) Review posted live
2 December 2005 (ewj) Original submission
• 14 August 2025 (sw) Comprehensive update posted live
• 26 March 2020 (bp) Comprehensive update posted live
• 14 November 2013 (me) Comprehensive update posted live
• 2 October 2008 (me) Comprehensive update posted live
• 18 April 2006 (me) Review posted live
• 2 December 2005 (ewj) Original submission
## Author Notes
Hugo Vega (
## Revision History
14 August 2025 (sw) Comprehensive update posted live
26 March 2020 (bp) Comprehensive update posted live
14 November 2013 (me) Comprehensive update posted live
2 October 2008 (me) Comprehensive update posted live
18 April 2006 (me) Review posted live
2 December 2005 (ewj) Original submission
• 14 August 2025 (sw) Comprehensive update posted live
• 26 March 2020 (bp) Comprehensive update posted live
• 14 November 2013 (me) Comprehensive update posted live
• 2 October 2008 (me) Comprehensive update posted live
• 18 April 2006 (me) Review posted live
• 2 December 2005 (ewj) Original submission
## References
## Literature Cited
C-banding of metaphase chromosomes. Arrows show selected chromosomes with premature centromere separation. Solid black arrowhead points to "splitting" of the Y chromosome heterochromatic region. Open arrowheads show selected chromosomes with normal C-banded regions.
Reprinted with permission from
|
[] |
18/4/2006
|
14/8/2025
|
14/4/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
rcdp
|
rcdp
|
[
"PEX7-Rhizomelic CDP",
"Rhizomelic Chondrodysplasia Punctata Type 1",
"Rhizomelic Chondrodysplasia Punctata Type 1",
"PEX7-Rhizomelic CDP",
"Peroxisomal targeting signal 2 receptor",
"PEX7",
"PEX7-Related Rhizomelic Chondrodysplasia Punctata"
] |
Nancy E Braverman, Ricki Carroll, Wedad Fallatah, Mahim Jain
|
Summary The diagnosis of
|
## Diagnosis
Congenital cataracts
Skeletal/radiographic findings
Rhizomelia (proximal shortening of the long bones)
Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
Cataracts (usually apparent by age 6 months)
Severe intellectual disability
Profound postnatal growth restriction
Evolution of skeletal/radiographic findings:
Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
Possible calcification of the intervertebral discs (See
Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
Congenital or childhood cataracts
CDP or, infrequently, chondrodysplasia manifesting as mild epiphyseal changes only (See
Joint contractures
Developmental delays and learning disability
Milder growth restriction than classic
Behavioral issues
The finding of deficiency of plasmalogens in red blood cells (RBC), increased plasma concentration of phytanic acid (when diet includes phytanic acid sources), and normal plasma concentration of very long-chain fatty acids (VLCFA) has consistently predicted the
Plasmalogen levels are valuable in distinguishing between classic and milder
Plasmalogens are a unique class of ether glycerophospholipids (GPs) containing a fatty alcohol with a vinyl ether bond at the sn-1 position, and enriched in polyunsaturated fatty acids at the sn-2 position of the glycerol backbone.
Plasmalogens were traditionally measured in RBC by gas chromatography-mass spectrometry (GC-MS), which detects the relative amounts of C16:0, C18:0, and C18:1 plasmalogens as dimethyl acetal derivatives of the ether-linked alkenes [
Recently, the GC-MS method was expanded to utilize dried blood spots in addition to RBC [
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
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 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
Sequence analysis 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.
Exon and multiexon
• Congenital cataracts
• Skeletal/radiographic findings
• Rhizomelia (proximal shortening of the long bones)
• Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
• Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
• Rhizomelia (proximal shortening of the long bones)
• Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
• Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
• Rhizomelia (proximal shortening of the long bones)
• Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
• Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
• Cataracts (usually apparent by age 6 months)
• Severe intellectual disability
• Profound postnatal growth restriction
• Evolution of skeletal/radiographic findings:
• Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
• Possible calcification of the intervertebral discs (See
• Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
• Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
• Possible calcification of the intervertebral discs (See
• Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
• Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
• Possible calcification of the intervertebral discs (See
• Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
• Congenital or childhood cataracts
• CDP or, infrequently, chondrodysplasia manifesting as mild epiphyseal changes only (See
• Joint contractures
• Developmental delays and learning disability
• Milder growth restriction than classic
• Behavioral issues
## Suggestive Findings
Congenital cataracts
Skeletal/radiographic findings
Rhizomelia (proximal shortening of the long bones)
Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
Cataracts (usually apparent by age 6 months)
Severe intellectual disability
Profound postnatal growth restriction
Evolution of skeletal/radiographic findings:
Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
Possible calcification of the intervertebral discs (See
Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
Congenital or childhood cataracts
CDP or, infrequently, chondrodysplasia manifesting as mild epiphyseal changes only (See
Joint contractures
Developmental delays and learning disability
Milder growth restriction than classic
Behavioral issues
• Congenital cataracts
• Skeletal/radiographic findings
• Rhizomelia (proximal shortening of the long bones)
• Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
• Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
• Rhizomelia (proximal shortening of the long bones)
• Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
• Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
• Rhizomelia (proximal shortening of the long bones)
• Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
• Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
• Cataracts (usually apparent by age 6 months)
• Severe intellectual disability
• Profound postnatal growth restriction
• Evolution of skeletal/radiographic findings:
• Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
• Possible calcification of the intervertebral discs (See
• Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
• Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
• Possible calcification of the intervertebral discs (See
• Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
• Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
• Possible calcification of the intervertebral discs (See
• Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
• Congenital or childhood cataracts
• CDP or, infrequently, chondrodysplasia manifesting as mild epiphyseal changes only (See
• Joint contractures
• Developmental delays and learning disability
• Milder growth restriction than classic
• Behavioral issues
## Classic (Severe)
Congenital cataracts
Skeletal/radiographic findings
Rhizomelia (proximal shortening of the long bones)
Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
Cataracts (usually apparent by age 6 months)
Severe intellectual disability
Profound postnatal growth restriction
Evolution of skeletal/radiographic findings:
Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
Possible calcification of the intervertebral discs (See
Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
• Congenital cataracts
• Skeletal/radiographic findings
• Rhizomelia (proximal shortening of the long bones)
• Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
• Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
• Rhizomelia (proximal shortening of the long bones)
• Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
• Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
• Rhizomelia (proximal shortening of the long bones)
• Chondrodysplasia punctata (CDP). Punctate calcifications observed in radiographs in the epiphyseal cartilage at the knee, hip, elbow, and shoulder that can be more extensive, involving the hyoid bone, larynx, costochondral junctions, and vertebrae. Metaphyseal abnormalities may be present (see
• Radiolucent coronal clefts of the vertebral bodies on lateral spine radiographs that represent unossified cartilage (See
• Cataracts (usually apparent by age 6 months)
• Severe intellectual disability
• Profound postnatal growth restriction
• Evolution of skeletal/radiographic findings:
• Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
• Possible calcification of the intervertebral discs (See
• Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
• Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
• Possible calcification of the intervertebral discs (See
• Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
• Resolution of the punctate calcifications leaving abnormal epiphyses and flared and irregular metaphyses after ages one to three years (See
• Possible calcification of the intervertebral discs (See
• Frontal bossing and a short, concave nasal bridge resulting from cartilaginous involvement (See
## Nonclassic (Mild)
Congenital or childhood cataracts
CDP or, infrequently, chondrodysplasia manifesting as mild epiphyseal changes only (See
Joint contractures
Developmental delays and learning disability
Milder growth restriction than classic
Behavioral issues
• Congenital or childhood cataracts
• CDP or, infrequently, chondrodysplasia manifesting as mild epiphyseal changes only (See
• Joint contractures
• Developmental delays and learning disability
• Milder growth restriction than classic
• Behavioral issues
## Biochemical Testing
The finding of deficiency of plasmalogens in red blood cells (RBC), increased plasma concentration of phytanic acid (when diet includes phytanic acid sources), and normal plasma concentration of very long-chain fatty acids (VLCFA) has consistently predicted the
Plasmalogen levels are valuable in distinguishing between classic and milder
Plasmalogens are a unique class of ether glycerophospholipids (GPs) containing a fatty alcohol with a vinyl ether bond at the sn-1 position, and enriched in polyunsaturated fatty acids at the sn-2 position of the glycerol backbone.
Plasmalogens were traditionally measured in RBC by gas chromatography-mass spectrometry (GC-MS), which detects the relative amounts of C16:0, C18:0, and C18:1 plasmalogens as dimethyl acetal derivatives of the ether-linked alkenes [
Recently, the GC-MS method was expanded to utilize dried blood spots in addition to RBC [
## 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
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 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
Sequence analysis 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.
Exon and multiexon
## Option 1
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 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
Sequence analysis 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.
Exon and multiexon
## Clinical Characteristics
The characteristic clinical features of classic
In a study including spine MRIs of children with classic
Recurrent calcium oxalate stones were identified in three of 24 individuals followed at one skeletal dysplasia clinic that could be related to chronic heart and lung disease, or bone demineralization from reduced mobility [C Muss & M Jain, personal observations].
Other malformations observed in one affected individual include: ureteropelvic junction obstruction [
This group is defined clinically by the ability to walk with or without support and the ability to use verbal or nonverbal types of communication [
Correlations between the predicted severity of
All individuals homozygous for the
In individuals who are compound heterozygotes for p.Leu292Ter and another pathogenic variant, the effect of the other allele is important in determining the phenotype. Several
The hypomorphic variant
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023],
The birth prevalence of
The high frequency of the
The hypomorphic variant
• Recurrent calcium oxalate stones were identified in three of 24 individuals followed at one skeletal dysplasia clinic that could be related to chronic heart and lung disease, or bone demineralization from reduced mobility [C Muss & M Jain, personal observations].
• Other malformations observed in one affected individual include: ureteropelvic junction obstruction [
• All individuals homozygous for the
• In individuals who are compound heterozygotes for p.Leu292Ter and another pathogenic variant, the effect of the other allele is important in determining the phenotype. Several
• The hypomorphic variant
## Clinical Description
The characteristic clinical features of classic
In a study including spine MRIs of children with classic
Recurrent calcium oxalate stones were identified in three of 24 individuals followed at one skeletal dysplasia clinic that could be related to chronic heart and lung disease, or bone demineralization from reduced mobility [C Muss & M Jain, personal observations].
Other malformations observed in one affected individual include: ureteropelvic junction obstruction [
This group is defined clinically by the ability to walk with or without support and the ability to use verbal or nonverbal types of communication [
• Recurrent calcium oxalate stones were identified in three of 24 individuals followed at one skeletal dysplasia clinic that could be related to chronic heart and lung disease, or bone demineralization from reduced mobility [C Muss & M Jain, personal observations].
• Other malformations observed in one affected individual include: ureteropelvic junction obstruction [
## Classic (Severe)
The characteristic clinical features of classic
In a study including spine MRIs of children with classic
Recurrent calcium oxalate stones were identified in three of 24 individuals followed at one skeletal dysplasia clinic that could be related to chronic heart and lung disease, or bone demineralization from reduced mobility [C Muss & M Jain, personal observations].
Other malformations observed in one affected individual include: ureteropelvic junction obstruction [
• Recurrent calcium oxalate stones were identified in three of 24 individuals followed at one skeletal dysplasia clinic that could be related to chronic heart and lung disease, or bone demineralization from reduced mobility [C Muss & M Jain, personal observations].
• Other malformations observed in one affected individual include: ureteropelvic junction obstruction [
## Nonclassic (Mild)
This group is defined clinically by the ability to walk with or without support and the ability to use verbal or nonverbal types of communication [
## Genotype-Phenotype Correlations
Correlations between the predicted severity of
All individuals homozygous for the
In individuals who are compound heterozygotes for p.Leu292Ter and another pathogenic variant, the effect of the other allele is important in determining the phenotype. Several
The hypomorphic variant
• All individuals homozygous for the
• In individuals who are compound heterozygotes for p.Leu292Ter and another pathogenic variant, the effect of the other allele is important in determining the phenotype. Several
• The hypomorphic variant
## Nomenclature
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [Unger et al 2023],
## Prevalence
The birth prevalence of
The high frequency of the
The hypomorphic variant
## Genetically Related (Allelic) Disorders
Some
## Differential Diagnosis
Genetic disorders in the differential diagnosis of
Absence of rhizomelia & cataracts
Males have nasomaxillary hypoplasia & brachytelephalangy.
Females are not affected.
Normal plasmalogen levels
Usually lethal in males
Phenotypic variability & asymmetric findings in females (due to X-chromosome inactivation)
Cataracts are asymmetric &/or sectorial.
Limb shortening is rhizomesomelic & usually asymmetric.
Normal plasmalogen levels
Severe ID
Early-onset epilepsy
Congenital cataracts
Growth restriction
Absence of rhizomelia & cataracts
Presence of nasomaxillary hypoplasia & brachytelephalangy, & bleeding disorder
Normal plasmalogen levels
AR = autosomal recessive; CDP = chondrodysplasia punctata; ID = intellectual disability; MOI = mode of inheritance; RCDP = rhizomelic chondrodysplasia punctata; XL = X-linked
• Absence of rhizomelia & cataracts
• Males have nasomaxillary hypoplasia & brachytelephalangy.
• Females are not affected.
• Normal plasmalogen levels
• Usually lethal in males
• Phenotypic variability & asymmetric findings in females (due to X-chromosome inactivation)
• Cataracts are asymmetric &/or sectorial.
• Limb shortening is rhizomesomelic & usually asymmetric.
• Normal plasmalogen levels
• Severe ID
• Early-onset epilepsy
• Congenital cataracts
• Growth restriction
• Absence of rhizomelia & cataracts
• Presence of nasomaxillary hypoplasia & brachytelephalangy, & bleeding disorder
• Normal plasmalogen levels
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Gross motor & fine motor skills
Contractures & assoc pain, 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 eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement & Nissen fundoplication.
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; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; RCDP = rhizomelic chondrodysplasia punctata
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
In classic (severe)
Mgmt per orthopedist / physical medicine & rehab specialist / PT & OT
Orthopedic procedures may improve function in some persons.
Feeding therapy
Gastrostomy tube placement & Nissen fundoplication may be required for persistent feeding issues.
Note: Improved nutrition does not enhance linear growth.
Use of RCDP disease-specific growth curves
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Persons w/
Consider regular follow up w/pediatric pulmonologist as needed.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
ASM = anti-seizure medication; OT = occupational therapist; PT = physical therapist; RCDP = rhizomelic chondrodysplasia punctata; RSV = respiratory syncytial virus
See Defeat Adult Refsum Everywhere (DARE), Refsum Diet
Based on the observation that phytanic acid that accumulates to levels observed in persons with adult Refsum disease can cause neurologic complications [
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 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 with nonclassic (mild)
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
Physical medicine, OT/PT assessment of mobility, range of motion
Monitor for development of kyphosis or scoliosis.
Neurologic exam for signs of myelopathy that could suggest cord compression
Assess for new manifestations such as seizures.
Monitor those w/seizures as clinically indicated.
Vision assessment
Assess need for vision services.
Measurement of growth parameters & plotting on RCDP-specific growth curves
Eval of nutritional status & safety of oral intake
Based on the health supervision guidelines for primary caretakers proposed in a retrospective review of the natural history of classic (severe)
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy; RCDP = rhizomelic chondrodysplasia punctata
Surveillance of phytanic acid levels in individuals with milder disease is useful to prevent neurologic consequences of phytanic acid accumulation [
Children with RCDP can experience pain and discomfort, most commonly related to their contractures, spasticity, and gastrointestinal motility. Perceived QOL by caregivers of children with RCDP can be assessed using a validated tool [
See
Anecdotal reports of natural plasmalogen precursor (alkylglycerol) supplementation in a few individuals with classic
Search
• Gross motor & fine motor skills
• Contractures & assoc pain, 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 eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement & Nissen fundoplication.
• 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
• Mgmt per orthopedist / physical medicine & rehab specialist / PT & OT
• Orthopedic procedures may improve function in some persons.
• Feeding therapy
• Gastrostomy tube placement & Nissen fundoplication may be required for persistent feeding issues.
• Note: Improved nutrition does not enhance linear growth.
• Use of RCDP disease-specific growth curves
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Persons w/
• Consider regular follow up w/pediatric pulmonologist as needed.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Care coordination 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 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).
• Physical medicine, OT/PT assessment of mobility, range of motion
• Monitor for development of kyphosis or scoliosis.
• Neurologic exam for signs of myelopathy that could suggest cord compression
• Assess for new manifestations such as seizures.
• Monitor those w/seizures as clinically indicated.
• Vision assessment
• Assess need for vision services.
• Measurement of growth parameters & plotting on RCDP-specific growth curves
• 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
Gross motor & fine motor skills
Contractures & assoc pain, 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 eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement & Nissen fundoplication.
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; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; RCDP = rhizomelic chondrodysplasia punctata
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Gross motor & fine motor skills
• Contractures & assoc pain, 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 eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement & Nissen fundoplication.
• 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
In classic (severe)
Mgmt per orthopedist / physical medicine & rehab specialist / PT & OT
Orthopedic procedures may improve function in some persons.
Feeding therapy
Gastrostomy tube placement & Nissen fundoplication may be required for persistent feeding issues.
Note: Improved nutrition does not enhance linear growth.
Use of RCDP disease-specific growth curves
Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Persons w/
Consider regular follow up w/pediatric pulmonologist as needed.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
ASM = anti-seizure medication; OT = occupational therapist; PT = physical therapist; RCDP = rhizomelic chondrodysplasia punctata; RSV = respiratory syncytial virus
See Defeat Adult Refsum Everywhere (DARE), Refsum Diet
Based on the observation that phytanic acid that accumulates to levels observed in persons with adult Refsum disease can cause neurologic complications [
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 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 with nonclassic (mild)
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.
• Mgmt per orthopedist / physical medicine & rehab specialist / PT & OT
• Orthopedic procedures may improve function in some persons.
• Feeding therapy
• Gastrostomy tube placement & Nissen fundoplication may be required for persistent feeding issues.
• Note: Improved nutrition does not enhance linear growth.
• Use of RCDP disease-specific growth curves
• Low threshold for clinical feeding eval &/or radiographic swallowing study if clinical signs or symptoms of dysphagia
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Persons w/
• Consider regular follow up w/pediatric pulmonologist as needed.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Care coordination 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 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).
## 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 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 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).
• 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 with nonclassic (mild)
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
Physical medicine, OT/PT assessment of mobility, range of motion
Monitor for development of kyphosis or scoliosis.
Neurologic exam for signs of myelopathy that could suggest cord compression
Assess for new manifestations such as seizures.
Monitor those w/seizures as clinically indicated.
Vision assessment
Assess need for vision services.
Measurement of growth parameters & plotting on RCDP-specific growth curves
Eval of nutritional status & safety of oral intake
Based on the health supervision guidelines for primary caretakers proposed in a retrospective review of the natural history of classic (severe)
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy; RCDP = rhizomelic chondrodysplasia punctata
Surveillance of phytanic acid levels in individuals with milder disease is useful to prevent neurologic consequences of phytanic acid accumulation [
Children with RCDP can experience pain and discomfort, most commonly related to their contractures, spasticity, and gastrointestinal motility. Perceived QOL by caregivers of children with RCDP can be assessed using a validated tool [
• Physical medicine, OT/PT assessment of mobility, range of motion
• Monitor for development of kyphosis or scoliosis.
• Neurologic exam for signs of myelopathy that could suggest cord compression
• Assess for new manifestations such as seizures.
• Monitor those w/seizures as clinically indicated.
• Vision assessment
• Assess need for vision services.
• Measurement of growth parameters & plotting on RCDP-specific growth curves
• Eval of nutritional status & safety of oral intake
## Quality of Life (QOL) and Palliative Care
Children with RCDP can experience pain and discomfort, most commonly related to their contractures, spasticity, and gastrointestinal motility. Perceived QOL by caregivers of children with RCDP can be assessed using a validated tool [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Anecdotal reports of natural plasmalogen precursor (alkylglycerol) supplementation in a few individuals with classic
Search
## Genetic Counseling
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.
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Note: Carriers cannot be identified by biochemical methods.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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 ancestry (see
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
• 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.
• Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry (see
## Mode of Inheritance
## 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
Molecular genetic carrier testing for at-risk relatives requires prior identification of the
Note: Carriers cannot be identified by biochemical methods.
## 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.
Carrier testing should be considered for the reproductive partners of known carriers, particularly if both partners are of the same ancestry (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 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 ancestry (see
## 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
PEX7-Related Rhizomelic Chondrodysplasia Punctata: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for PEX7-Related Rhizomelic Chondrodysplasia Punctata (
AGPS (required for plasmalogen synthesis)
PHYH (required for phytanic acid oxidation)
ACAA1 (involved in fatty acid B oxidation, but not required)
Peroxisomal targeting signal 2 receptor (PEX7) binds to these enzymes and has a second binding site for the
Variants associated with a milder
Missense variants located on the surface of PEX7 and, thus, unlikely to disrupt its structural integrity (p.Ser25Phe, p.His285Arg, p.Thr14Pro, p.Ile245Phe, p.Ser116Ile, p.Tyr40Cys, p.Asp177Glu) [
"Leaky" alleles, potentially able to generate residual amounts of normal PEX7 protein (c.-45C>T, c.340-10A>G), to reinitiate translation in-frame (p.His18ArgfsTer35), or located at a downstream methionine residue (p.Gly7ValfsTer51) [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Homozygous individuals have classic (severe)
The pathogenic variant p.Leu292Ter is the most common, accounting for 51% of pathogenic variants; p.Leu292Ter, p.Gly217Arg, and p.Ala218Val together account for up to 68% of pathogenic variants; c.903+1G>C, p.Gly217Arg, and p.Ala218Val together account for 17% of pathogenic variants.
• AGPS (required for plasmalogen synthesis)
• PHYH (required for phytanic acid oxidation)
• ACAA1 (involved in fatty acid B oxidation, but not required)
• Missense variants located on the surface of PEX7 and, thus, unlikely to disrupt its structural integrity (p.Ser25Phe, p.His285Arg, p.Thr14Pro, p.Ile245Phe, p.Ser116Ile, p.Tyr40Cys, p.Asp177Glu) [
• "Leaky" alleles, potentially able to generate residual amounts of normal PEX7 protein (c.-45C>T, c.340-10A>G), to reinitiate translation in-frame (p.His18ArgfsTer35), or located at a downstream methionine residue (p.Gly7ValfsTer51) [
## Molecular Pathogenesis
AGPS (required for plasmalogen synthesis)
PHYH (required for phytanic acid oxidation)
ACAA1 (involved in fatty acid B oxidation, but not required)
Peroxisomal targeting signal 2 receptor (PEX7) binds to these enzymes and has a second binding site for the
Variants associated with a milder
Missense variants located on the surface of PEX7 and, thus, unlikely to disrupt its structural integrity (p.Ser25Phe, p.His285Arg, p.Thr14Pro, p.Ile245Phe, p.Ser116Ile, p.Tyr40Cys, p.Asp177Glu) [
"Leaky" alleles, potentially able to generate residual amounts of normal PEX7 protein (c.-45C>T, c.340-10A>G), to reinitiate translation in-frame (p.His18ArgfsTer35), or located at a downstream methionine residue (p.Gly7ValfsTer51) [
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Homozygous individuals have classic (severe)
The pathogenic variant p.Leu292Ter is the most common, accounting for 51% of pathogenic variants; p.Leu292Ter, p.Gly217Arg, and p.Ala218Val together account for up to 68% of pathogenic variants; c.903+1G>C, p.Gly217Arg, and p.Ala218Val together account for 17% of pathogenic variants.
• AGPS (required for plasmalogen synthesis)
• PHYH (required for phytanic acid oxidation)
• ACAA1 (involved in fatty acid B oxidation, but not required)
• Missense variants located on the surface of PEX7 and, thus, unlikely to disrupt its structural integrity (p.Ser25Phe, p.His285Arg, p.Thr14Pro, p.Ile245Phe, p.Ser116Ile, p.Tyr40Cys, p.Asp177Glu) [
• "Leaky" alleles, potentially able to generate residual amounts of normal PEX7 protein (c.-45C>T, c.340-10A>G), to reinitiate translation in-frame (p.His18ArgfsTer35), or located at a downstream methionine residue (p.Gly7ValfsTer51) [
## Chapter Notes
Michael B Bober, PhD, MD (2020-2025)Nancy E Braverman, MS, MD (2001-present)Ricki Carroll, MD, MBE (2025-present)Angela Duker, MS, CGC (2020-2025)Wedad Fallatah, MD, MAS (2020-present)Mahim Jain, MD, PhD (2025-present)Ann B Moser, BA; Kennedy Krieger Institute (2001-2020)Steven K Steinberg, PhD (2001-2025)
7 August 2025 (sw) Comprehensive update posted live
30 January 2020 (bp) Comprehensive update posted live
13 September 2012 (me) Comprehensive update posted live
2 March 2010 (me) Comprehensive update posted live
18 July 2006 (me) Comprehensive update posted live
13 February 2004 (me) Comprehensive update posted live
16 November 2001 (me) Review posted live
10 June 2001 (nb) Original submission
• 7 August 2025 (sw) Comprehensive update posted live
• 30 January 2020 (bp) Comprehensive update posted live
• 13 September 2012 (me) Comprehensive update posted live
• 2 March 2010 (me) Comprehensive update posted live
• 18 July 2006 (me) Comprehensive update posted live
• 13 February 2004 (me) Comprehensive update posted live
• 16 November 2001 (me) Review posted live
• 10 June 2001 (nb) Original submission
## Author History
Michael B Bober, PhD, MD (2020-2025)Nancy E Braverman, MS, MD (2001-present)Ricki Carroll, MD, MBE (2025-present)Angela Duker, MS, CGC (2020-2025)Wedad Fallatah, MD, MAS (2020-present)Mahim Jain, MD, PhD (2025-present)Ann B Moser, BA; Kennedy Krieger Institute (2001-2020)Steven K Steinberg, PhD (2001-2025)
## Revision History
7 August 2025 (sw) Comprehensive update posted live
30 January 2020 (bp) Comprehensive update posted live
13 September 2012 (me) Comprehensive update posted live
2 March 2010 (me) Comprehensive update posted live
18 July 2006 (me) Comprehensive update posted live
13 February 2004 (me) Comprehensive update posted live
16 November 2001 (me) Review posted live
10 June 2001 (nb) Original submission
• 7 August 2025 (sw) Comprehensive update posted live
• 30 January 2020 (bp) Comprehensive update posted live
• 13 September 2012 (me) Comprehensive update posted live
• 2 March 2010 (me) Comprehensive update posted live
• 18 July 2006 (me) Comprehensive update posted live
• 13 February 2004 (me) Comprehensive update posted live
• 16 November 2001 (me) Review posted live
• 10 June 2001 (nb) Original submission
## References
## Literature Cited
Radiograph of a newborn with classic (severe)
Lateral Infant spine showing vertebral coronal clefting (arrow)
a. Progression of radiographic changes in a child with classic (severe)
b. Calcification of intervertebral discs (blue arrows)
Characteristic facial features of classic (severe)
Radiographs of nonclassic (mild)
Girl age five years with nonclassic
|
[] |
16/11/2001
|
7/8/2025
|
7/2/2005
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
refsum
|
refsum
|
[
"Classic Refsum Disease",
"Classic Refsum Disease",
"Peroxisomal targeting signal 2 receptor",
"Phytanoyl-CoA dioxygenase, peroxisomal",
"PEX7",
"PHYH",
"Adult Refsum Disease"
] |
Adult Refsum Disease
|
Hans R Waterham, Ronald JA Wanders, Bart P Leroy
|
Summary Adult Refsum disease (ARD) is associated with elevated plasma phytanic acid levels, late childhood-onset (or later) retinitis pigmentosa, and variable combinations of anosmia, polyneuropathy, deafness, ataxia, and ichthyosis. Onset of symptoms ranges from age seven months to older than age 50 years. Cardiac arrhythmia and heart failure caused by cardiomyopathy are potentially severe health problems that develop later in life. The diagnosis of ARD is established in a proband with suggestive clinical and biochemical findings by identification of biallelic pathogenic variants in either ARD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
Adult Refsum disease (ARD), also referred to as "classic Refsum disease," is a peroxisomal disorder. In the majority of individuals, it is caused by a deficiency of the peroxisomal enzyme phytanoyl-CoA hydroxylase due to biallelic pathogenic variants in
No consensus clinical diagnostic criteria for ARD have been published.
ARD
Anosmia
Polyneuropathy (sensory and motor)
Hearing loss
Ataxia
Ichthyosis
Short metacarpals and metatarsals present from birth
Cardiac arrhythmias and cardiomyopathy
Note: (1) The full constellation of signs and symptoms is rarely seen in an affected individual. (2) Most features develop with age.
Comparison of Peroxisomal Metabolites in Adult Refsum Disease by Gene Involved
Plasma very-long-chain fatty acids (VLCFA) are normal in adult Refsum disease.
Measured by gas chromatography
Plasma phytanic acid concentration may vary considerably because phytanic acid intake is dependent on local diet and may be deceptively low in populations with lower intakes of saturated fatty acids and cholesterol.
The diagnosis of ARD
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 [
If molecular genetic testing is unavailable or the results are not diagnostic,
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. 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 Adult Refsum Disease
ARD = adult Refsum disease
Genes are listed in order of frequency of causation.
See
See Molecular Genetics for information on variants detected in these genes.
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.
Waterham & Wanders, unpublished observations
Data derived from the subscription-based professional view of Human Gene Mutation Database [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Measurement of phytanoyl-CoA hydroxylase enzyme activity in fibroblasts has been used in the past to confirm the diagnosis of ARD – or when the diagnosis of ARD could not be confirmed by molecular genetic testing. However, this testing is no longer available on a clinical basis.
As an alternative, cellular phytanic acid alpha-oxidation (the conversion of phytanoyl-CoA into 2-hydroxyphytanoyl-CoAl; which is expected to be deficient in ARD) can be measured. This test does not allow differentiation between ARD due to variants in
• Anosmia
• Polyneuropathy (sensory and motor)
• Hearing loss
• Ataxia
• Ichthyosis
• Short metacarpals and metatarsals present from birth
• Cardiac arrhythmias and cardiomyopathy
## Suggestive Findings
ARD
Anosmia
Polyneuropathy (sensory and motor)
Hearing loss
Ataxia
Ichthyosis
Short metacarpals and metatarsals present from birth
Cardiac arrhythmias and cardiomyopathy
Note: (1) The full constellation of signs and symptoms is rarely seen in an affected individual. (2) Most features develop with age.
Comparison of Peroxisomal Metabolites in Adult Refsum Disease by Gene Involved
Plasma very-long-chain fatty acids (VLCFA) are normal in adult Refsum disease.
Measured by gas chromatography
Plasma phytanic acid concentration may vary considerably because phytanic acid intake is dependent on local diet and may be deceptively low in populations with lower intakes of saturated fatty acids and cholesterol.
• Anosmia
• Polyneuropathy (sensory and motor)
• Hearing loss
• Ataxia
• Ichthyosis
• Short metacarpals and metatarsals present from birth
• Cardiac arrhythmias and cardiomyopathy
## Establishing the Diagnosis
The diagnosis of ARD
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 [
If molecular genetic testing is unavailable or the results are not diagnostic,
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. 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 Adult Refsum Disease
ARD = adult Refsum disease
Genes are listed in order of frequency of causation.
See
See Molecular Genetics for information on variants detected in these genes.
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.
Waterham & Wanders, unpublished observations
Data derived from the subscription-based professional view of Human Gene Mutation Database [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Measurement of phytanoyl-CoA hydroxylase enzyme activity in fibroblasts has been used in the past to confirm the diagnosis of ARD – or when the diagnosis of ARD could not be confirmed by molecular genetic testing. However, this testing is no longer available on a clinical basis.
As an alternative, cellular phytanic acid alpha-oxidation (the conversion of phytanoyl-CoA into 2-hydroxyphytanoyl-CoAl; which is expected to be deficient in ARD) can be measured. This test does not allow differentiation between ARD due to variants in
## Molecular Genetic Testing
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. 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 Adult Refsum Disease
ARD = adult Refsum disease
Genes are listed in order of frequency of causation.
See
See Molecular Genetics for information on variants detected in these genes.
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.
Waterham & Wanders, unpublished observations
Data derived from the subscription-based professional view of Human Gene Mutation Database [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
##
For an introduction to multigene panels click
##
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Adult Refsum Disease
ARD = adult Refsum disease
Genes are listed in order of frequency of causation.
See
See Molecular Genetics for information on variants detected in these genes.
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.
Waterham & Wanders, unpublished observations
Data derived from the subscription-based professional view of Human Gene Mutation Database [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Specialized Biochemical Testing
Measurement of phytanoyl-CoA hydroxylase enzyme activity in fibroblasts has been used in the past to confirm the diagnosis of ARD – or when the diagnosis of ARD could not be confirmed by molecular genetic testing. However, this testing is no longer available on a clinical basis.
As an alternative, cellular phytanic acid alpha-oxidation (the conversion of phytanoyl-CoA into 2-hydroxyphytanoyl-CoAl; which is expected to be deficient in ARD) can be measured. This test does not allow differentiation between ARD due to variants in
## Clinical Characteristics
Clinical manifestations in adult Refsum disease (ARD) are retinitis pigmentosa, anosmia (loss of sense of smell), sensorineural hearing loss, polyneuropathy (sensory and motor), ataxia (balance issues), ichthyosis, skeletal abnormalities including shortened fingers and toes, and cardiac arrhythmias and cardiomyopathy.
To date, more than 200 individuals have been identified with biallelic pathogenic variants in
Adult Refsum Disease: Frequency of Select Features
Data derived from
Features are listed in decreasing order of frequency.
Some investigators distinguish between acute ARD and chronic ARD. In acute ARD, polyneuropathy, weakness, ataxia, sudden visual deterioration, and often auditory deterioration are often accompanied by ichthyosis, possibly cardiac arrhythmias, and elevated liver transaminases and bilirubin. Triggers for acute presentations include weight loss, stress, trauma, and infections. In contrast, in chronic ARD, retinitis pigmentosa is present, but the other features of ARD are relatively subtle.
Virtually every individual ultimately diagnosed with ARD experiences visual symptoms first. If a detailed past medical history is obtained, many individuals confirm the onset of night blindness in childhood. In one study of 23 individuals, the delay between first ophthalmologic evaluation and diagnosis ranged between one and 28 years (mean: 11 years) [
Typically, individuals with ARD experience night blindness years before the progressive changes of constricted visual fields and decreased central visual acuity appear. Because night blindness can be difficult to ascertain, particularly in children, electroretinography, which shows either a reduction or a complete absence of rod and cone responses, can support the diagnosis in early stages (see
In general, individuals with retinitis pigmentosa due to ARD keep some visual function until late in life, albeit with severely concentrically constricted visual fields [
Cataracts in ARD often develop at an earlier age than age-related cataracts, similar to what is seen in individuals with other forms of rod-cone dystrophy. The cataracts in ARD are of the posterior subcapsular type, in addition to the classic corticonuclear type.
Cataract surgery (see
Almost without exception, individuals with ARD have peripheral sensory disturbances, most often impairment of deep sensation, particularly perception of vibration and position-motion in the distal legs.
No clinically relevant genotype-phenotype correlations have been identified.
Even in a family with identical pathogenic variants, the manifestations of ARD may vary considerably among affected individuals, comparable to those seen among affected individuals from different families. The observed phenotypic variation may be related to the dietary intake and subsequent accumulation of phytanic acid.
ARD was first described in 1946 by the Norwegian neurologist Sigwald Refsum as a distinct autosomal recessive neurologic entity, which he called "heredopathia atactica polyneuritiformis."
In the literature, ARD is also referred to as "classic Refsum disease" (CRD) or "Refsum disease." The terms ARD and CRD are preferred over the term “Refsum disease” because ARD and CRD distinguish the disorder from so-called "infantile Refsum disease" (IRD), which is a
No estimates of the prevalence of ARD have been reported. The fact that most individuals described in the literature have been identified in the United Kingdom and Norway, where awareness of ARD is high, suggests that worldwide prevalence may be higher than expected. The estimated incidence is around one in 1,000,000 in the United Kingdom.
## Clinical Description
Clinical manifestations in adult Refsum disease (ARD) are retinitis pigmentosa, anosmia (loss of sense of smell), sensorineural hearing loss, polyneuropathy (sensory and motor), ataxia (balance issues), ichthyosis, skeletal abnormalities including shortened fingers and toes, and cardiac arrhythmias and cardiomyopathy.
To date, more than 200 individuals have been identified with biallelic pathogenic variants in
Adult Refsum Disease: Frequency of Select Features
Data derived from
Features are listed in decreasing order of frequency.
Some investigators distinguish between acute ARD and chronic ARD. In acute ARD, polyneuropathy, weakness, ataxia, sudden visual deterioration, and often auditory deterioration are often accompanied by ichthyosis, possibly cardiac arrhythmias, and elevated liver transaminases and bilirubin. Triggers for acute presentations include weight loss, stress, trauma, and infections. In contrast, in chronic ARD, retinitis pigmentosa is present, but the other features of ARD are relatively subtle.
Virtually every individual ultimately diagnosed with ARD experiences visual symptoms first. If a detailed past medical history is obtained, many individuals confirm the onset of night blindness in childhood. In one study of 23 individuals, the delay between first ophthalmologic evaluation and diagnosis ranged between one and 28 years (mean: 11 years) [
Typically, individuals with ARD experience night blindness years before the progressive changes of constricted visual fields and decreased central visual acuity appear. Because night blindness can be difficult to ascertain, particularly in children, electroretinography, which shows either a reduction or a complete absence of rod and cone responses, can support the diagnosis in early stages (see
In general, individuals with retinitis pigmentosa due to ARD keep some visual function until late in life, albeit with severely concentrically constricted visual fields [
Cataracts in ARD often develop at an earlier age than age-related cataracts, similar to what is seen in individuals with other forms of rod-cone dystrophy. The cataracts in ARD are of the posterior subcapsular type, in addition to the classic corticonuclear type.
Cataract surgery (see
Almost without exception, individuals with ARD have peripheral sensory disturbances, most often impairment of deep sensation, particularly perception of vibration and position-motion in the distal legs.
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been identified.
Even in a family with identical pathogenic variants, the manifestations of ARD may vary considerably among affected individuals, comparable to those seen among affected individuals from different families. The observed phenotypic variation may be related to the dietary intake and subsequent accumulation of phytanic acid.
## Nomenclature
ARD was first described in 1946 by the Norwegian neurologist Sigwald Refsum as a distinct autosomal recessive neurologic entity, which he called "heredopathia atactica polyneuritiformis."
In the literature, ARD is also referred to as "classic Refsum disease" (CRD) or "Refsum disease." The terms ARD and CRD are preferred over the term “Refsum disease” because ARD and CRD distinguish the disorder from so-called "infantile Refsum disease" (IRD), which is a
## Prevalence
No estimates of the prevalence of ARD have been reported. The fact that most individuals described in the literature have been identified in the United Kingdom and Norway, where awareness of ARD is high, suggests that worldwide prevalence may be higher than expected. The estimated incidence is around one in 1,000,000 in the United Kingdom.
## Genetically Related (Allelic) Disorders
Classic (severe) RCDP1 is characterized by proximal shortening of the humerus and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities, coronal clefts of the vertebral bodies, and cataracts. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and the majority of children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period.
Nonclassic (mild) RCDP1 is characterized by congenital or childhood cataracts, chondrodysplasia punctata or infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, variable rhizomelia, and milder intellectual disability and growth restriction than classic RCDP1.
Adult Refsum disease (ARD) can be easily distinguished from classic (severe) RCDP1. The phenotype in individuals with nonclassic (mild) RCDP1 may overlap that of ARD [
• Classic (severe) RCDP1 is characterized by proximal shortening of the humerus and to a lesser degree the femur, punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities, coronal clefts of the vertebral bodies, and cataracts. Birth weight, length, and head circumference are often at the lower range of normal; postnatal growth deficiency is profound. Intellectual disability is severe, and the majority of children develop seizures. Most affected children do not survive the first decade of life; a proportion die in the neonatal period.
• Nonclassic (mild) RCDP1 is characterized by congenital or childhood cataracts, chondrodysplasia punctata or infrequently, chondrodysplasia manifesting only as mild epiphyseal changes, variable rhizomelia, and milder intellectual disability and growth restriction than classic RCDP1.
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Adult Refsum Disease
AD = autosomal dominant; AR = autosomal recessive; ARD = adult Refsum disease; CSF = cerebrospinal fluid; MOI = mode of inheritance; PEO = progressive external ophthalmoplegia; RP = retinitis pigmentosa; SNHL = sensorineural hearing loss; VLCFA = very-long-chain fatty acids; XL = X-linked
The enzyme AMACR plays a key role in the breakdown of pristanic acid and the C27-bile acid intermediates di- and trihydroxycholestanoic acid. As a consequence of the impaired degradation of pristanic acid, both pristanic acid and phytanic acid accumulate with pristanic concentrations much more elevated than phytanic acid concentrations (see
>90% of ZSD is attributed to pathogenic variants in the listed genes. ZSD is also associated with pathogenic variants in
OMIM
~65% of BBS is attributed to pathogenic variants in the listed genes. See
## Management
No clinical practice guidelines for adult Refsum disease (ARD) have been published.
To establish the extent of disease and needs in an individual diagnosed with ARD, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Adult Refsum Disease
Visual field testing
Electroretinography
Autofluorescence imaging
Spectral domain optical coherence tomography
ARD = adult Refsum disease; BAER = brain stem auditory evoked response; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Management by multidisciplinary specialists including ophthalmologist, neurologist, cardiologist, ENT specialist or audiologist, dietician, dermatologist, and clinical geneticist is recommended.
Treatment of Manifestations in Individuals with Adult Refsum Disease
Can be used if acute arrhythmias or extreme weakness because phytanic acid is transported on lipoproteins
Plasma phytanic acid concentrations can be ↓ by 50%-70%, typically to ~100-300 µmol/L.
A low-phytanic acid diet can be given orally or by nasogastric tube.
If oral intake is restricted, appropriate parenteral nutrition & fluid therapies are needed to maintain plasma glucose concentrations & prevent ketosis.
A high-calorie diet is necessary to avoid mobilization of stored lipids (incl phytanic acid) into the plasma.
Plasma phytanic acid concentrations can be ↓ by 50%-70%, typically to ~100-300 µmol/L.
↓ in plasma phytanic acid concentration successfully resolves symptoms of ichthyosis, sensory neuropathy, & ataxia (in approx that order).
Despite strict dietary treatment, RP appears to be very slowly progressive [BP Leroy, unpublished observations].
It is unknown if treatment affects progression of anosmia & deafness.
Strict diet may slow evolution.
Low vision aids are useful where & when required.
Iris hooks may be required during cataract surgery to allow sufficient pupillary enlargement (pupils do not dilate well if at all in ARD).
An anterior chamber lens w/iris fixation may be needed because the brittleness of the zonular fibers holding the lens capsule may prevent positioning of an intraocular lens in the capsular bag after cataract removal.
However, capsular tension rings may provide further stability to zonular fibers & capsule during cataract surgery.
Regular care by cardiologist for cardiac arrhythmias & cardiomyopathy in order to treat signs & symptoms properly w/antiarrhythmic & cardiogenic supportive drugs
Once cardiomyopathy has become difficult to treat, cardiac transplantation can be life saving. 2 persons w/ARD have had successful heart transplant [BP Leroy 2007 & 2015, personal observations].
RP = retinitis pigmentosa
Recommended Surveillance for Individuals with Adult Refsum Disease
Identify vision loss from cataracts
Quantify extent of visual loss from RP (rod-cone dystrophy) w/visual fields & electroretinography where & when suitable
RP = retinitis pigmentosa
Avoid the following:
It is appropriate to evaluate sibs of a proband before symptoms of ARD occur in order to institute early treatment to reduce plasma phytanic acid concentration. Evaluations include:
Molecular genetic testing if the pathogenic variants in the family are known;
Measurement of phytanic acid concentration in plasma or serum if the pathogenic variants in the family are not known.
See
Because of the tendency for pregnancy to induce catabolism, it is extremely important to manage plasma phytanic acid concentration during pregnancy in women with ARD.
Fairly rapid reduction of visual fields has been observed during the third trimester of pregnancy [BP Leroy, unpublished observations], possibly due to increased plasma phytanic acid concentration resulting from increased catabolism. However,
Unaffected children born to mothers with ARD do not have ARD-related health concerns [
Search
• Visual field testing
• Electroretinography
• Autofluorescence imaging
• Spectral domain optical coherence tomography
• Can be used if acute arrhythmias or extreme weakness because phytanic acid is transported on lipoproteins
• Plasma phytanic acid concentrations can be ↓ by 50%-70%, typically to ~100-300 µmol/L.
• A low-phytanic acid diet can be given orally or by nasogastric tube.
• If oral intake is restricted, appropriate parenteral nutrition & fluid therapies are needed to maintain plasma glucose concentrations & prevent ketosis.
• A high-calorie diet is necessary to avoid mobilization of stored lipids (incl phytanic acid) into the plasma.
• Plasma phytanic acid concentrations can be ↓ by 50%-70%, typically to ~100-300 µmol/L.
• ↓ in plasma phytanic acid concentration successfully resolves symptoms of ichthyosis, sensory neuropathy, & ataxia (in approx that order).
• Despite strict dietary treatment, RP appears to be very slowly progressive [BP Leroy, unpublished observations].
• It is unknown if treatment affects progression of anosmia & deafness.
• Strict diet may slow evolution.
• Low vision aids are useful where & when required.
• Iris hooks may be required during cataract surgery to allow sufficient pupillary enlargement (pupils do not dilate well if at all in ARD).
• An anterior chamber lens w/iris fixation may be needed because the brittleness of the zonular fibers holding the lens capsule may prevent positioning of an intraocular lens in the capsular bag after cataract removal.
• However, capsular tension rings may provide further stability to zonular fibers & capsule during cataract surgery.
• Regular care by cardiologist for cardiac arrhythmias & cardiomyopathy in order to treat signs & symptoms properly w/antiarrhythmic & cardiogenic supportive drugs
• Once cardiomyopathy has become difficult to treat, cardiac transplantation can be life saving. 2 persons w/ARD have had successful heart transplant [BP Leroy 2007 & 2015, personal observations].
• Identify vision loss from cataracts
• Quantify extent of visual loss from RP (rod-cone dystrophy) w/visual fields & electroretinography where & when suitable
• Molecular genetic testing if the pathogenic variants in the family are known;
• Measurement of phytanic acid concentration in plasma or serum 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 ARD, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Adult Refsum Disease
Visual field testing
Electroretinography
Autofluorescence imaging
Spectral domain optical coherence tomography
ARD = adult Refsum disease; BAER = brain stem auditory evoked response; MOI = mode of inheritance
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Visual field testing
• Electroretinography
• Autofluorescence imaging
• Spectral domain optical coherence tomography
## Treatment of Manifestations
Management by multidisciplinary specialists including ophthalmologist, neurologist, cardiologist, ENT specialist or audiologist, dietician, dermatologist, and clinical geneticist is recommended.
Treatment of Manifestations in Individuals with Adult Refsum Disease
Can be used if acute arrhythmias or extreme weakness because phytanic acid is transported on lipoproteins
Plasma phytanic acid concentrations can be ↓ by 50%-70%, typically to ~100-300 µmol/L.
A low-phytanic acid diet can be given orally or by nasogastric tube.
If oral intake is restricted, appropriate parenteral nutrition & fluid therapies are needed to maintain plasma glucose concentrations & prevent ketosis.
A high-calorie diet is necessary to avoid mobilization of stored lipids (incl phytanic acid) into the plasma.
Plasma phytanic acid concentrations can be ↓ by 50%-70%, typically to ~100-300 µmol/L.
↓ in plasma phytanic acid concentration successfully resolves symptoms of ichthyosis, sensory neuropathy, & ataxia (in approx that order).
Despite strict dietary treatment, RP appears to be very slowly progressive [BP Leroy, unpublished observations].
It is unknown if treatment affects progression of anosmia & deafness.
Strict diet may slow evolution.
Low vision aids are useful where & when required.
Iris hooks may be required during cataract surgery to allow sufficient pupillary enlargement (pupils do not dilate well if at all in ARD).
An anterior chamber lens w/iris fixation may be needed because the brittleness of the zonular fibers holding the lens capsule may prevent positioning of an intraocular lens in the capsular bag after cataract removal.
However, capsular tension rings may provide further stability to zonular fibers & capsule during cataract surgery.
Regular care by cardiologist for cardiac arrhythmias & cardiomyopathy in order to treat signs & symptoms properly w/antiarrhythmic & cardiogenic supportive drugs
Once cardiomyopathy has become difficult to treat, cardiac transplantation can be life saving. 2 persons w/ARD have had successful heart transplant [BP Leroy 2007 & 2015, personal observations].
RP = retinitis pigmentosa
• Can be used if acute arrhythmias or extreme weakness because phytanic acid is transported on lipoproteins
• Plasma phytanic acid concentrations can be ↓ by 50%-70%, typically to ~100-300 µmol/L.
• A low-phytanic acid diet can be given orally or by nasogastric tube.
• If oral intake is restricted, appropriate parenteral nutrition & fluid therapies are needed to maintain plasma glucose concentrations & prevent ketosis.
• A high-calorie diet is necessary to avoid mobilization of stored lipids (incl phytanic acid) into the plasma.
• Plasma phytanic acid concentrations can be ↓ by 50%-70%, typically to ~100-300 µmol/L.
• ↓ in plasma phytanic acid concentration successfully resolves symptoms of ichthyosis, sensory neuropathy, & ataxia (in approx that order).
• Despite strict dietary treatment, RP appears to be very slowly progressive [BP Leroy, unpublished observations].
• It is unknown if treatment affects progression of anosmia & deafness.
• Strict diet may slow evolution.
• Low vision aids are useful where & when required.
• Iris hooks may be required during cataract surgery to allow sufficient pupillary enlargement (pupils do not dilate well if at all in ARD).
• An anterior chamber lens w/iris fixation may be needed because the brittleness of the zonular fibers holding the lens capsule may prevent positioning of an intraocular lens in the capsular bag after cataract removal.
• However, capsular tension rings may provide further stability to zonular fibers & capsule during cataract surgery.
• Regular care by cardiologist for cardiac arrhythmias & cardiomyopathy in order to treat signs & symptoms properly w/antiarrhythmic & cardiogenic supportive drugs
• Once cardiomyopathy has become difficult to treat, cardiac transplantation can be life saving. 2 persons w/ARD have had successful heart transplant [BP Leroy 2007 & 2015, personal observations].
## Surveillance
Recommended Surveillance for Individuals with Adult Refsum Disease
Identify vision loss from cataracts
Quantify extent of visual loss from RP (rod-cone dystrophy) w/visual fields & electroretinography where & when suitable
RP = retinitis pigmentosa
• Identify vision loss from cataracts
• Quantify extent of visual loss from RP (rod-cone dystrophy) w/visual fields & electroretinography where & when suitable
## Agents/Circumstances to Avoid
Avoid the following:
## Evaluation of Relatives at Risk
It is appropriate to evaluate sibs of a proband before symptoms of ARD occur in order to institute early treatment to reduce plasma phytanic acid concentration. Evaluations include:
Molecular genetic testing if the pathogenic variants in the family are known;
Measurement of phytanic acid concentration in plasma or serum if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Measurement of phytanic acid concentration in plasma or serum if the pathogenic variants in the family are not known.
## Pregnancy Management
Because of the tendency for pregnancy to induce catabolism, it is extremely important to manage plasma phytanic acid concentration during pregnancy in women with ARD.
Fairly rapid reduction of visual fields has been observed during the third trimester of pregnancy [BP Leroy, unpublished observations], possibly due to increased plasma phytanic acid concentration resulting from increased catabolism. However,
Unaffected children born to mothers with ARD do not have ARD-related health concerns [
## Therapies Under Investigation
Search
## Genetic Counseling
Adult Refsum disease (ARD) is inherited in an autosomal recessive manner.
The parents of an affected individual 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
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
Manifestations of ARD may vary considerably between sibs with identical pathogenic variants. These phenotypic differences are comparable to those among affected individuals from different families.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Carrier testing for at-risk relatives requires prior identification of the
Biochemical testing is not accurate for carrier testing, as the biochemical findings (i.e., plasma phytanic acid concentration) in obligate heterozygotes (carriers) are near normal [
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 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
• 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
• Manifestations of ARD may vary considerably between sibs with identical pathogenic variants. These phenotypic differences are comparable to those among affected individuals from different families.
• 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
Adult Refsum disease (ARD) 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
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
Manifestations of ARD may vary considerably between sibs with identical pathogenic variants. These phenotypic differences are comparable to those among affected individuals from different families.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• The parents of an affected individual 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
• 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
• Manifestations of ARD may vary considerably between sibs with identical pathogenic variants. These phenotypic differences are comparable to those among affected individuals from different families.
• 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
Biochemical testing is not accurate for carrier testing, as the biochemical findings (i.e., plasma phytanic acid concentration) in obligate heterozygotes (carriers) are near normal [
## Related Genetic Counseling Issues
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 optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
P.O.Box 865
Windham ME 04062
PO Box 5801
Bethesda MD 20824
United Kingdom
•
• P.O.Box 865
• Windham ME 04062
•
•
• PO Box 5801
• Bethesda MD 20824
•
•
•
•
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
Adult Refsum Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Adult Refsum Disease (
Pathogenic variants in
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is derived from dietary sources only, mainly from dairy and ruminant fats. Phytanic acid is a 3-methyl branched-chain fatty acid, which cannot undergo straightforward beta-oxidation like other fatty acids since the presence of the methyl group at the 3 position blocks beta-oxidation. Nature has resolved this problem by creating an alpha-oxidation mechanism in which the terminal carboxyl group is released as CO
ARD is caused by deficits in the first step in this process by one of two causes:
Deficient enzyme phytanoyl-CoA hydroxylase (encoded by
Deficient PTS2 receptor (encoded by
As a consequence of the phytanoyl-CoA hydroxylase deficiency, phytanic acid cannot be degraded and will accumulate in body tissues to toxic levels.
• Deficient enzyme phytanoyl-CoA hydroxylase (encoded by
• Deficient PTS2 receptor (encoded by
## Molecular Pathogenesis
Pathogenic variants in
Phytanic acid (3,7,11,15-tetramethylhexadecanoic acid) is derived from dietary sources only, mainly from dairy and ruminant fats. Phytanic acid is a 3-methyl branched-chain fatty acid, which cannot undergo straightforward beta-oxidation like other fatty acids since the presence of the methyl group at the 3 position blocks beta-oxidation. Nature has resolved this problem by creating an alpha-oxidation mechanism in which the terminal carboxyl group is released as CO
ARD is caused by deficits in the first step in this process by one of two causes:
Deficient enzyme phytanoyl-CoA hydroxylase (encoded by
Deficient PTS2 receptor (encoded by
As a consequence of the phytanoyl-CoA hydroxylase deficiency, phytanic acid cannot be degraded and will accumulate in body tissues to toxic levels.
• Deficient enzyme phytanoyl-CoA hydroxylase (encoded by
• Deficient PTS2 receptor (encoded by
## Chapter Notes
30 September 2021 (ha) Comprehensive update posted live
11 June 2015 (me) Comprehensive update posted live
22 April 2010 (me) Comprehensive update posted live
20 March 2006 (me) Review posted live
30 March 2004 (rw) Original submission
• 30 September 2021 (ha) Comprehensive update posted live
• 11 June 2015 (me) Comprehensive update posted live
• 22 April 2010 (me) Comprehensive update posted live
• 20 March 2006 (me) Review posted live
• 30 March 2004 (rw) Original submission
## Revision History
30 September 2021 (ha) Comprehensive update posted live
11 June 2015 (me) Comprehensive update posted live
22 April 2010 (me) Comprehensive update posted live
20 March 2006 (me) Review posted live
30 March 2004 (rw) Original submission
• 30 September 2021 (ha) Comprehensive update posted live
• 11 June 2015 (me) Comprehensive update posted live
• 22 April 2010 (me) Comprehensive update posted live
• 20 March 2006 (me) Review posted live
• 30 March 2004 (rw) Original submission
## References
## Literature Cited
Metabolic pathway showing the different steps involved in the alpha-oxidation of phytanoyl-CoA to pristanoyl-CoA as catalyzed by the enzymes: phytanoyl-CoA, 2-hydroxylase (PHYH), 2-hydroxyphytanoyl-CoA lyase (HACL), a hitherto uncharacterized aldehyde dehydrogenase (AldDH) and the enzyme pristanoyl-CoA synthetase (VLCS/ACSVL1) [
|
[] |
20/3/2006
|
30/9/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
rere-dis
|
rere-dis
|
[
"Neurodevelopmental Disorder with or without Anomalies of the Brain, Eye, or Heart (NEDBEH)",
"Neurodevelopmental Disorder with or without Anomalies of the Brain, Eye, or Heart (NEDBEH)",
"Arginine-glutamic acid dipeptide repeats protein",
"RERE",
"RERE-Related Disorders"
] |
Daryl A Scott, Elliott H Sherr
|
Summary The diagnosis of
|
## Diagnosis
No clinical diagnostic criteria have been published.
Behavioral issues, including attention-deficit/hyperactivity disorder and self-injurious behavior
Generalized hypotonia of infancy
Infant feeding difficulties
Eye/vision problems:
Structural eye defects (coloboma, optic nerve atrophy/hypoplasia, micropthalmia, and/or Peter's anomaly)
Vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia, and/or ptosis)
Sensorineural hearing loss
Congenital heart defects, especially septal defects
Epilepsy
Genitourinary anomalies including vesicoureteral reflux, hypospadias, and cryptorchidism
Choanal atresia
The diagnosis of
Note: 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 [
For an introduction to multigene panels click
For an introduction to exome sequencing 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 with a larger 1p36 deletion) may not be detected by these methods.
Although a 317-kb deletion encompassing exons 1-10 was detected by chromosomal microarray analysis (CMA) [
CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
• Behavioral issues, including attention-deficit/hyperactivity disorder and self-injurious behavior
• Generalized hypotonia of infancy
• Infant feeding difficulties
• Eye/vision problems:
• Structural eye defects (coloboma, optic nerve atrophy/hypoplasia, micropthalmia, and/or Peter's anomaly)
• Vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia, and/or ptosis)
• Structural eye defects (coloboma, optic nerve atrophy/hypoplasia, micropthalmia, and/or Peter's anomaly)
• Vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia, and/or ptosis)
• Sensorineural hearing loss
• Congenital heart defects, especially septal defects
• Epilepsy
• Genitourinary anomalies including vesicoureteral reflux, hypospadias, and cryptorchidism
• Choanal atresia
• Structural eye defects (coloboma, optic nerve atrophy/hypoplasia, micropthalmia, and/or Peter's anomaly)
• Vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia, and/or ptosis)
• For an introduction to multigene panels click
• For an introduction to exome sequencing click
## Suggestive Findings
Behavioral issues, including attention-deficit/hyperactivity disorder and self-injurious behavior
Generalized hypotonia of infancy
Infant feeding difficulties
Eye/vision problems:
Structural eye defects (coloboma, optic nerve atrophy/hypoplasia, micropthalmia, and/or Peter's anomaly)
Vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia, and/or ptosis)
Sensorineural hearing loss
Congenital heart defects, especially septal defects
Epilepsy
Genitourinary anomalies including vesicoureteral reflux, hypospadias, and cryptorchidism
Choanal atresia
• Behavioral issues, including attention-deficit/hyperactivity disorder and self-injurious behavior
• Generalized hypotonia of infancy
• Infant feeding difficulties
• Eye/vision problems:
• Structural eye defects (coloboma, optic nerve atrophy/hypoplasia, micropthalmia, and/or Peter's anomaly)
• Vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia, and/or ptosis)
• Structural eye defects (coloboma, optic nerve atrophy/hypoplasia, micropthalmia, and/or Peter's anomaly)
• Vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia, and/or ptosis)
• Sensorineural hearing loss
• Congenital heart defects, especially septal defects
• Epilepsy
• Genitourinary anomalies including vesicoureteral reflux, hypospadias, and cryptorchidism
• Choanal atresia
• Structural eye defects (coloboma, optic nerve atrophy/hypoplasia, micropthalmia, and/or Peter's anomaly)
• Vision issues (myopia, anisometropia, astigmatism, exotropia, esotropia, and/or ptosis)
## Establishing the Diagnosis
The diagnosis of
Note: 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 [
For an introduction to multigene panels click
For an introduction to exome sequencing 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 with a larger 1p36 deletion) may not be detected by these methods.
Although a 317-kb deletion encompassing exons 1-10 was detected by chromosomal microarray analysis (CMA) [
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 exome sequencing click
## Clinical Characteristics
To date, 19 individuals have been identified with a pathogenic variant in
6/19 (~30%) of affected individuals have structural
4/19 (~20%) of affected individuals have sensorineural
Cranial nerve dysfunction has been identified in one affected individual.
In general, pathogenic missense variants affecting the atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, genitourinary anomalies, and sensorineural hearing loss when compared with loss-of-function variants [
The
The prevalence of this condition is unknown. Approximately 19 individuals with
• 6/19 (~30%) of affected individuals have structural
• 4/19 (~20%) of affected individuals have sensorineural
• Cranial nerve dysfunction has been identified in one affected individual.
## Clinical Description
To date, 19 individuals have been identified with a pathogenic variant in
6/19 (~30%) of affected individuals have structural
4/19 (~20%) of affected individuals have sensorineural
Cranial nerve dysfunction has been identified in one affected individual.
• 6/19 (~30%) of affected individuals have structural
• 4/19 (~20%) of affected individuals have sensorineural
• Cranial nerve dysfunction has been identified in one affected individual.
## Genotype-Phenotype Correlations
In general, pathogenic missense variants affecting the atrophin-1 domain of RERE are associated with an increased risk of structural eye defects, congenital heart defects, genitourinary anomalies, and sensorineural hearing loss when compared with loss-of-function variants [
The
## Prevalence
The prevalence of this condition is unknown. Approximately 19 individuals with
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Because the phenotypic features associated with
Disorders to Consider in the Differential Diagnosis of
Colobomata, congenital heart defects, choanal atresia, ear anomalies, & genitourinary anomalies
Neurocognitive defects
Hearing loss
Growth deficiencies
Cranial nerve dysfunction or anomaly
Semicircular canal defects
Tracheoesophageal fistula
Central nervous system anomalies, ophthalmologic abnormalities, congenital heart defects, & renal & genitourinary anomalies
Neurocognitive abnormalities
Hearing loss
Typical dysmorphic features (straight eyebrows, deeply set eyes, midface retrusion, wide & depressed nasal bridge, long philtrum, pointed chin, epicanthal folds, posteriorly rotated & low-set ears)
Late-closing anterior fontanelle
AD = autosomal dominant; MOI = mode of inheritance
Risks to family members depend on the mechanism of origin of the deletion.
• Colobomata, congenital heart defects, choanal atresia, ear anomalies, & genitourinary anomalies
• Neurocognitive defects
• Hearing loss
• Growth deficiencies
• Cranial nerve dysfunction or anomaly
• Semicircular canal defects
• Tracheoesophageal fistula
• Central nervous system anomalies, ophthalmologic abnormalities, congenital heart defects, & renal & genitourinary anomalies
• Neurocognitive abnormalities
• Hearing loss
• Typical dysmorphic features (straight eyebrows, deeply set eyes, midface retrusion, wide & depressed nasal bridge, long philtrum, pointed chin, epicanthal folds, posteriorly rotated & low-set ears)
• Late-closing anterior fontanelle
## 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; EEG = electroencephalogram; GERD = gastroesophageal reflux disease; MRI = magnetic resonance imaging; VCUG = voiding cystourethrogram
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 assist 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, 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
• 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 assist 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; EEG = electroencephalogram; GERD = gastroesophageal reflux disease; MRI = magnetic resonance imaging; VCUG = voiding cystourethrogram
## 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 assist 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, 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.
• 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 assist 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 assist 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 assist 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, 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
All probands reported to date with
Theoretically, if the parent is the individual in whom 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
• Theoretically, if the parent is the individual in whom 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
Theoretically, if the parent is the individual in whom the
If the
• All probands reported to date with
• Theoretically, if the parent is the individual in whom 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
•
•
•
•
## Molecular Genetics
RERE-Related Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for RERE-Related Disorders (
RERE is a nuclear receptor coregulator that functions in protein complexes to both positively and negatively modulate the transcription of target genes.
See
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
RERE is a nuclear receptor coregulator that functions in protein complexes to both positively and negatively modulate the transcription of target genes.
See
Variants listed in the table have been provided by the authors.
## Chapter Notes
Daryl A Scott, MD, PhDBaylor College of MedicineTexas Children's HospitalR813, One Baylor PlazaBCM225Houston, TX 77030
Dr Scott is a pediatric clinical geneticist whose research interests focus on identifying and characterizing genes that cause common, life-threatening birth defects.
Elliott H Sherr MD, PhDUniversity of California, San FranciscoDepartment of Neurology675 Nelson Rising LaneSan Francisco, CA 94158
Dr Sherr is a child neurologist whose research focuses on autism and other disorders of neurodevelopment, including malformations of cortical development.
21 March 2019 (ma) Review posted live
31 July 2018 (ds) Original submission
• 21 March 2019 (ma) Review posted live
• 31 July 2018 (ds) Original submission
## Author Notes
Daryl A Scott, MD, PhDBaylor College of MedicineTexas Children's HospitalR813, One Baylor PlazaBCM225Houston, TX 77030
Dr Scott is a pediatric clinical geneticist whose research interests focus on identifying and characterizing genes that cause common, life-threatening birth defects.
Elliott H Sherr MD, PhDUniversity of California, San FranciscoDepartment of Neurology675 Nelson Rising LaneSan Francisco, CA 94158
Dr Sherr is a child neurologist whose research focuses on autism and other disorders of neurodevelopment, including malformations of cortical development.
## Revision History
21 March 2019 (ma) Review posted live
31 July 2018 (ds) Original submission
• 21 March 2019 (ma) Review posted live
• 31 July 2018 (ds) Original submission
## References
## Literature Cited
|
[
"B Fregeau, BJ Kim, A Hernández-García, VK Jordan, MT Cho, RE Schnur, KG Monaghan, J Juusola, JA Rosenfeld, E Bhoj, EH Zackai, S Sacharow, K Barañano, DGM Bosch, BBA de Vries, K Lindstrom, A Schroeder, P James, P Kulch, SR Lalani, MM van Haelst, KLI van Gassen, E van Binsbergen, AJ Barkovich, DA Scott, EH Sherr. De novo mutations of RERE cause a genetic syndrome with features that overlap those associated with proximal 1p36 deletions.. Am J Hum Genet. 2016;98:963-70",
"VK Jordan, B Fregeau, X Ge, J Giordano, RJ Wapner, TB Balci, MT Carter, JA Bernat, AN Moccia, A Srivastava, DM Martin, SL Bielas, J Pappas, MD Svoboda, M Rio, N Boddaert, V Cantagrel, AM Lewis, F Scaglia, JN Kohler, JA Bernstein, AM Dries, JA Rosenfeld, C DeFilippo, W Thorson, Y Yang, EH Sherr, W Bi, DA Scott. Genotype-phenotype correlations in individuals with pathogenic RERE variants.. Hum Mutat 2018;39:666-75",
"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"
] |
21/3/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
retinoblastoma
|
retinoblastoma
|
[
"Retinoblastoma-associated protein",
"RB1",
"Retinoblastoma"
] |
Retinoblastoma
|
Dietmar R Lohmann, Brenda L Gallie
|
Summary Retinoblastoma is a malignant tumor of the developing retina that occurs in children, usually before age five years. Retinoblastoma may be unifocal or multifocal. About 60% of affected individuals have unilateral retinoblastoma with a mean age of diagnosis of 24 months; about 40% have bilateral retinoblastoma with a mean age of diagnosis of 15 months. Heritable retinoblastoma is associated with susceptibility for retinoblastoma as well as non-ocular tumors. The diagnosis of retinoblastoma is usually established by examination of the fundus of the eye using indirect ophthalmoscopy. Imaging studies can be used to support the diagnosis and stage the tumor. Almost all retinoblastomas develop following biallelic inactivation of The following staging has been recommended for individuals with retinoblastoma and/or risk of heritable retinoblastoma to describe the genetic risk of a germline pathogenic variant in ( Heritable retinoblastoma is inherited in an autosomal dominant manner. The majority of individuals with heritable retinoblastoma represent simplex cases (i.e., the only person in the family known to be affected). Some individuals diagnosed with heritable retinoblastoma inherited an
|
## Diagnosis
Guidelines for diagnosis and care of children and families affected by retinoblastoma have been published [
Leukocoria (white pupil)
Strabismus
Change in eye appearance
Reduced visual acuity
Diagnosis of retinoblastoma, including unilateral (unifocal and multifocal) and bilateral involvement
Retinoma
Family history of retinoblastoma
The diagnosis of
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 [
The following staging has been recommended to clarify genetic risk of a germline
(
Molecular genetic testing approaches to identify individuals with
If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of
If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of
Molecular Genetic Testing Used in Heritable Retinoblastoma
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. 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
Approximately 6%-8% of individuals with retinoblastoma have a chromosome deletion of 13q14. Such chromosome abnormalities are often associated with developmental delay and birth defects [
Hypermethylation of
Testing for loss of heterozygosity in tumors. Comparative genotyping of polymorphic loci within and flanking
About 1.5% of children with unilateral retinoblastoma and no family history have high-level
Probability of a Proband with Retinoblastoma Having an
Positive = more than one affected family member (10% of individuals with retinoblastoma)
Negative = only the proband is affected (90% of individuals with retinoblastoma)
Note: (1) If neither
• Leukocoria (white pupil)
• Strabismus
• Change in eye appearance
• Reduced visual acuity
• Diagnosis of retinoblastoma, including unilateral (unifocal and multifocal) and bilateral involvement
• Retinoma
• Family history of retinoblastoma
• (
•
• If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of
• If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of
• If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of
• If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of
• If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of
• If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of
## Suggestive Findings
Leukocoria (white pupil)
Strabismus
Change in eye appearance
Reduced visual acuity
Diagnosis of retinoblastoma, including unilateral (unifocal and multifocal) and bilateral involvement
Retinoma
Family history of retinoblastoma
• Leukocoria (white pupil)
• Strabismus
• Change in eye appearance
• Reduced visual acuity
• Diagnosis of retinoblastoma, including unilateral (unifocal and multifocal) and bilateral involvement
• Retinoma
• Family history of retinoblastoma
## Establishing the Diagnosis
The diagnosis of
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 [
The following staging has been recommended to clarify genetic risk of a germline
(
Molecular genetic testing approaches to identify individuals with
If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of
If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of
Molecular Genetic Testing Used in Heritable Retinoblastoma
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. 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
Approximately 6%-8% of individuals with retinoblastoma have a chromosome deletion of 13q14. Such chromosome abnormalities are often associated with developmental delay and birth defects [
Hypermethylation of
Testing for loss of heterozygosity in tumors. Comparative genotyping of polymorphic loci within and flanking
About 1.5% of children with unilateral retinoblastoma and no family history have high-level
Probability of a Proband with Retinoblastoma Having an
Positive = more than one affected family member (10% of individuals with retinoblastoma)
Negative = only the proband is affected (90% of individuals with retinoblastoma)
Note: (1) If neither
• (
•
• If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of
• If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of
• If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of
• If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of
• If tumor tissue is not available, sequence analysis and gene-targeted deletion/duplication analysis of
• If tumor tissue is available, sequence analysis and gene-targeted deletion/duplication analysis of
## Clinical Characteristics
Probands with retinoblastoma usually present in one of the following clinical settings:
Negative family history and unilateral retinoblastoma (60% of probands)
Negative family history and bilateral retinoblastoma (30% of probands)
Positive family history and unilateral or bilateral retinoblastoma (~10% of probands). For H1 individuals (see
Chromosome deletion involving band 13q14. Up to 5% of all probands with unifocal retinoblastoma and 7.5% of all probands with multifocal retinoblastoma have a chromosome deletion of 13q14. Such chromosome abnormalities are often associated with developmental delay and birth defects [
Retinoblastoma is:
In the majority of families with heritable retinoblastoma, all members who inherited the germline pathogenic variant develop multiple tumors in both eyes. It is not unusual to find, however, that the founder (i.e., the first person in the family to have retinoblastoma) has only unilateral retinoblastoma. These families may have
Fewer than 10% of families show a "low-penetrance" phenotype with reduced expressivity (i.e., increased prevalence of unilateral retinoblastoma) and reduced penetrance (i.e., ≤25%). This low-penetrance phenotype is usually associated with
A third category of families show differential penetrance depending on the parental origin of the pathogenic allele (parent-of-origin effect) [
Cytogenetically visible deletions of 13q14 that include genes adjacent to
See
Glioma retinae is a historical name for retinoblastoma.
The incidence of retinoblastoma is estimated at between 1:15,000 and 1:20,000 live births [
• Negative family history and unilateral retinoblastoma (60% of probands)
• Negative family history and bilateral retinoblastoma (30% of probands)
• Positive family history and unilateral or bilateral retinoblastoma (~10% of probands). For H1 individuals (see
• Chromosome deletion involving band 13q14. Up to 5% of all probands with unifocal retinoblastoma and 7.5% of all probands with multifocal retinoblastoma have a chromosome deletion of 13q14. Such chromosome abnormalities are often associated with developmental delay and birth defects [
## Clinical Description
Probands with retinoblastoma usually present in one of the following clinical settings:
Negative family history and unilateral retinoblastoma (60% of probands)
Negative family history and bilateral retinoblastoma (30% of probands)
Positive family history and unilateral or bilateral retinoblastoma (~10% of probands). For H1 individuals (see
Chromosome deletion involving band 13q14. Up to 5% of all probands with unifocal retinoblastoma and 7.5% of all probands with multifocal retinoblastoma have a chromosome deletion of 13q14. Such chromosome abnormalities are often associated with developmental delay and birth defects [
Retinoblastoma is:
• Negative family history and unilateral retinoblastoma (60% of probands)
• Negative family history and bilateral retinoblastoma (30% of probands)
• Positive family history and unilateral or bilateral retinoblastoma (~10% of probands). For H1 individuals (see
• Chromosome deletion involving band 13q14. Up to 5% of all probands with unifocal retinoblastoma and 7.5% of all probands with multifocal retinoblastoma have a chromosome deletion of 13q14. Such chromosome abnormalities are often associated with developmental delay and birth defects [
## Genotype-Phenotype Correlations
In the majority of families with heritable retinoblastoma, all members who inherited the germline pathogenic variant develop multiple tumors in both eyes. It is not unusual to find, however, that the founder (i.e., the first person in the family to have retinoblastoma) has only unilateral retinoblastoma. These families may have
Fewer than 10% of families show a "low-penetrance" phenotype with reduced expressivity (i.e., increased prevalence of unilateral retinoblastoma) and reduced penetrance (i.e., ≤25%). This low-penetrance phenotype is usually associated with
A third category of families show differential penetrance depending on the parental origin of the pathogenic allele (parent-of-origin effect) [
Cytogenetically visible deletions of 13q14 that include genes adjacent to
## Penetrance
See
## Nomenclature
Glioma retinae is a historical name for retinoblastoma.
## Prevalence
The incidence of retinoblastoma is estimated at between 1:15,000 and 1:20,000 live births [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Sporadic tumors including bladder urothelial cancer, endometrial cancer, sarcoma, squamous cell cancer of the lung, and lung adenocarcinoma (
## Differential Diagnosis
Several hereditary ocular conditions of childhood can clinically simulate retinoblastoma:
Norrie disease (See
Familial exudative vitreoretinopathy (See
Ocular infestation by
•
• Norrie disease (See
•
• Familial exudative vitreoretinopathy (See
•
## Management
Guidelines for retinoblastoma care have been developed (see
To establish the extent of disease and needs in an individual diagnosed with retinoblastoma, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Prior to planning therapy, the extent of the tumor within and outside the eye should be determined. Each affected eye is assigned a cancer stage, depending on the extent of disease and the risk that the cancer has spread outside the eye [
For very large tumors with risk factors for extraocular disease, bone marrow aspiration and examination of cerebrospinal fluid may also be performed at diagnosis, or when pathologic examination of the enucleated eye reveals optic nerve invasion or significant risks for extraocular extension.
If retinoblastoma has spread outside the eye, the stage of cancer will be evaluated to determine the most appropriate care for the child.
In individuals with a family history of retinoblastoma, and in uncommon circumstances in which the child presents with strabismus or poor vision, the retinal tumors may be small and detected by optical coherence tomography [
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 retinoblastoma can facilitate medical and personal decision making.
Goals of treatment in order of priority are preservation of life and then sight. As optimal treatment may be complex, specialists skilled in the treatment of retinoblastoma from various fields including ophthalmology, pediatric oncology, pathology, and radiation oncology collaborate to deliver optimized care.
In addition to eye and tumor stage, choice of treatment depends on many factors, including the number of tumor foci (unifocal, unilateral multifocal, or bilateral), localization and size of the tumor(s) within the eye(s), presence of vitreous seeding, potential for useful vision, extent and kind of extraocular extension, and resources available.
Treatment options for the eye include enucleation; cryotherapy; laser; systemic or local ocular chemotherapy, including intra-arterial chemotherapy, combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy.
If possible, radiation (including x-ray, CT scan, and external beam radiation) is avoided to minimize the lifetime risk of developing late-onset subsequent malignant neoplasms. Such tests may be used when critical in essential health care.
Although subsequent malignant neoplasms share a molecular feature (
Guidelines for clinical screening for children at risk have been published [
Retinoblastoma: Recommended Surveillance for Individuals at Risk and Affected Individuals
Eye exam under anesthesia (in young children)
Clinical eye exams w/o anesthesia once children are cooperative w/exam
Every 3-4 wks until age 6 mos
Every 2 mos from age 6 mos-3 yrs
Every 3-6 mos from age 3-7 yrs
Annually from age 7-10 yrs
Every 2 yrs from age 10 yrs
Prompt clinical investigation of any signs/symptoms of subsequent non-ocular malignant neoplasms
Clinical eye exam (w/o anesthesia)
Eye ultrasound
Every 3-6 mos from diagnosis to 7 yrs
Every 2 yrs from age 7 yrs
Retinal exams
Photographic imaging to detect any change early
Total-body MRI at regular intervals is under investigation to determine when the technology will be specific and sensitive enough for screening for subsequent malignant neoplasms in persons with a heterozygous germline
H0* individuals are at risk for low-level mosaicism and can develop a tumor in the other eye [
It has been suggested by
The American Society of Clinical Oncologists identifies heritable retinoblastoma as a Group 1 disorder – a hereditary syndrome for which genetic testing is considered part of the standard management for at-risk family members [
Molecular genetic testing if the pathogenic variant in the family is known, which reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant [
Eye examinations by an ophthalmologist experienced in the treatment of retinoblastoma starting directly after birth (see
See
Search
• Prior to planning therapy, the extent of the tumor within and outside the eye should be determined. Each affected eye is assigned a cancer stage, depending on the extent of disease and the risk that the cancer has spread outside the eye [
• For very large tumors with risk factors for extraocular disease, bone marrow aspiration and examination of cerebrospinal fluid may also be performed at diagnosis, or when pathologic examination of the enucleated eye reveals optic nerve invasion or significant risks for extraocular extension.
• If retinoblastoma has spread outside the eye, the stage of cancer will be evaluated to determine the most appropriate care for the child.
• In individuals with a family history of retinoblastoma, and in uncommon circumstances in which the child presents with strabismus or poor vision, the retinal tumors may be small and detected by optical coherence tomography [
• 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 retinoblastoma can facilitate medical and personal decision making.
• Eye exam under anesthesia (in young children)
• Clinical eye exams w/o anesthesia once children are cooperative w/exam
• Every 3-4 wks until age 6 mos
• Every 2 mos from age 6 mos-3 yrs
• Every 3-6 mos from age 3-7 yrs
• Annually from age 7-10 yrs
• Every 2 yrs from age 10 yrs
• Clinical eye exam (w/o anesthesia)
• Eye ultrasound
• Every 3-6 mos from diagnosis to 7 yrs
• Every 2 yrs from age 7 yrs
• Retinal exams
• Photographic imaging to detect any change early
• Molecular genetic testing if the pathogenic variant in the family is known, which reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant [
• Eye examinations by an ophthalmologist experienced in the treatment of retinoblastoma starting directly after birth (see
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with retinoblastoma, the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Prior to planning therapy, the extent of the tumor within and outside the eye should be determined. Each affected eye is assigned a cancer stage, depending on the extent of disease and the risk that the cancer has spread outside the eye [
For very large tumors with risk factors for extraocular disease, bone marrow aspiration and examination of cerebrospinal fluid may also be performed at diagnosis, or when pathologic examination of the enucleated eye reveals optic nerve invasion or significant risks for extraocular extension.
If retinoblastoma has spread outside the eye, the stage of cancer will be evaluated to determine the most appropriate care for the child.
In individuals with a family history of retinoblastoma, and in uncommon circumstances in which the child presents with strabismus or poor vision, the retinal tumors may be small and detected by optical coherence tomography [
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 retinoblastoma can facilitate medical and personal decision making.
• Prior to planning therapy, the extent of the tumor within and outside the eye should be determined. Each affected eye is assigned a cancer stage, depending on the extent of disease and the risk that the cancer has spread outside the eye [
• For very large tumors with risk factors for extraocular disease, bone marrow aspiration and examination of cerebrospinal fluid may also be performed at diagnosis, or when pathologic examination of the enucleated eye reveals optic nerve invasion or significant risks for extraocular extension.
• If retinoblastoma has spread outside the eye, the stage of cancer will be evaluated to determine the most appropriate care for the child.
• In individuals with a family history of retinoblastoma, and in uncommon circumstances in which the child presents with strabismus or poor vision, the retinal tumors may be small and detected by optical coherence tomography [
• 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 retinoblastoma can facilitate medical and personal decision making.
## Treatment of Manifestations
Goals of treatment in order of priority are preservation of life and then sight. As optimal treatment may be complex, specialists skilled in the treatment of retinoblastoma from various fields including ophthalmology, pediatric oncology, pathology, and radiation oncology collaborate to deliver optimized care.
In addition to eye and tumor stage, choice of treatment depends on many factors, including the number of tumor foci (unifocal, unilateral multifocal, or bilateral), localization and size of the tumor(s) within the eye(s), presence of vitreous seeding, potential for useful vision, extent and kind of extraocular extension, and resources available.
Treatment options for the eye include enucleation; cryotherapy; laser; systemic or local ocular chemotherapy, including intra-arterial chemotherapy, combined with or followed by laser or cryotherapy; radiation therapy using episcleral plaques; and, as a last resort, external beam radiotherapy.
If possible, radiation (including x-ray, CT scan, and external beam radiation) is avoided to minimize the lifetime risk of developing late-onset subsequent malignant neoplasms. Such tests may be used when critical in essential health care.
Although subsequent malignant neoplasms share a molecular feature (
## Surveillance
Guidelines for clinical screening for children at risk have been published [
Retinoblastoma: Recommended Surveillance for Individuals at Risk and Affected Individuals
Eye exam under anesthesia (in young children)
Clinical eye exams w/o anesthesia once children are cooperative w/exam
Every 3-4 wks until age 6 mos
Every 2 mos from age 6 mos-3 yrs
Every 3-6 mos from age 3-7 yrs
Annually from age 7-10 yrs
Every 2 yrs from age 10 yrs
Prompt clinical investigation of any signs/symptoms of subsequent non-ocular malignant neoplasms
Clinical eye exam (w/o anesthesia)
Eye ultrasound
Every 3-6 mos from diagnosis to 7 yrs
Every 2 yrs from age 7 yrs
Retinal exams
Photographic imaging to detect any change early
Total-body MRI at regular intervals is under investigation to determine when the technology will be specific and sensitive enough for screening for subsequent malignant neoplasms in persons with a heterozygous germline
H0* individuals are at risk for low-level mosaicism and can develop a tumor in the other eye [
• Eye exam under anesthesia (in young children)
• Clinical eye exams w/o anesthesia once children are cooperative w/exam
• Every 3-4 wks until age 6 mos
• Every 2 mos from age 6 mos-3 yrs
• Every 3-6 mos from age 3-7 yrs
• Annually from age 7-10 yrs
• Every 2 yrs from age 10 yrs
• Clinical eye exam (w/o anesthesia)
• Eye ultrasound
• Every 3-6 mos from diagnosis to 7 yrs
• Every 2 yrs from age 7 yrs
• Retinal exams
• Photographic imaging to detect any change early
## Agents/Circumstances to Avoid
It has been suggested by
## Evaluation of Relatives at Risk
The American Society of Clinical Oncologists identifies heritable retinoblastoma as a Group 1 disorder – a hereditary syndrome for which genetic testing is considered part of the standard management for at-risk family members [
Molecular genetic testing if the pathogenic variant in the family is known, which reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant [
Eye examinations by an ophthalmologist experienced in the treatment of retinoblastoma starting directly after birth (see
See
• Molecular genetic testing if the pathogenic variant in the family is known, which reduces the need for costly screening procedures in those at-risk family members who have not inherited the pathogenic variant [
• Eye examinations by an ophthalmologist experienced in the treatment of retinoblastoma starting directly after birth (see
## Therapies Under Investigation
Search
## Genetic Counseling
Heritable retinoblastoma is an autosomal dominant disorder.
The majority of individuals with heritable retinoblastoma represent simplex cases (i.e., the only person in the family known to be affected).
Most individuals with bilateral tumors who represent simplex cases have heritable retinoblastoma as the result of a
Approximately 5% of individuals with bilateral tumors who represent simplex cases have the disorder as the result of an
Some individuals diagnosed with heritable retinoblastoma inherited an
If a germline
* The possibility that a parent has an
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 parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, can be considered.
* 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 have fewer (unilateral) or no retinoblastomas.
The family history of some individuals diagnosed with heritable retinoblastoma may appear to be negative because of failure to recognize a retinoma in a family member, low-level mosaicism, or reduced penetrance. Therefore, a negative family history may require both clinical evaluation and molecular genetic testing demonstrating that neither parent is heterozygous for the
Risk to sibs based on the phenotype of the parents:
If a parent of the proband and the proband have bilateral retinoblastoma, the risk to the sibs is 50%. In rare families with "familial low-penetrance retinoblastoma," the risk of tumor development in a sib with the germline pathogenic variant is reduced (see
If the parents are clinically unaffected, the risk to the sibs appears to be low (i.e., 1%-2%; see
Risk to sibs based on the genetic status of the parents:
If a parent is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50% and testing of sibs for the
If the
If the proband clearly shows mosaicism for an
If molecular genetic testing is not available or is uninformative, empiric risks based on tumor presentation (e.g., unifocal or multifocal) and family history can be used (see
If a parent has a cytogenetically detectable balanced chromosome 13 translocation or rearrangement, the sibs are at increased risk of inheriting an unbalanced chromosome rearrangement.
Pretest Empiric Risks for Development of Retinoblastoma in Sibs of a Proband Based on Family History and Retinoblastoma Presentation in the Proband
In families with unilateral retinoblastoma, penetrance varies widely.
If there is no unaffected sib [
If the
If one of the pathogenic variants identified in the proband's tumor is found to be mosaic in DNA from leukocytes of the proband, the level of germline involvement is uncertain. All offspring should have molecular genetic testing for the pathogenic variant identified in leukocyte DNA of the proband.
Predictive DNA testing in offspring is possible if the cancer-predisposing
If molecular genetic testing is not available or is uninformative in the proband, empiric risks based on tumor presentation and family history can be used (see
Pretest Empiric Risks for Development of Retinoblastoma in Offspring of a Proband Based on Family History and Retinoblastoma Presentation in the Proband
In families with unilateral retinoblastoma, penetrance varies widely.
In families with "familial low-penetrance retinoblastoma," the risk for tumor development in persons with the low-penetrance
See Management,
Predictive testing for at-risk asymptomatic family members requires prior identification of the germline
Predictive molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management,
Potential consequences of such testing – including but not limited to 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 [
If the germline
When there is a family history of retinoblastoma, various options are available to optimize management of an at-risk pregnancy [
If an
If 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 majority of individuals with heritable retinoblastoma represent simplex cases (i.e., the only person in the family known to be affected).
• Most individuals with bilateral tumors who represent simplex cases have heritable retinoblastoma as the result of a
• Approximately 5% of individuals with bilateral tumors who represent simplex cases have the disorder as the result of an
• Most individuals with bilateral tumors who represent simplex cases have heritable retinoblastoma as the result of a
• Approximately 5% of individuals with bilateral tumors who represent simplex cases have the disorder as the result of an
• Some individuals diagnosed with heritable retinoblastoma inherited an
• If a germline
• * The possibility that a parent has an
• 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 parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, can be considered.
• * 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 have fewer (unilateral) or no retinoblastomas.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* 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 mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, can be considered.
• * 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 have fewer (unilateral) or no retinoblastomas.
• The family history of some individuals diagnosed with heritable retinoblastoma may appear to be negative because of failure to recognize a retinoma in a family member, low-level mosaicism, or reduced penetrance. Therefore, a negative family history may require both clinical evaluation and molecular genetic testing demonstrating that neither parent is heterozygous for the
• Most individuals with bilateral tumors who represent simplex cases have heritable retinoblastoma as the result of a
• Approximately 5% of individuals with bilateral tumors who represent simplex cases have the disorder as the result of an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* 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 mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, can be considered.
• * 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 have fewer (unilateral) or no retinoblastomas.
• Risk to sibs based on the phenotype of the parents:
• If a parent of the proband and the proband have bilateral retinoblastoma, the risk to the sibs is 50%. In rare families with "familial low-penetrance retinoblastoma," the risk of tumor development in a sib with the germline pathogenic variant is reduced (see
• If the parents are clinically unaffected, the risk to the sibs appears to be low (i.e., 1%-2%; see
• If a parent of the proband and the proband have bilateral retinoblastoma, the risk to the sibs is 50%. In rare families with "familial low-penetrance retinoblastoma," the risk of tumor development in a sib with the germline pathogenic variant is reduced (see
• If the parents are clinically unaffected, the risk to the sibs appears to be low (i.e., 1%-2%; see
• Risk to sibs based on the genetic status of the parents:
• If a parent is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50% and testing of sibs for the
• If the
• If a parent is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50% and testing of sibs for the
• If the
• If the proband clearly shows mosaicism for an
• If molecular genetic testing is not available or is uninformative, empiric risks based on tumor presentation (e.g., unifocal or multifocal) and family history can be used (see
• If a parent has a cytogenetically detectable balanced chromosome 13 translocation or rearrangement, the sibs are at increased risk of inheriting an unbalanced chromosome rearrangement.
• If a parent of the proband and the proband have bilateral retinoblastoma, the risk to the sibs is 50%. In rare families with "familial low-penetrance retinoblastoma," the risk of tumor development in a sib with the germline pathogenic variant is reduced (see
• If the parents are clinically unaffected, the risk to the sibs appears to be low (i.e., 1%-2%; see
• If a parent is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50% and testing of sibs for the
• If the
• If the
• If one of the pathogenic variants identified in the proband's tumor is found to be mosaic in DNA from leukocytes of the proband, the level of germline involvement is uncertain. All offspring should have molecular genetic testing for the pathogenic variant identified in leukocyte DNA of the proband.
• Predictive DNA testing in offspring is possible if the cancer-predisposing
• If molecular genetic testing is not available or is uninformative in the proband, empiric risks based on tumor presentation and family history can be used (see
• Predictive testing for at-risk asymptomatic family members requires prior identification of the germline
• Predictive molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management,
• Potential consequences of such testing – including but not limited to 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 [
• If an
• If the
## Mode of Inheritance
Heritable retinoblastoma is an autosomal dominant disorder.
## Risk to Family Members
The majority of individuals with heritable retinoblastoma represent simplex cases (i.e., the only person in the family known to be affected).
Most individuals with bilateral tumors who represent simplex cases have heritable retinoblastoma as the result of a
Approximately 5% of individuals with bilateral tumors who represent simplex cases have the disorder as the result of an
Some individuals diagnosed with heritable retinoblastoma inherited an
If a germline
* The possibility that a parent has an
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 parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, can be considered.
* 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 have fewer (unilateral) or no retinoblastomas.
The family history of some individuals diagnosed with heritable retinoblastoma may appear to be negative because of failure to recognize a retinoma in a family member, low-level mosaicism, or reduced penetrance. Therefore, a negative family history may require both clinical evaluation and molecular genetic testing demonstrating that neither parent is heterozygous for the
Risk to sibs based on the phenotype of the parents:
If a parent of the proband and the proband have bilateral retinoblastoma, the risk to the sibs is 50%. In rare families with "familial low-penetrance retinoblastoma," the risk of tumor development in a sib with the germline pathogenic variant is reduced (see
If the parents are clinically unaffected, the risk to the sibs appears to be low (i.e., 1%-2%; see
Risk to sibs based on the genetic status of the parents:
If a parent is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50% and testing of sibs for the
If the
If the proband clearly shows mosaicism for an
If molecular genetic testing is not available or is uninformative, empiric risks based on tumor presentation (e.g., unifocal or multifocal) and family history can be used (see
If a parent has a cytogenetically detectable balanced chromosome 13 translocation or rearrangement, the sibs are at increased risk of inheriting an unbalanced chromosome rearrangement.
Pretest Empiric Risks for Development of Retinoblastoma in Sibs of a Proband Based on Family History and Retinoblastoma Presentation in the Proband
In families with unilateral retinoblastoma, penetrance varies widely.
If there is no unaffected sib [
If the
If one of the pathogenic variants identified in the proband's tumor is found to be mosaic in DNA from leukocytes of the proband, the level of germline involvement is uncertain. All offspring should have molecular genetic testing for the pathogenic variant identified in leukocyte DNA of the proband.
Predictive DNA testing in offspring is possible if the cancer-predisposing
If molecular genetic testing is not available or is uninformative in the proband, empiric risks based on tumor presentation and family history can be used (see
Pretest Empiric Risks for Development of Retinoblastoma in Offspring of a Proband Based on Family History and Retinoblastoma Presentation in the Proband
In families with unilateral retinoblastoma, penetrance varies widely.
In families with "familial low-penetrance retinoblastoma," the risk for tumor development in persons with the low-penetrance
• The majority of individuals with heritable retinoblastoma represent simplex cases (i.e., the only person in the family known to be affected).
• Most individuals with bilateral tumors who represent simplex cases have heritable retinoblastoma as the result of a
• Approximately 5% of individuals with bilateral tumors who represent simplex cases have the disorder as the result of an
• Most individuals with bilateral tumors who represent simplex cases have heritable retinoblastoma as the result of a
• Approximately 5% of individuals with bilateral tumors who represent simplex cases have the disorder as the result of an
• Some individuals diagnosed with heritable retinoblastoma inherited an
• If a germline
• * The possibility that a parent has an
• 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 parents using peripheral blood leukocyte-derived DNA may not detect all instances of somatic mosaicism. Molecular genetic tests sensitive enough to detect low-level mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, can be considered.
• * 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 have fewer (unilateral) or no retinoblastomas.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* 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 mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, can be considered.
• * 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 have fewer (unilateral) or no retinoblastomas.
• The family history of some individuals diagnosed with heritable retinoblastoma may appear to be negative because of failure to recognize a retinoma in a family member, low-level mosaicism, or reduced penetrance. Therefore, a negative family history may require both clinical evaluation and molecular genetic testing demonstrating that neither parent is heterozygous for the
• Most individuals with bilateral tumors who represent simplex cases have heritable retinoblastoma as the result of a
• Approximately 5% of individuals with bilateral tumors who represent simplex cases have the disorder as the result of an
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* 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 mosaicism, such as high-coverage next-generation sequencing or allele-specific PCR, can be considered.
• * 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 have fewer (unilateral) or no retinoblastomas.
• Risk to sibs based on the phenotype of the parents:
• If a parent of the proband and the proband have bilateral retinoblastoma, the risk to the sibs is 50%. In rare families with "familial low-penetrance retinoblastoma," the risk of tumor development in a sib with the germline pathogenic variant is reduced (see
• If the parents are clinically unaffected, the risk to the sibs appears to be low (i.e., 1%-2%; see
• If a parent of the proband and the proband have bilateral retinoblastoma, the risk to the sibs is 50%. In rare families with "familial low-penetrance retinoblastoma," the risk of tumor development in a sib with the germline pathogenic variant is reduced (see
• If the parents are clinically unaffected, the risk to the sibs appears to be low (i.e., 1%-2%; see
• Risk to sibs based on the genetic status of the parents:
• If a parent is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50% and testing of sibs for the
• If the
• If a parent is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50% and testing of sibs for the
• If the
• If the proband clearly shows mosaicism for an
• If molecular genetic testing is not available or is uninformative, empiric risks based on tumor presentation (e.g., unifocal or multifocal) and family history can be used (see
• If a parent has a cytogenetically detectable balanced chromosome 13 translocation or rearrangement, the sibs are at increased risk of inheriting an unbalanced chromosome rearrangement.
• If a parent of the proband and the proband have bilateral retinoblastoma, the risk to the sibs is 50%. In rare families with "familial low-penetrance retinoblastoma," the risk of tumor development in a sib with the germline pathogenic variant is reduced (see
• If the parents are clinically unaffected, the risk to the sibs appears to be low (i.e., 1%-2%; see
• If a parent is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50% and testing of sibs for the
• If the
• If the
• If one of the pathogenic variants identified in the proband's tumor is found to be mosaic in DNA from leukocytes of the proband, the level of germline involvement is uncertain. All offspring should have molecular genetic testing for the pathogenic variant identified in leukocyte DNA of the proband.
• Predictive DNA testing in offspring is possible if the cancer-predisposing
• If molecular genetic testing is not available or is uninformative in the proband, empiric risks based on tumor presentation and family history can be used (see
## Related Genetic Counseling Issues
See Management,
Predictive testing for at-risk asymptomatic family members requires prior identification of the germline
Predictive molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management,
Potential consequences of such testing – including but not limited to 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 [
• Predictive testing for at-risk asymptomatic family members requires prior identification of the germline
• Predictive molecular genetic testing of young, at-risk family members is appropriate for guiding medical management (see Management,
• Potential consequences of such testing – including but not limited to 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
If the germline
When there is a family history of retinoblastoma, various options are available to optimize management of an at-risk pregnancy [
If an
If 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.
• If an
• If the
## Resources
United Kingdom
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• United Kingdom
•
•
•
•
•
•
•
•
•
•
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•
•
## Molecular Genetics
Retinoblastoma: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Retinoblastoma (
The majority of
## Molecular Pathogenesis
The majority of
## Chapter Notes
Contact Dr Dietmar Lohmann (
Norbert Bornfeld, MD; University of Essen (2000-2004)Brenda L Gallie, MD (2004-present)Bernhard Horsthemke, PhD; University of Essen (2000-2004)Dietmar R Lohmann, MD (2000-present)Eberhard Passarge, MD; University of Essen (2000-2004)
21 September 2023 (sw) Comprehensive update posted live
21 November 2018 (sw) Comprehensive update posted live
19 November 2015 (me) Comprehensive update posted live
28 March 2013 (me) Comprehensive update posted live
10 June 2010 (me) Comprehensive update posted live
7 May 2007 (me) Comprehensive update posted live
28 December 2004 (me) Comprehensive update posted live
21 January 2003 (me) Comprehensive update posted live
18 July 2000 (me) Review posted live
21 January 1999 (dl) Original submission
• 21 September 2023 (sw) Comprehensive update posted live
• 21 November 2018 (sw) Comprehensive update posted live
• 19 November 2015 (me) Comprehensive update posted live
• 28 March 2013 (me) Comprehensive update posted live
• 10 June 2010 (me) Comprehensive update posted live
• 7 May 2007 (me) Comprehensive update posted live
• 28 December 2004 (me) Comprehensive update posted live
• 21 January 2003 (me) Comprehensive update posted live
• 18 July 2000 (me) Review posted live
• 21 January 1999 (dl) Original submission
## Author Notes
Contact Dr Dietmar Lohmann (
## Author History
Norbert Bornfeld, MD; University of Essen (2000-2004)Brenda L Gallie, MD (2004-present)Bernhard Horsthemke, PhD; University of Essen (2000-2004)Dietmar R Lohmann, MD (2000-present)Eberhard Passarge, MD; University of Essen (2000-2004)
## Revision History
21 September 2023 (sw) Comprehensive update posted live
21 November 2018 (sw) Comprehensive update posted live
19 November 2015 (me) Comprehensive update posted live
28 March 2013 (me) Comprehensive update posted live
10 June 2010 (me) Comprehensive update posted live
7 May 2007 (me) Comprehensive update posted live
28 December 2004 (me) Comprehensive update posted live
21 January 2003 (me) Comprehensive update posted live
18 July 2000 (me) Review posted live
21 January 1999 (dl) Original submission
• 21 September 2023 (sw) Comprehensive update posted live
• 21 November 2018 (sw) Comprehensive update posted live
• 19 November 2015 (me) Comprehensive update posted live
• 28 March 2013 (me) Comprehensive update posted live
• 10 June 2010 (me) Comprehensive update posted live
• 7 May 2007 (me) Comprehensive update posted live
• 28 December 2004 (me) Comprehensive update posted live
• 21 January 2003 (me) Comprehensive update posted live
• 18 July 2000 (me) Review posted live
• 21 January 1999 (dl) Original submission
## References
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available
American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. 2003.
Canadian Retinoblastoma Society. National Retinoblastoma Strategy Canadian Guidelines for Care: Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44:S1-88. [
Kenya Ministry of Health Ophthalmic Services Unit. Kenya national retinoblastoma strategy best practice guidelines 2014. Available
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available
• American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. 2003.
• Canadian Retinoblastoma Society. National Retinoblastoma Strategy Canadian Guidelines for Care: Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44:S1-88. [
• Kenya Ministry of Health Ophthalmic Services Unit. Kenya national retinoblastoma strategy best practice guidelines 2014. Available
## Published Guidelines / Consensus Statements
American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available
American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. 2003.
Canadian Retinoblastoma Society. National Retinoblastoma Strategy Canadian Guidelines for Care: Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44:S1-88. [
Kenya Ministry of Health Ophthalmic Services Unit. Kenya national retinoblastoma strategy best practice guidelines 2014. Available
• American Society of Clinical Oncology. Policy statement update: genetic testing for cancer susceptibility. Available
• American Society of Clinical Oncology. Statement on genetic testing for cancer susceptibility. 2003.
• Canadian Retinoblastoma Society. National Retinoblastoma Strategy Canadian Guidelines for Care: Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44:S1-88. [
• Kenya Ministry of Health Ophthalmic Services Unit. Kenya national retinoblastoma strategy best practice guidelines 2014. Available
## Literature Cited
Schematic of the molecular genetic mechanisms that result in non-heritable and heritable retinoblastoma. Retinoblastoma occurs in retinal cells with biallelic
In non-heritable retinoblastoma, both pathogenic variants occur in somatic cells. The pathogenic variants are not present in DNA from constitutional cells (e.g., peripheral blood), and two normal alleles are present (RB RB).
In heritable retinoblastoma, the first pathogenic variant is present in constitutional cells (either a
In some affected individuals the first pathogenic variant occurs during embryonal development. The affected individual is somatic mosaic for the first pathogenic variant. A second pathogenic variant can occur in retinal cells containing the first somatic variant, resulting in development of a retinoblastoma (rb rb).
|
[] |
18/7/2000
|
21/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
retinoschisis
|
retinoschisis
|
[
"X-Linked Retinoschisis",
"X-Linked Retinoschisis",
"Retinoschisin",
"RS1",
"X-Linked Congenital Retinoschisis"
] |
X-Linked Congenital Retinoschisis
|
Paul A Sieving, Ian M MacDonald, Stephanie Hoang
|
Summary X-linked congenital retinoschisis (XLRS) is characterized by symmetric bilateral macular involvement with onset in the first decade of life, in some cases as early as age three months. Fundus examination shows areas of schisis (splitting of the nerve fiber layer of the retina) in the macula, sometimes giving the impression of a spoke wheel pattern. Schisis of the peripheral retina, predominantly inferotemporally, occurs in approximately 50% of individuals. Affected males typically have 20/60 to 20/120 vision. Visual acuity often deteriorates during the first and second decades of life but then remains relatively stable until the fifth or sixth decade. The diagnosis of XLRS is established in a male proband with suggestive ophthalmologic findings and a hemizygous pathogenic variant in Low-vision aids such as large-print textbooks; preferential seating in the front of the classroom; and use of handouts with high contrast. Surgery may be required to address the infrequent complications of vitreous hemorrhage and full-thickness retinal detachment. XLRS is inherited in an X-linked manner. Heterozygous females have a 50% chance of transmitting the pathogenic variant in each pregnancy: males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will nearly always have normal visual function. Affected males transmit the pathogenic variant to all of their daughters and none of their sons. Once the
|
## Diagnosis
X-linked congenital retinoschisis (XLRS)
Bilaterally reduced visual acuity, typically between 20/60 and 20/120
No presenting complaint of “night blindness” (i.e., vision difficulty in dim lighting)
Fundus examination revealing:
Areas of schisis (cavities and splitting through the deeper retinal layers) in the macula, frequently giving the impression of a spoke wheel pattern (
Schisis of the peripheral retina, predominantly inferotemporally, in approximately 50% of individuals [
On occasion:
More severe involvement of the macula (
Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
Spectral domain optical coherence tomography (SD-OCT), currently the major diagnostic technique for XLRS, reveals characteristic intraretinal foveal schisis in younger men, while cystic spaces become less evident by middle age as the flattening of cysts (with the appearance of partial macular atrophy) occurs with age [
Electroretinogram (ERG) in more than half of affected males shows characteristic changes of greatly diminished dark-adapted b-wave amplitude despite relative preservation of the a-wave amplitude, termed an "electronegative ERG" [
Increased fundus autofluorescence in the fovea [
Intravenous fluorescein angiogram appears normal in younger boys, with no apparent leakage, whereas older individuals may have atrophic changes and involvement of the retinal pigment epithelium.
The diagnosis of XLRS
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
Note: Targeted analysis can be performed first for the following pathogenic variants in individuals of Finnish ancestry [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Congenital Retinoschisis
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.
• Bilaterally reduced visual acuity, typically between 20/60 and 20/120
• No presenting complaint of “night blindness” (i.e., vision difficulty in dim lighting)
• Fundus examination revealing:
• Areas of schisis (cavities and splitting through the deeper retinal layers) in the macula, frequently giving the impression of a spoke wheel pattern (
• Schisis of the peripheral retina, predominantly inferotemporally, in approximately 50% of individuals [
• On occasion:
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
• Areas of schisis (cavities and splitting through the deeper retinal layers) in the macula, frequently giving the impression of a spoke wheel pattern (
• Schisis of the peripheral retina, predominantly inferotemporally, in approximately 50% of individuals [
• On occasion:
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
• Spectral domain optical coherence tomography (SD-OCT), currently the major diagnostic technique for XLRS, reveals characteristic intraretinal foveal schisis in younger men, while cystic spaces become less evident by middle age as the flattening of cysts (with the appearance of partial macular atrophy) occurs with age [
• Electroretinogram (ERG) in more than half of affected males shows characteristic changes of greatly diminished dark-adapted b-wave amplitude despite relative preservation of the a-wave amplitude, termed an "electronegative ERG" [
• Increased fundus autofluorescence in the fovea [
• Intravenous fluorescein angiogram appears normal in younger boys, with no apparent leakage, whereas older individuals may have atrophic changes and involvement of the retinal pigment epithelium.
• Areas of schisis (cavities and splitting through the deeper retinal layers) in the macula, frequently giving the impression of a spoke wheel pattern (
• Schisis of the peripheral retina, predominantly inferotemporally, in approximately 50% of individuals [
• On occasion:
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
•
•
•
## Suggestive Findings
X-linked congenital retinoschisis (XLRS)
Bilaterally reduced visual acuity, typically between 20/60 and 20/120
No presenting complaint of “night blindness” (i.e., vision difficulty in dim lighting)
Fundus examination revealing:
Areas of schisis (cavities and splitting through the deeper retinal layers) in the macula, frequently giving the impression of a spoke wheel pattern (
Schisis of the peripheral retina, predominantly inferotemporally, in approximately 50% of individuals [
On occasion:
More severe involvement of the macula (
Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
Spectral domain optical coherence tomography (SD-OCT), currently the major diagnostic technique for XLRS, reveals characteristic intraretinal foveal schisis in younger men, while cystic spaces become less evident by middle age as the flattening of cysts (with the appearance of partial macular atrophy) occurs with age [
Electroretinogram (ERG) in more than half of affected males shows characteristic changes of greatly diminished dark-adapted b-wave amplitude despite relative preservation of the a-wave amplitude, termed an "electronegative ERG" [
Increased fundus autofluorescence in the fovea [
Intravenous fluorescein angiogram appears normal in younger boys, with no apparent leakage, whereas older individuals may have atrophic changes and involvement of the retinal pigment epithelium.
• Bilaterally reduced visual acuity, typically between 20/60 and 20/120
• No presenting complaint of “night blindness” (i.e., vision difficulty in dim lighting)
• Fundus examination revealing:
• Areas of schisis (cavities and splitting through the deeper retinal layers) in the macula, frequently giving the impression of a spoke wheel pattern (
• Schisis of the peripheral retina, predominantly inferotemporally, in approximately 50% of individuals [
• On occasion:
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
• Areas of schisis (cavities and splitting through the deeper retinal layers) in the macula, frequently giving the impression of a spoke wheel pattern (
• Schisis of the peripheral retina, predominantly inferotemporally, in approximately 50% of individuals [
• On occasion:
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
• Spectral domain optical coherence tomography (SD-OCT), currently the major diagnostic technique for XLRS, reveals characteristic intraretinal foveal schisis in younger men, while cystic spaces become less evident by middle age as the flattening of cysts (with the appearance of partial macular atrophy) occurs with age [
• Electroretinogram (ERG) in more than half of affected males shows characteristic changes of greatly diminished dark-adapted b-wave amplitude despite relative preservation of the a-wave amplitude, termed an "electronegative ERG" [
• Increased fundus autofluorescence in the fovea [
• Intravenous fluorescein angiogram appears normal in younger boys, with no apparent leakage, whereas older individuals may have atrophic changes and involvement of the retinal pigment epithelium.
• Areas of schisis (cavities and splitting through the deeper retinal layers) in the macula, frequently giving the impression of a spoke wheel pattern (
• Schisis of the peripheral retina, predominantly inferotemporally, in approximately 50% of individuals [
• On occasion:
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
• More severe involvement of the macula (
• Presence of the Mizuo phenomenon, a color change in the retina after dark adaptation with the onset of light
• Pigmentary retinal scarring in the periphery from resolution of pervious tears of the inner retina layers
## Establishing the Diagnosis
The diagnosis of XLRS
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
Note: Targeted analysis can be performed first for the following pathogenic variants in individuals of Finnish ancestry [
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Congenital Retinoschisis
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.
•
•
•
## Option 1
Note: Targeted analysis can be performed first for the following pathogenic variants in individuals of Finnish ancestry [
For an introduction to multigene panels click
•
•
•
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Congenital Retinoschisis
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.
## Clinical Characteristics
X-linked congenital retinoschisis (XLRS) is a symmetric bilateral macular disorder with onset in the first decade of life in males, and, in some instances, as early as age three months. Affected males generally present with reduction in vision by early elementary school. Affected males typically have vision of 20/60 to 20/120 on first presentation.
Visual acuity may deteriorate slightly during the first and second decades of life but then remains relatively stable until the fifth or sixth decade, when slowly progressive macular atrophy can occur [
Variations in disease severity and progression are observed even among members of the same family.
Appearance of foveal lesions varies from largely radial striations (3%), microcystic lesions (34%), honeycomb-like cysts (8%), or their combinations (31%) to non-cystic-appearing foveal changes including pigment mottling (8%), loss of the foveal reflex (8%), or an atrophic-appearing lesion (8%) [
XLRS progresses to retinal detachment in an estimated 5% to 22% of affected individuals. Retinal detachment can occur in infants with severe retinoschisis. About 4% to 40% of individuals with XLRS develop vitreous hemorrhage.
The phenotype comprises a spectrum ranging from a few schisis cavities at the mild end to major retinoschisis detachment (not surgically repairable) at the severe end. The following general genotype-phenotype correlations have been reported:
Pathogenic variants that are predicted to result in loss of protein function are typically associated with greater clinical severity [
Missense pathogenic variants are more commonly associated in milder clinical features, possibly due to residual protein function [
Molecular modeling indicates that predicted change and/or damage to retinoschisin determines progression rate and clinical severity as evaluated by ERG. Importantly, molecular alterations that result in nonsense, splice site, and cysteine disulfide bond variants appear to be associated with the most severe functional deterioration [
Other terms correctly used in the past to refer to X-linked congenital retinoschisis:
X-linked juvenile retinoschisis
Juvenile macular degeneration/dystrophy
Degenerative retinoschisis
Vitreous veils of the retina
Other terms incorrectly used in the past to refer to X-linked congenital retinoschisis:
Cone dystrophy
Macular hole
According to the
• Pathogenic variants that are predicted to result in loss of protein function are typically associated with greater clinical severity [
• Missense pathogenic variants are more commonly associated in milder clinical features, possibly due to residual protein function [
• X-linked juvenile retinoschisis
• Juvenile macular degeneration/dystrophy
• Degenerative retinoschisis
• Vitreous veils of the retina
• Cone dystrophy
• Macular hole
## Clinical Description
X-linked congenital retinoschisis (XLRS) is a symmetric bilateral macular disorder with onset in the first decade of life in males, and, in some instances, as early as age three months. Affected males generally present with reduction in vision by early elementary school. Affected males typically have vision of 20/60 to 20/120 on first presentation.
Visual acuity may deteriorate slightly during the first and second decades of life but then remains relatively stable until the fifth or sixth decade, when slowly progressive macular atrophy can occur [
Variations in disease severity and progression are observed even among members of the same family.
Appearance of foveal lesions varies from largely radial striations (3%), microcystic lesions (34%), honeycomb-like cysts (8%), or their combinations (31%) to non-cystic-appearing foveal changes including pigment mottling (8%), loss of the foveal reflex (8%), or an atrophic-appearing lesion (8%) [
XLRS progresses to retinal detachment in an estimated 5% to 22% of affected individuals. Retinal detachment can occur in infants with severe retinoschisis. About 4% to 40% of individuals with XLRS develop vitreous hemorrhage.
## Genotype-Phenotype Correlations
The phenotype comprises a spectrum ranging from a few schisis cavities at the mild end to major retinoschisis detachment (not surgically repairable) at the severe end. The following general genotype-phenotype correlations have been reported:
Pathogenic variants that are predicted to result in loss of protein function are typically associated with greater clinical severity [
Missense pathogenic variants are more commonly associated in milder clinical features, possibly due to residual protein function [
Molecular modeling indicates that predicted change and/or damage to retinoschisin determines progression rate and clinical severity as evaluated by ERG. Importantly, molecular alterations that result in nonsense, splice site, and cysteine disulfide bond variants appear to be associated with the most severe functional deterioration [
• Pathogenic variants that are predicted to result in loss of protein function are typically associated with greater clinical severity [
• Missense pathogenic variants are more commonly associated in milder clinical features, possibly due to residual protein function [
## Nomenclature
Other terms correctly used in the past to refer to X-linked congenital retinoschisis:
X-linked juvenile retinoschisis
Juvenile macular degeneration/dystrophy
Degenerative retinoschisis
Vitreous veils of the retina
Other terms incorrectly used in the past to refer to X-linked congenital retinoschisis:
Cone dystrophy
Macular hole
• X-linked juvenile retinoschisis
• Juvenile macular degeneration/dystrophy
• Degenerative retinoschisis
• Vitreous veils of the retina
• Cone dystrophy
• Macular hole
## Prevalence
According to the
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
While the presence of retinoschisis in an individual with a positive family history of X-linked congenital retinoschisis (XLRS) establishes the diagnosis in that person, making the diagnosis in a male with no known family history may be more difficult.
Genes of Interest in the Differential Diagnosis of X-Linked Congenital Retinoschisis
AD = autosomal dominant; AR = autosomal recessive; ERG = electroretinogram; MOI = mode of inheritance; XL = X-linked; XLRP = X-linked retinitis pigmentosa; XLRS = X-linked congenital retinoschisis
More than 80 genes are known to be associated with RP (see
## Hereditary Disorders
Genes of Interest in the Differential Diagnosis of X-Linked Congenital Retinoschisis
AD = autosomal dominant; AR = autosomal recessive; ERG = electroretinogram; MOI = mode of inheritance; XL = X-linked; XLRP = X-linked retinitis pigmentosa; XLRS = X-linked congenital retinoschisis
More than 80 genes are known to be associated with RP (see
## Acquired Disorders and Hereditary Disorders of Unknown Genetic Cause
## Management
To establish the extent of disease and needs in an individual diagnosed with X-linked congenital retinoschisis (XLRS), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Complete ophthalmologic examination including:
Best corrected visual acuity
Refractive error
Possible amblyopia
Visual fields, by Goldmann or other perimetry
Fundoscopic examination
Optical coherence tomography
Electroretinogram; confirmatory for half or more of cases by an electronegative configuration or b-wave amplitude reduction disproportionate to a-wave loss
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse for the purpose of informing affected individuals and their families about the nature, mode of inheritance, and implications of XLRS in order to facilitate medical and personal decision making
Note:
Note that amblyopia prevention therapy is indicated following surgical intervention to treat vitreous hemorrhage or retinal detachment, or in cases of severe retinoschisis or hypermetropia [
Care of a retinal surgeon may be required to address the infrequent complications of vitreous hemorrhage and full-thickness retinal detachment. Because the clinical presentation of a large area of peripheral retinoschisis may mask a true retinal detachment, consultation with an ophthalmologist or retinal surgeon is recommended when in doubt.
Public school systems are mandated by federal law to provide appropriate education for children who have vision impairment.
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.
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.
Annual evaluation of children younger than age ten years by a pediatric ophthalmologist to diagnose refractive errors or by a retina specialist to examine the peripheral retina for schisis or detachment is recommended.
Older children and adults need less frequent monitoring as they would be more apt to report changes in vision.
Patient education and close follow up are the only clinical options that may allow for early identification and treatment of vision-threatening complications such as retinal detachment (
Although retinal detachment and vitreous hemorrhage occur in a minority of affected individuals (5%-22% and 4%-40%, respectively), generally avoiding head trauma and high-contact sports is recommended.
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk male relatives of an affected individual in order to identify as early as possible those who would benefit from institution of treatment for retinal detachment and preventive measures (see
If the
If the pathogenic variant in the family is not known, examination by an ophthalmologist can clarify the affected status of at-risk relatives.
See
Successful ocular gene therapy has been demonstrated in mouse XLRS models [
Two human XLRS gene therapy trials were initiated in 2015 (National Eye Institute: ClinicalTrials.gov
The NEI trial found closure of schisis cavities in one individual at higher dosing, which also caused ocular inflammation [
The AGTC trial was halted by inflammation and lack of positive clinical treatment signs.
Search
Note: See
• Complete ophthalmologic examination including:
• Best corrected visual acuity
• Refractive error
• Possible amblyopia
• Best corrected visual acuity
• Refractive error
• Possible amblyopia
• Visual fields, by Goldmann or other perimetry
• Fundoscopic examination
• Optical coherence tomography
• Electroretinogram; confirmatory for half or more of cases by an electronegative configuration or b-wave amplitude reduction disproportionate to a-wave loss
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse for the purpose of informing affected individuals and their families about the nature, mode of inheritance, and implications of XLRS in order to facilitate medical and personal decision making
• Note:
• Best corrected visual acuity
• Refractive error
• Possible amblyopia
• 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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.
• 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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.
• If the
• If the pathogenic variant in the family is not known, examination by an ophthalmologist can clarify the affected status of at-risk relatives.
• The NEI trial found closure of schisis cavities in one individual at higher dosing, which also caused ocular inflammation [
• The AGTC trial was halted by inflammation and lack of positive clinical treatment signs.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with X-linked congenital retinoschisis (XLRS), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Complete ophthalmologic examination including:
Best corrected visual acuity
Refractive error
Possible amblyopia
Visual fields, by Goldmann or other perimetry
Fundoscopic examination
Optical coherence tomography
Electroretinogram; confirmatory for half or more of cases by an electronegative configuration or b-wave amplitude reduction disproportionate to a-wave loss
Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse for the purpose of informing affected individuals and their families about the nature, mode of inheritance, and implications of XLRS in order to facilitate medical and personal decision making
Note:
• Complete ophthalmologic examination including:
• Best corrected visual acuity
• Refractive error
• Possible amblyopia
• Best corrected visual acuity
• Refractive error
• Possible amblyopia
• Visual fields, by Goldmann or other perimetry
• Fundoscopic examination
• Optical coherence tomography
• Electroretinogram; confirmatory for half or more of cases by an electronegative configuration or b-wave amplitude reduction disproportionate to a-wave loss
• Consultation with a medical geneticist, certified genetic counselor, or certified advanced genetic nurse for the purpose of informing affected individuals and their families about the nature, mode of inheritance, and implications of XLRS in order to facilitate medical and personal decision making
• Note:
• Best corrected visual acuity
• Refractive error
• Possible amblyopia
## Treatment of Manifestations
Note that amblyopia prevention therapy is indicated following surgical intervention to treat vitreous hemorrhage or retinal detachment, or in cases of severe retinoschisis or hypermetropia [
Care of a retinal surgeon may be required to address the infrequent complications of vitreous hemorrhage and full-thickness retinal detachment. Because the clinical presentation of a large area of peripheral retinoschisis may mask a true retinal detachment, consultation with an ophthalmologist or retinal surgeon is recommended when in doubt.
Public school systems are mandated by federal law to provide appropriate education for children who have vision impairment.
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.
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.
• 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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.
• 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.
• An IEP provides specially designed instruction and related services to children who qualify.
• IEP services will be reviewed annually to determine whether any changes are needed.
• Special education law requires that children participating in 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.
## Surveillance
Annual evaluation of children younger than age ten years by a pediatric ophthalmologist to diagnose refractive errors or by a retina specialist to examine the peripheral retina for schisis or detachment is recommended.
Older children and adults need less frequent monitoring as they would be more apt to report changes in vision.
Patient education and close follow up are the only clinical options that may allow for early identification and treatment of vision-threatening complications such as retinal detachment (
## Agents/Circumstances to Avoid
Although retinal detachment and vitreous hemorrhage occur in a minority of affected individuals (5%-22% and 4%-40%, respectively), generally avoiding head trauma and high-contact sports is recommended.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic older and younger at-risk male relatives of an affected individual in order to identify as early as possible those who would benefit from institution of treatment for retinal detachment and preventive measures (see
If the
If the pathogenic variant in the family is not known, examination by an ophthalmologist can clarify the affected status of at-risk relatives.
See
• If the
• If the pathogenic variant in the family is not known, examination by an ophthalmologist can clarify the affected status of at-risk relatives.
## Therapies Under Investigation
Successful ocular gene therapy has been demonstrated in mouse XLRS models [
Two human XLRS gene therapy trials were initiated in 2015 (National Eye Institute: ClinicalTrials.gov
The NEI trial found closure of schisis cavities in one individual at higher dosing, which also caused ocular inflammation [
The AGTC trial was halted by inflammation and lack of positive clinical treatment signs.
Search
Note: See
• The NEI trial found closure of schisis cavities in one individual at higher dosing, which also caused ocular inflammation [
• The AGTC trial was halted by inflammation and lack of positive clinical treatment signs.
## Genetic Counseling
X-linked congenital retinoschisis (XLRS) 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 (carrier). Note: If a woman has more than one affected son and no other affected relatives, and if the
Heterozygous females do not exhibit any signs in the macula, and only rarely are peripheral retinal changes associated with the carrier state.
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected. Intrafamilial variability in disease severity and progression is observed in XLRS [
Females who inherit the pathogenic variant will be carriers. Carriers nearly always have normal ocular examination, visual function, and electrophysiology (i.e., ERG).
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
All of their daughters will be (heterozygous) carriers and nearly always have normal visual function and normal electrophysiology (i.e., ERG); and
None of their sons.
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 is most informative if the
Note: (1) Females who are carriers for this X-linked disorder nearly always have normal visual function and normal electrophysiology (i.e., ERG). (2) Identification of female heterozygotes requires either (a) prior identification of the
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.
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 (carrier). Note: If a woman has more than one affected son and no other affected relatives, and if the
• Heterozygous females do not exhibit any signs in the macula, and only rarely are peripheral retinal changes associated with the carrier state.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected. Intrafamilial variability in disease severity and progression is observed in XLRS [
• Females who inherit the pathogenic variant will be carriers. Carriers nearly always have normal ocular examination, visual function, and electrophysiology (i.e., ERG).
• Males who inherit the pathogenic variant will be affected. Intrafamilial variability in disease severity and progression is observed in XLRS [
• Females who inherit the pathogenic variant will be carriers. Carriers nearly always have normal ocular examination, visual function, and electrophysiology (i.e., ERG).
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit the pathogenic variant will be affected. Intrafamilial variability in disease severity and progression is observed in XLRS [
• Females who inherit the pathogenic variant will be carriers. Carriers nearly always have normal ocular examination, visual function, and electrophysiology (i.e., ERG).
• All of their daughters will be (heterozygous) carriers and nearly always have normal visual function and normal electrophysiology (i.e., ERG); and
• None of their sons.
• 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
X-linked congenital retinoschisis (XLRS) 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 (carrier). Note: If a woman has more than one affected son and no other affected relatives, and if the
Heterozygous females do not exhibit any signs in the macula, and only rarely are peripheral retinal changes associated with the carrier state.
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
If the mother of the proband has an
Males who inherit the pathogenic variant will be affected. Intrafamilial variability in disease severity and progression is observed in XLRS [
Females who inherit the pathogenic variant will be carriers. Carriers nearly always have normal ocular examination, visual function, and electrophysiology (i.e., ERG).
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
All of their daughters will be (heterozygous) carriers and nearly always have normal visual function and normal electrophysiology (i.e., ERG); and
None of their sons.
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 (carrier). Note: If a woman has more than one affected son and no other affected relatives, and if the
• Heterozygous females do not exhibit any signs in the macula, and only rarely are peripheral retinal changes associated with the carrier state.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
• If the mother of the proband has an
• Males who inherit the pathogenic variant will be affected. Intrafamilial variability in disease severity and progression is observed in XLRS [
• Females who inherit the pathogenic variant will be carriers. Carriers nearly always have normal ocular examination, visual function, and electrophysiology (i.e., ERG).
• Males who inherit the pathogenic variant will be affected. Intrafamilial variability in disease severity and progression is observed in XLRS [
• Females who inherit the pathogenic variant will be carriers. Carriers nearly always have normal ocular examination, visual function, and electrophysiology (i.e., ERG).
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Males who inherit the pathogenic variant will be affected. Intrafamilial variability in disease severity and progression is observed in XLRS [
• Females who inherit the pathogenic variant will be carriers. Carriers nearly always have normal ocular examination, visual function, and electrophysiology (i.e., ERG).
• All of their daughters will be (heterozygous) carriers and nearly always have normal visual function and normal electrophysiology (i.e., ERG); and
• None of their sons.
## Carrier Detection
Molecular genetic testing of at-risk female relatives to determine their genetic status is most informative if the
Note: (1) Females who are carriers for this X-linked disorder nearly always have normal visual function and normal electrophysiology (i.e., ERG). (2) Identification of female heterozygotes requires either (a) prior identification of the
## Related Genetic Counseling Issues
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.
• 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
Ireland
•
•
•
•
•
• Ireland
•
## Molecular Genetics
X-Linked Congenital Retinoschisis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for X-Linked Congenital Retinoschisis (
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
Stephanie Hoang, MSc (2014-present)Ian M MacDonald, MD, CM (2003-present)Paul A Sieving, MD, PhD (2003-present)Meira Rina Meltzer, MA, MS; National Institutes of Health (2003-2014)Nizar Smaoui, MD, FACMG; GeneDx (2003-2014)
5 November 2020 (bp) Comprehensive update posted live
28 August 2014 (me) Comprehensive update posted live
12 May 2009 (me) Comprehensive update posted live
18 January 2006 (me) Comprehensive update posted live
24 October 2003 (me) Review posted live
1 July 2003 (ps) Original submission
• 5 November 2020 (bp) Comprehensive update posted live
• 28 August 2014 (me) Comprehensive update posted live
• 12 May 2009 (me) Comprehensive update posted live
• 18 January 2006 (me) Comprehensive update posted live
• 24 October 2003 (me) Review posted live
• 1 July 2003 (ps) Original submission
## Author History
Stephanie Hoang, MSc (2014-present)Ian M MacDonald, MD, CM (2003-present)Paul A Sieving, MD, PhD (2003-present)Meira Rina Meltzer, MA, MS; National Institutes of Health (2003-2014)Nizar Smaoui, MD, FACMG; GeneDx (2003-2014)
## Revision History
5 November 2020 (bp) Comprehensive update posted live
28 August 2014 (me) Comprehensive update posted live
12 May 2009 (me) Comprehensive update posted live
18 January 2006 (me) Comprehensive update posted live
24 October 2003 (me) Review posted live
1 July 2003 (ps) Original submission
• 5 November 2020 (bp) Comprehensive update posted live
• 28 August 2014 (me) Comprehensive update posted live
• 12 May 2009 (me) Comprehensive update posted live
• 18 January 2006 (me) Comprehensive update posted live
• 24 October 2003 (me) Review posted live
• 1 July 2003 (ps) Original submission
## References
AAO Task Force on Genetic Testing. American Academy of Ophthalmology Recommendations for Genetic Testing of Inherited Eye Diseases - 2014. Available
• AAO Task Force on Genetic Testing. American Academy of Ophthalmology Recommendations for Genetic Testing of Inherited Eye Diseases - 2014. Available
## Published Guidelines / Consensus Statements
AAO Task Force on Genetic Testing. American Academy of Ophthalmology Recommendations for Genetic Testing of Inherited Eye Diseases - 2014. Available
• AAO Task Force on Genetic Testing. American Academy of Ophthalmology Recommendations for Genetic Testing of Inherited Eye Diseases - 2014. Available
## Literature Cited
Fundus photo of a male with congenital retinoschisis. Arrow points to typical spoke-wheel pattern of foveal cysts.
Fundus photo of the peripheral retina of a male with congenital retinoschisis. Area marked with arrows shows a partial-thickness retinal hole.
Fundus photo of a male with congenital retinoschisis showing atypical, more severe findings with arrows pointing to atrophic macular changes
|
[] |
24/10/2003
|
5/11/2020
|
18/6/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
rett
|
rett
|
[
"MECP2 Classic Rett Syndrome",
"MECP2-Related Severe Neonatal Encephalopathy",
"Pyramidal Signs, Parkinsonism, and Macroorchidism (PPM-X) Syndrome",
"Variant Rett Syndrome",
"Methyl-CpG-binding protein 2",
"MECP2",
"MECP2 Disorders"
] |
Simranpreet Kaur, John Christodoulou
|
Summary The spectrum of The diagnosis of a
|
Variant Rett syndrome
Mild learning disabilities
Pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome
Syndromic/nonsyndromic intellectual disability
For other genetic causes of these phenotypes see
Note: The allelic disorder
• Variant Rett syndrome
• Mild learning disabilities
• Pyramidal signs, parkinsonism, and macroorchidism (PPM-X) syndrome
• Syndromic/nonsyndromic intellectual disability
## Diagnosis
Note: Duplication of
A
Most distinguishing finding: A period of regression (range: ages 1-4 years) followed by recovery or stabilization (range: ages 2-10 years; mean: age 5 years)
Main findings
Partial or complete loss of acquired purposeful hand skills
Partial or complete loss of acquired spoken language or language skill (e.g., babble)
Gait abnormalities: impaired (dyspraxic) or absence of ability
Stereotypic hand movements including hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms
Supportive findings
Breathing disturbances when awake
Bruxism when awake
Impaired sleep pattern
Abnormal muscle tone
Peripheral vasomotor disturbances
Scoliosis/kyphosis
Growth restriction
Small, cold hands and feet
Inappropriate laughing/screaming spells
Diminished response to pain
Intense eye communication – "eye pointing"
Exclusionary findings
Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection that causes neurologic problems
Grossly abnormal psychomotor development in the first six months of life, with early milestones not being met
Microcephaly
Relentless clinical course that follows a metabolic-degenerative type of pattern
Abnormal tone
Involuntary movements
Severe seizures
Breathing abnormalities (including central hypoventilation or respiratory insufficiency)
Moderate-to-severe intellectual disability
Resting tremor
Slowness of movements
Ataxia
PPM-X syndrome:
No seizures or microcephaly
Usually normal brain MRI, EEG, EMG, and nerve conduction velocity studies
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 clinical findings suggest the diagnosis of a
Various
For an introduction to multigene panels click
When the phenotype overlaps with many other inherited disorders characterized by intellectual disability and/or neonatal encephalopathy,
If exome sequencing is not diagnostic,
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. 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
The sizes of many reported disease-associated deletions are at the upper limits of detection by sequence analysis and the lower limits of detection by gene-targeted deletion/duplication analysis; therefore, the proportion of pathogenic variants detected by either method depends on the methods used by a laboratory.
• Most distinguishing finding: A period of regression (range: ages 1-4 years) followed by recovery or stabilization (range: ages 2-10 years; mean: age 5 years)
• Main findings
• Partial or complete loss of acquired purposeful hand skills
• Partial or complete loss of acquired spoken language or language skill (e.g., babble)
• Gait abnormalities: impaired (dyspraxic) or absence of ability
• Stereotypic hand movements including hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms
• Partial or complete loss of acquired purposeful hand skills
• Partial or complete loss of acquired spoken language or language skill (e.g., babble)
• Gait abnormalities: impaired (dyspraxic) or absence of ability
• Stereotypic hand movements including hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms
• Supportive findings
• Breathing disturbances when awake
• Bruxism when awake
• Impaired sleep pattern
• Abnormal muscle tone
• Peripheral vasomotor disturbances
• Scoliosis/kyphosis
• Growth restriction
• Small, cold hands and feet
• Inappropriate laughing/screaming spells
• Diminished response to pain
• Intense eye communication – "eye pointing"
• Breathing disturbances when awake
• Bruxism when awake
• Impaired sleep pattern
• Abnormal muscle tone
• Peripheral vasomotor disturbances
• Scoliosis/kyphosis
• Growth restriction
• Small, cold hands and feet
• Inappropriate laughing/screaming spells
• Diminished response to pain
• Intense eye communication – "eye pointing"
• Exclusionary findings
• Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection that causes neurologic problems
• Grossly abnormal psychomotor development in the first six months of life, with early milestones not being met
• Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection that causes neurologic problems
• Grossly abnormal psychomotor development in the first six months of life, with early milestones not being met
• Partial or complete loss of acquired purposeful hand skills
• Partial or complete loss of acquired spoken language or language skill (e.g., babble)
• Gait abnormalities: impaired (dyspraxic) or absence of ability
• Stereotypic hand movements including hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms
• Breathing disturbances when awake
• Bruxism when awake
• Impaired sleep pattern
• Abnormal muscle tone
• Peripheral vasomotor disturbances
• Scoliosis/kyphosis
• Growth restriction
• Small, cold hands and feet
• Inappropriate laughing/screaming spells
• Diminished response to pain
• Intense eye communication – "eye pointing"
• Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection that causes neurologic problems
• Grossly abnormal psychomotor development in the first six months of life, with early milestones not being met
• Microcephaly
• Relentless clinical course that follows a metabolic-degenerative type of pattern
• Abnormal tone
• Involuntary movements
• Severe seizures
• Breathing abnormalities (including central hypoventilation or respiratory insufficiency)
• Moderate-to-severe intellectual disability
• Resting tremor
• Slowness of movements
• Ataxia
• PPM-X syndrome:
• No seizures or microcephaly
• Usually normal brain MRI, EEG, EMG, and nerve conduction velocity studies
• Various
• For an introduction to multigene panels click
## Suggestive Findings in Females
A
Most distinguishing finding: A period of regression (range: ages 1-4 years) followed by recovery or stabilization (range: ages 2-10 years; mean: age 5 years)
Main findings
Partial or complete loss of acquired purposeful hand skills
Partial or complete loss of acquired spoken language or language skill (e.g., babble)
Gait abnormalities: impaired (dyspraxic) or absence of ability
Stereotypic hand movements including hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms
Supportive findings
Breathing disturbances when awake
Bruxism when awake
Impaired sleep pattern
Abnormal muscle tone
Peripheral vasomotor disturbances
Scoliosis/kyphosis
Growth restriction
Small, cold hands and feet
Inappropriate laughing/screaming spells
Diminished response to pain
Intense eye communication – "eye pointing"
Exclusionary findings
Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection that causes neurologic problems
Grossly abnormal psychomotor development in the first six months of life, with early milestones not being met
• Most distinguishing finding: A period of regression (range: ages 1-4 years) followed by recovery or stabilization (range: ages 2-10 years; mean: age 5 years)
• Main findings
• Partial or complete loss of acquired purposeful hand skills
• Partial or complete loss of acquired spoken language or language skill (e.g., babble)
• Gait abnormalities: impaired (dyspraxic) or absence of ability
• Stereotypic hand movements including hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms
• Partial or complete loss of acquired purposeful hand skills
• Partial or complete loss of acquired spoken language or language skill (e.g., babble)
• Gait abnormalities: impaired (dyspraxic) or absence of ability
• Stereotypic hand movements including hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms
• Supportive findings
• Breathing disturbances when awake
• Bruxism when awake
• Impaired sleep pattern
• Abnormal muscle tone
• Peripheral vasomotor disturbances
• Scoliosis/kyphosis
• Growth restriction
• Small, cold hands and feet
• Inappropriate laughing/screaming spells
• Diminished response to pain
• Intense eye communication – "eye pointing"
• Breathing disturbances when awake
• Bruxism when awake
• Impaired sleep pattern
• Abnormal muscle tone
• Peripheral vasomotor disturbances
• Scoliosis/kyphosis
• Growth restriction
• Small, cold hands and feet
• Inappropriate laughing/screaming spells
• Diminished response to pain
• Intense eye communication – "eye pointing"
• Exclusionary findings
• Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection that causes neurologic problems
• Grossly abnormal psychomotor development in the first six months of life, with early milestones not being met
• Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection that causes neurologic problems
• Grossly abnormal psychomotor development in the first six months of life, with early milestones not being met
• Partial or complete loss of acquired purposeful hand skills
• Partial or complete loss of acquired spoken language or language skill (e.g., babble)
• Gait abnormalities: impaired (dyspraxic) or absence of ability
• Stereotypic hand movements including hand wringing/squeezing, clapping/tapping, mouthing, and washing/rubbing automatisms
• Breathing disturbances when awake
• Bruxism when awake
• Impaired sleep pattern
• Abnormal muscle tone
• Peripheral vasomotor disturbances
• Scoliosis/kyphosis
• Growth restriction
• Small, cold hands and feet
• Inappropriate laughing/screaming spells
• Diminished response to pain
• Intense eye communication – "eye pointing"
• Brain injury secondary to peri- or postnatal trauma, neurometabolic disease, or severe infection that causes neurologic problems
• Grossly abnormal psychomotor development in the first six months of life, with early milestones not being met
## Suggestive Findings in Males
Microcephaly
Relentless clinical course that follows a metabolic-degenerative type of pattern
Abnormal tone
Involuntary movements
Severe seizures
Breathing abnormalities (including central hypoventilation or respiratory insufficiency)
Moderate-to-severe intellectual disability
Resting tremor
Slowness of movements
Ataxia
PPM-X syndrome:
No seizures or microcephaly
Usually normal brain MRI, EEG, EMG, and nerve conduction velocity studies
• Microcephaly
• Relentless clinical course that follows a metabolic-degenerative type of pattern
• Abnormal tone
• Involuntary movements
• Severe seizures
• Breathing abnormalities (including central hypoventilation or respiratory insufficiency)
• Moderate-to-severe intellectual disability
• Resting tremor
• Slowness of movements
• Ataxia
• PPM-X syndrome:
• No seizures or microcephaly
• Usually normal brain MRI, EEG, EMG, and nerve conduction velocity studies
## 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 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 clinical findings suggest the diagnosis of a
Various
For an introduction to multigene panels click
When the phenotype overlaps with many other inherited disorders characterized by intellectual disability and/or neonatal encephalopathy,
If exome sequencing is not diagnostic,
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. 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
The sizes of many reported disease-associated deletions are at the upper limits of detection by sequence analysis and the lower limits of detection by gene-targeted deletion/duplication analysis; therefore, the proportion of pathogenic variants detected by either method depends on the methods used by a laboratory.
• Various
• For an introduction to multigene panels click
## Option 1
When the clinical findings suggest the diagnosis of a
Various
For an introduction to multigene panels click
• Various
• For an introduction to multigene panels click
## Option 2
When the phenotype overlaps with many other inherited disorders characterized by intellectual disability and/or neonatal encephalopathy,
If exome sequencing is not diagnostic,
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. 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
The sizes of many reported disease-associated deletions are at the upper limits of detection by sequence analysis and the lower limits of detection by gene-targeted deletion/duplication analysis; therefore, the proportion of pathogenic variants detected by either method depends on the methods used by a laboratory.
## Clinical Characteristics
In females the spectrum of
Features of MECP2 Disorders in Females
Although early development is reportedly normal in children with classic Rett syndrome, parents – in retrospect – often identify subtle differences compared to unaffected sibs. Most (but not all) affected children have acquired microcephaly; stereotypic hand movements and breathing irregularities are seen in the majority.
Features of
The severe encephalopathy phenotype appears to be rare in females [
Genotype-phenotype correlations are inconsistent, due in part to the pattern of X-chromosome inactivation (XCI); females who have a
The worldwide prevalence is 1:10,000-1:23,000 female births [
## Clinical Description
In females the spectrum of
Features of MECP2 Disorders in Females
Although early development is reportedly normal in children with classic Rett syndrome, parents – in retrospect – often identify subtle differences compared to unaffected sibs. Most (but not all) affected children have acquired microcephaly; stereotypic hand movements and breathing irregularities are seen in the majority.
Features of
The severe encephalopathy phenotype appears to be rare in females [
Features of MECP2 Disorders in Females
Although early development is reportedly normal in children with classic Rett syndrome, parents – in retrospect – often identify subtle differences compared to unaffected sibs. Most (but not all) affected children have acquired microcephaly; stereotypic hand movements and breathing irregularities are seen in the majority.
Features of
The severe encephalopathy phenotype appears to be rare in females [
## Genotype-Phenotype Correlations
Genotype-phenotype correlations are inconsistent, due in part to the pattern of X-chromosome inactivation (XCI); females who have a
## Prevalence
The worldwide prevalence is 1:10,000-1:23,000 female births [
## Genetically Related (Allelic) Disorders
Duplications of
The birth prevalence of
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of
AD = autosomal dominant; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
The risk to sibs of a proband depends on the genetic mechanism leading to the loss of
Overlapping features and a similar facial appearance between individuals with
## Management
To establish the extent of disease and needs in an individual diagnosed with a
Recommended Evaluations Following Initial Diagnosis in Individuals with a
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Scoliosis
Mobility & activities of daily living & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Eval of aspiration risk & nutritional status
History of constipation & GERD
Analysis for abnormalities of breathing regularity
Noninvasive assessment of pulmonary gas exchange
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
Treatment needs to be individualized following an assessment of the affected individual's clinical problems and needs.
Management is symptomatic and focuses on optimizing the individual's abilities using a multidisciplinary approach with input from a pediatric or adult specialist physician, dietician, occupational therapist, speech therapist, music therapist, dentist, and other medical subspecialists as needed.
Treatment of Manifestations in Individuals with a
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Constipation: stool softeners, prokinetics, osmotic agents, or laxatives as needed
GERD: anti-reflux agents, smaller & thickened feedings, & positioning
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
ASM = anti-seizure medication; DD = developmental delay; GERD = gastroesophageal reflux disease; 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 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 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.
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.
Many of the clinical features in females with atypical Rett syndrome (
Recommended Surveillance for Individuals with a
Measurement of growth parameters
Eval 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.
Physical medicine, OT/PT assessment of mobility, self-help skills
Monitor scoliosis.
OT = occupational therapy; PT = physical therapy
Because individuals with
Prokinetic agents (e.g., cisapride)
Antipsychotics (e.g., thioridazine), tricyclic antidepressants (e.g., imipramine)
Antiarrhythmics (e.g., quinidine, sotolol, amiodarone)
Anesthetic agents (e.g., thiopental, succinylcholine)
Antibiotics (e.g., erythromycin, ketoconazole)
See
See
A number of clinical trials are currently under way, including observational studies, studies focused on improvement of language and communication skills, and drug trials.
For details see
Search
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Scoliosis
• Mobility & activities of daily living & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Eval of aspiration risk & nutritional status
• History of constipation & GERD
• Analysis for abnormalities of breathing regularity
• Noninvasive assessment of pulmonary gas exchange
• 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
• Constipation: stool softeners, prokinetics, osmotic agents, or laxatives as needed
• GERD: anti-reflux agents, smaller & thickened feedings, & positioning
• 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
• 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 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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, e.g., seizures, changes in tone, movement disorders.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Monitor scoliosis.
• Prokinetic agents (e.g., cisapride)
• Antipsychotics (e.g., thioridazine), tricyclic antidepressants (e.g., imipramine)
• Antiarrhythmics (e.g., quinidine, sotolol, amiodarone)
• Anesthetic agents (e.g., thiopental, succinylcholine)
• Antibiotics (e.g., erythromycin, ketoconazole)
## 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
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Scoliosis
Mobility & activities of daily living & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
Eval of aspiration risk & nutritional status
History of constipation & GERD
Analysis for abnormalities of breathing regularity
Noninvasive assessment of pulmonary gas exchange
Community or
Social work involvement for parental support;
Home nursing referral.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Scoliosis
• Mobility & activities of daily living & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• Eval of aspiration risk & nutritional status
• History of constipation & GERD
• Analysis for abnormalities of breathing regularity
• Noninvasive assessment of pulmonary gas exchange
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment needs to be individualized following an assessment of the affected individual's clinical problems and needs.
Management is symptomatic and focuses on optimizing the individual's abilities using a multidisciplinary approach with input from a pediatric or adult specialist physician, dietician, occupational therapist, speech therapist, music therapist, dentist, and other medical subspecialists as needed.
Treatment of Manifestations in Individuals with a
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Constipation: stool softeners, prokinetics, osmotic agents, or laxatives as needed
GERD: anti-reflux agents, smaller & thickened feedings, & positioning
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
ASM = anti-seizure medication; DD = developmental delay; GERD = gastroesophageal reflux disease; 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 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 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.
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.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Constipation: stool softeners, prokinetics, osmotic agents, or laxatives as needed
• GERD: anti-reflux agents, smaller & thickened feedings, & positioning
• 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
• 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 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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 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 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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
Many of the clinical features in females with atypical Rett syndrome (
Recommended Surveillance for Individuals with a
Measurement of growth parameters
Eval 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.
Physical medicine, OT/PT assessment of mobility, self-help skills
Monitor scoliosis.
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, e.g., seizures, changes in tone, movement disorders.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Monitor scoliosis.
## Agents/Circumstances to Avoid
Because individuals with
Prokinetic agents (e.g., cisapride)
Antipsychotics (e.g., thioridazine), tricyclic antidepressants (e.g., imipramine)
Antiarrhythmics (e.g., quinidine, sotolol, amiodarone)
Anesthetic agents (e.g., thiopental, succinylcholine)
Antibiotics (e.g., erythromycin, ketoconazole)
See
• Prokinetic agents (e.g., cisapride)
• Antipsychotics (e.g., thioridazine), tricyclic antidepressants (e.g., imipramine)
• Antiarrhythmics (e.g., quinidine, sotolol, amiodarone)
• Anesthetic agents (e.g., thiopental, succinylcholine)
• Antibiotics (e.g., erythromycin, ketoconazole)
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
A number of clinical trials are currently under way, including observational studies, studies focused on improvement of language and communication skills, and drug trials.
For details see
Search
## Genetic Counseling
Approximately 99.5% of affected individuals represent simplex cases (i.e., a single occurrence in the family).
Female proband.
Male proband.
The mother of a proband who is found to be heterozygous for a
If the
Maternal germline mosaicism was reported in one of nine pregnancies [
Paternal germline mosaicism was reported in five fathers of affected daugthers from 21 families [
If the mother of the proband has a
Females who inherit the pathogenic variant are at high risk of developing a
Males who inherit the variant may have a severe neonatal encephalopathy or, if they survive the first year, will most likely have a severe intellectual disability syndrome.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Each child of a female proband with a
Males with 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 young adults who are mildly affected or are at risk of having a pathogenic
Once the
Note: Because parental germline mosaicism for a
• Approximately 99.5% of affected individuals represent simplex cases (i.e., a single occurrence in the family).
• Female proband.
• Male proband.
• The mother of a proband who is found to be heterozygous for a
• If the
• Maternal germline mosaicism was reported in one of nine pregnancies [
• Paternal germline mosaicism was reported in five fathers of affected daugthers from 21 families [
• Maternal germline mosaicism was reported in one of nine pregnancies [
• Paternal germline mosaicism was reported in five fathers of affected daugthers from 21 families [
• Maternal germline mosaicism was reported in one of nine pregnancies [
• Paternal germline mosaicism was reported in five fathers of affected daugthers from 21 families [
• If the mother of the proband has a
• Females who inherit the pathogenic variant are at high risk of developing a
• Males who inherit the variant may have a severe neonatal encephalopathy or, if they survive the first year, will most likely have a severe intellectual disability syndrome.
• Females who inherit the pathogenic variant are at high risk of developing a
• Males who inherit the variant may have a severe neonatal encephalopathy or, if they survive the first year, will most likely have a severe intellectual disability syndrome.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Females who inherit the pathogenic variant are at high risk of developing a
• Males who inherit the variant may have a severe neonatal encephalopathy or, if they survive the first year, will most likely have a severe intellectual disability syndrome.
• Each child of a female proband with a
• Males with 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 young adults who are mildly affected or are at risk of having a pathogenic
## Mode of Inheritance
## Risk to Family Members
Approximately 99.5% of affected individuals represent simplex cases (i.e., a single occurrence in the family).
Female proband.
Male proband.
The mother of a proband who is found to be heterozygous for a
If the
Maternal germline mosaicism was reported in one of nine pregnancies [
Paternal germline mosaicism was reported in five fathers of affected daugthers from 21 families [
If the mother of the proband has a
Females who inherit the pathogenic variant are at high risk of developing a
Males who inherit the variant may have a severe neonatal encephalopathy or, if they survive the first year, will most likely have a severe intellectual disability syndrome.
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
Each child of a female proband with a
Males with a
• Approximately 99.5% of affected individuals represent simplex cases (i.e., a single occurrence in the family).
• Female proband.
• Male proband.
• The mother of a proband who is found to be heterozygous for a
• If the
• Maternal germline mosaicism was reported in one of nine pregnancies [
• Paternal germline mosaicism was reported in five fathers of affected daugthers from 21 families [
• Maternal germline mosaicism was reported in one of nine pregnancies [
• Paternal germline mosaicism was reported in five fathers of affected daugthers from 21 families [
• Maternal germline mosaicism was reported in one of nine pregnancies [
• Paternal germline mosaicism was reported in five fathers of affected daugthers from 21 families [
• If the mother of the proband has a
• Females who inherit the pathogenic variant are at high risk of developing a
• Males who inherit the variant may have a severe neonatal encephalopathy or, if they survive the first year, will most likely have a severe intellectual disability syndrome.
• Females who inherit the pathogenic variant are at high risk of developing a
• Males who inherit the variant may have a severe neonatal encephalopathy or, if they survive the first year, will most likely have a severe intellectual disability syndrome.
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Females who inherit the pathogenic variant are at high risk of developing a
• Males who inherit the variant may have a severe neonatal encephalopathy or, if they survive the first year, will most likely have a severe intellectual disability syndrome.
• Each child of a female proband with a
• Males with a
## 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 mildly affected or are at risk of having a pathogenic
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are mildly affected or are at risk of having a pathogenic
## Prenatal Testing and Preimplantation Genetic Testing
Once the
Note: Because parental germline mosaicism for a
## Resources
Telethon Kids Institute
Australia
New Zealand
United Kingdom
•
• Telethon Kids Institute
• Australia
•
•
•
•
•
•
•
•
•
•
• New Zealand
•
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
MECP2 Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for MECP2 Disorders (
Loss of the protein MeCP2 leads to epigenetic aberrations of chromatin, suggesting that MeCP2 deficiency could lead to loss of imprinting, thereby contributing to the pathogenesis of Rett syndrome [
The nuclear MeCP2 protein functional domains include:
Methyl binding domain (MBD): binds specifically to DNA at symmetrically methylated CpGs within chromatin [
Transcription repression domain (TRD): responsible for recruiting other proteins that mediate transcription repression
A-T hook domain: basic residues that bind A-T rich DNA [
WW domain: conserved C-terminal domain [
It has also been shown that MeCP2 plays a role in gene splicing [
Although the isoforms are nearly identical, use of two alternative start codons creates alternative N-termini. The e1 transcript is much more highly expressed in brain than the e2 transcript [
Exon 1 (
Exon 2 (
The majority of pathogenic variants occur in the region encoding the methyl binding domain (MBD, exons 3 and 4; amino acids 90-174 of the MeCP2 e2 isoform), affecting the ability of the MeCP2 protein to bind to target DNA. A number of highly recurrent nonsense variants are found in the transcriptional repression domain (TRD, exon 4; amino acids 219-322 of the MeCP2 e2 isoform) and beyond the TRD, a large number of frameshift variants delete the C-terminal end of the protein (3' end of exon 4).
Notable
ID = intellectual disability
Variants listed in the table have been provided by the authors.
• Methyl binding domain (MBD): binds specifically to DNA at symmetrically methylated CpGs within chromatin [
• Transcription repression domain (TRD): responsible for recruiting other proteins that mediate transcription repression
• A-T hook domain: basic residues that bind A-T rich DNA [
• WW domain: conserved C-terminal domain [
• Exon 1 (
• Exon 2 (
## Molecular Pathogenesis
Loss of the protein MeCP2 leads to epigenetic aberrations of chromatin, suggesting that MeCP2 deficiency could lead to loss of imprinting, thereby contributing to the pathogenesis of Rett syndrome [
The nuclear MeCP2 protein functional domains include:
Methyl binding domain (MBD): binds specifically to DNA at symmetrically methylated CpGs within chromatin [
Transcription repression domain (TRD): responsible for recruiting other proteins that mediate transcription repression
A-T hook domain: basic residues that bind A-T rich DNA [
WW domain: conserved C-terminal domain [
It has also been shown that MeCP2 plays a role in gene splicing [
Although the isoforms are nearly identical, use of two alternative start codons creates alternative N-termini. The e1 transcript is much more highly expressed in brain than the e2 transcript [
Exon 1 (
Exon 2 (
The majority of pathogenic variants occur in the region encoding the methyl binding domain (MBD, exons 3 and 4; amino acids 90-174 of the MeCP2 e2 isoform), affecting the ability of the MeCP2 protein to bind to target DNA. A number of highly recurrent nonsense variants are found in the transcriptional repression domain (TRD, exon 4; amino acids 219-322 of the MeCP2 e2 isoform) and beyond the TRD, a large number of frameshift variants delete the C-terminal end of the protein (3' end of exon 4).
Notable
ID = intellectual disability
Variants listed in the table have been provided by the authors.
• Methyl binding domain (MBD): binds specifically to DNA at symmetrically methylated CpGs within chromatin [
• Transcription repression domain (TRD): responsible for recruiting other proteins that mediate transcription repression
• A-T hook domain: basic residues that bind A-T rich DNA [
• WW domain: conserved C-terminal domain [
• Exon 1 (
• Exon 2 (
## Chapter Notes
Vicky L Brandt; Baylor College of Medicine (2000-2004)John Christodoulou, MBBS, PhD, FRACP, FRCPA, FHGSA (2006-present)Gladys Ho, MSc; Children's Hospital at Westmead, Sydney (2009-2019)Simranpreet Kaur, MSci, MPhil (2019-present)Huda Y Zoghbi, MD; Baylor College of Medicine (2004-2006)
19 September 2019 (bp) Comprehensive update posted live
28 June 2012 (me) Comprehensive update posted live
2 April 2009 (me) Comprehensive update posted live
15 August 2006 (me) Comprehensive update posted live
11 February 2004 (me) Comprehensive update posted live
3 October 2001 (me) Review posted live
September 2000 (vb) Original submission
• 19 September 2019 (bp) Comprehensive update posted live
• 28 June 2012 (me) Comprehensive update posted live
• 2 April 2009 (me) Comprehensive update posted live
• 15 August 2006 (me) Comprehensive update posted live
• 11 February 2004 (me) Comprehensive update posted live
• 3 October 2001 (me) Review posted live
• September 2000 (vb) Original submission
## Author History
Vicky L Brandt; Baylor College of Medicine (2000-2004)John Christodoulou, MBBS, PhD, FRACP, FRCPA, FHGSA (2006-present)Gladys Ho, MSc; Children's Hospital at Westmead, Sydney (2009-2019)Simranpreet Kaur, MSci, MPhil (2019-present)Huda Y Zoghbi, MD; Baylor College of Medicine (2004-2006)
## Revision History
19 September 2019 (bp) Comprehensive update posted live
28 June 2012 (me) Comprehensive update posted live
2 April 2009 (me) Comprehensive update posted live
15 August 2006 (me) Comprehensive update posted live
11 February 2004 (me) Comprehensive update posted live
3 October 2001 (me) Review posted live
September 2000 (vb) Original submission
• 19 September 2019 (bp) Comprehensive update posted live
• 28 June 2012 (me) Comprehensive update posted live
• 2 April 2009 (me) Comprehensive update posted live
• 15 August 2006 (me) Comprehensive update posted live
• 11 February 2004 (me) Comprehensive update posted live
• 3 October 2001 (me) Review posted live
• September 2000 (vb) Original submission
## References
Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, van Bosse H, Bebbington A, Larsson EL, Smith BG, Baikie G, Fyfe S, Leonard H. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine. 2009;34:E607-17.
• Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, van Bosse H, Bebbington A, Larsson EL, Smith BG, Baikie G, Fyfe S, Leonard H. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine. 2009;34:E607-17.
## Published Guidelines / Consensus Statements
Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, van Bosse H, Bebbington A, Larsson EL, Smith BG, Baikie G, Fyfe S, Leonard H. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine. 2009;34:E607-17.
• Downs J, Bergman A, Carter P, Anderson A, Palmer GM, Roye D, van Bosse H, Bebbington A, Larsson EL, Smith BG, Baikie G, Fyfe S, Leonard H. Guidelines for management of scoliosis in Rett syndrome patients based on expert consensus and clinical evidence. Spine. 2009;34:E607-17.
## Literature Cited
|
[] |
3/10/2001
|
19/9/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
rfc1-canvas
|
rfc1-canvas
|
[
"RFC1-CANVAS",
"RFC1-Cerebellar Ataxia, Neuropathy, Vestibular Areflexia Syndrome",
"Replication factor C subunit 1",
"RFC1",
"RFC1 CANVAS / Spectrum Disorder"
] |
Andrea Cortese, Mary M Reilly, Henry Houlden
|
Summary The phenotypic spectrum associated with biallelic The diagnosis of
|
The phenotypic spectrum associated with biallelic intronic AAGGG pentanucleotide expansions in
## Diagnosis
Formal diagnostic criteria for
Symptoms include unsteadiness (imbalance, dizziness), falls, clumsiness of hands.
Examination reveals progressive ataxia of gait and limb dysmetria.
Symptoms include unsteadiness, loss of feeling, pins and needles, pain and cramps.
On examination:
Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
Reflexes can be normal, decreased/abolished, or brisk.
Positive Romberg and dysmetria worsened by eye closure
Normal muscle bulk, strength, and tone
Flexor plantar responses
Symptoms include oscillopsia.
Examination reveals bilateral vestibular hypofunction:
Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
Note: Vertigo, defined as an abnormal sensation of motion in which the individual or the individual's surroundings seem to whirl dizzily, stemming from a subacute/acute imbalance of vestibular inputs,
Symptoms include dysarthria, dysphagia.
Examination reveals abnormal eye movements (downbeat, horizontal, rotatory gaze-evoked nystagmus, broken pursuits, dysmetric saccades), dysdiadokokinesia, normal/reduced muscle tone.
Symptoms include postural hypotension; erectile dysfunction; urinary dysfunction; chronic constipation and/or diarrhea; nausea, vomiting or bloating after a small meal; anhidrosis or increased sweating; dry mouth/eyes.
Examination includes autonomic testing (in some cases) for sympathetic dysfunction (measuring blood pressure response to change in posture and handgrip and sympathetic skin response) and/or parasympathetic dysfunction (ECG monitoring of heart rate variation during Valsalva maneuver, deep breathing and standing).
Reduced or absent sensory action potential (SAP). When the individual already has a clear ataxic gait, SAPs are often absent throughout.
Usually normal motor study
Abnormal blink reflex (trigeminal neuronopathy), preserved H–reflex (Hoffmann reflex)
Electromyography is usually normal.
Bilaterally abnormal video head impulse test
Bilaterally reduced caloric response
Vestibulo-ocular reflex gain tested using a rotatory chair
Brain MRI shows cerebellar atrophy (vermian atrophy, crus I atrophy).
Spine MRI shows cord atrophy and T
Nerve ultrasound shows reduced cross-sectional area of upper and lower limb nerves (reported by 1 group) [
Consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity)
Family history may alternatively be consistent with pseudodominant inheritance (i.e., the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) due to the high heterozygote carrier frequency of
Absence of a known family history does not preclude the diagnosis.
The diagnosis of
Note: Pathogenic AAGGG repeat expansions in
AAAAG
AAAAG
AAAGG
Most commonly AAGGG repeat expansion, most frequently ranging from 400 to more than 2000 repeats (maximum number of repeats in Authors' series = 2750) (allele frequency = 0.01-0.04)
Additional pathogenic repeat expansions recently identified in specific populations:
ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
(AAAGG)
Molecular Genetic Testing Used in
See
See
After exclusion of biallelic AAGGG expansions, targeted analysis for ACAGG repeats can also be advised in typical CANVAS cases of Asian and Asian Pacific origin, based on current and evolving knowledge.
• Symptoms include unsteadiness (imbalance, dizziness), falls, clumsiness of hands.
• Examination reveals progressive ataxia of gait and limb dysmetria.
• Symptoms include unsteadiness, loss of feeling, pins and needles, pain and cramps.
• On examination:
• Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
• Reflexes can be normal, decreased/abolished, or brisk.
• Positive Romberg and dysmetria worsened by eye closure
• Normal muscle bulk, strength, and tone
• Flexor plantar responses
• Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
• Reflexes can be normal, decreased/abolished, or brisk.
• Positive Romberg and dysmetria worsened by eye closure
• Normal muscle bulk, strength, and tone
• Flexor plantar responses
• Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
• Reflexes can be normal, decreased/abolished, or brisk.
• Positive Romberg and dysmetria worsened by eye closure
• Normal muscle bulk, strength, and tone
• Flexor plantar responses
• Symptoms include oscillopsia.
• Examination reveals bilateral vestibular hypofunction:
• Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
• Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
• Note: Vertigo, defined as an abnormal sensation of motion in which the individual or the individual's surroundings seem to whirl dizzily, stemming from a subacute/acute imbalance of vestibular inputs,
• Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
• Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
• Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
• Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
• Symptoms include dysarthria, dysphagia.
• Examination reveals abnormal eye movements (downbeat, horizontal, rotatory gaze-evoked nystagmus, broken pursuits, dysmetric saccades), dysdiadokokinesia, normal/reduced muscle tone.
• Symptoms include postural hypotension; erectile dysfunction; urinary dysfunction; chronic constipation and/or diarrhea; nausea, vomiting or bloating after a small meal; anhidrosis or increased sweating; dry mouth/eyes.
• Examination includes autonomic testing (in some cases) for sympathetic dysfunction (measuring blood pressure response to change in posture and handgrip and sympathetic skin response) and/or parasympathetic dysfunction (ECG monitoring of heart rate variation during Valsalva maneuver, deep breathing and standing).
• Reduced or absent sensory action potential (SAP). When the individual already has a clear ataxic gait, SAPs are often absent throughout.
• Usually normal motor study
• Abnormal blink reflex (trigeminal neuronopathy), preserved H–reflex (Hoffmann reflex)
• Bilaterally abnormal video head impulse test
• Bilaterally reduced caloric response
• Vestibulo-ocular reflex gain tested using a rotatory chair
• Brain MRI shows cerebellar atrophy (vermian atrophy, crus I atrophy).
• Spine MRI shows cord atrophy and T
• Nerve ultrasound shows reduced cross-sectional area of upper and lower limb nerves (reported by 1 group) [
• Consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity)
• Family history may alternatively be consistent with pseudodominant inheritance (i.e., the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) due to the high heterozygote carrier frequency of
• Absence of a known family history does not preclude the diagnosis.
• AAAAG
• AAAAG
• AAAGG
• Most commonly AAGGG repeat expansion, most frequently ranging from 400 to more than 2000 repeats (maximum number of repeats in Authors' series = 2750) (allele frequency = 0.01-0.04)
• Additional pathogenic repeat expansions recently identified in specific populations:
• ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
• (AAAGG)
• ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
• (AAAGG)
• ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
• (AAAGG)
## Suggestive Findings
Symptoms include unsteadiness (imbalance, dizziness), falls, clumsiness of hands.
Examination reveals progressive ataxia of gait and limb dysmetria.
Symptoms include unsteadiness, loss of feeling, pins and needles, pain and cramps.
On examination:
Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
Reflexes can be normal, decreased/abolished, or brisk.
Positive Romberg and dysmetria worsened by eye closure
Normal muscle bulk, strength, and tone
Flexor plantar responses
Symptoms include oscillopsia.
Examination reveals bilateral vestibular hypofunction:
Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
Note: Vertigo, defined as an abnormal sensation of motion in which the individual or the individual's surroundings seem to whirl dizzily, stemming from a subacute/acute imbalance of vestibular inputs,
Symptoms include dysarthria, dysphagia.
Examination reveals abnormal eye movements (downbeat, horizontal, rotatory gaze-evoked nystagmus, broken pursuits, dysmetric saccades), dysdiadokokinesia, normal/reduced muscle tone.
Symptoms include postural hypotension; erectile dysfunction; urinary dysfunction; chronic constipation and/or diarrhea; nausea, vomiting or bloating after a small meal; anhidrosis or increased sweating; dry mouth/eyes.
Examination includes autonomic testing (in some cases) for sympathetic dysfunction (measuring blood pressure response to change in posture and handgrip and sympathetic skin response) and/or parasympathetic dysfunction (ECG monitoring of heart rate variation during Valsalva maneuver, deep breathing and standing).
Reduced or absent sensory action potential (SAP). When the individual already has a clear ataxic gait, SAPs are often absent throughout.
Usually normal motor study
Abnormal blink reflex (trigeminal neuronopathy), preserved H–reflex (Hoffmann reflex)
Electromyography is usually normal.
Bilaterally abnormal video head impulse test
Bilaterally reduced caloric response
Vestibulo-ocular reflex gain tested using a rotatory chair
Brain MRI shows cerebellar atrophy (vermian atrophy, crus I atrophy).
Spine MRI shows cord atrophy and T
Nerve ultrasound shows reduced cross-sectional area of upper and lower limb nerves (reported by 1 group) [
Consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity)
Family history may alternatively be consistent with pseudodominant inheritance (i.e., the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) due to the high heterozygote carrier frequency of
Absence of a known family history does not preclude the diagnosis.
• Symptoms include unsteadiness (imbalance, dizziness), falls, clumsiness of hands.
• Examination reveals progressive ataxia of gait and limb dysmetria.
• Symptoms include unsteadiness, loss of feeling, pins and needles, pain and cramps.
• On examination:
• Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
• Reflexes can be normal, decreased/abolished, or brisk.
• Positive Romberg and dysmetria worsened by eye closure
• Normal muscle bulk, strength, and tone
• Flexor plantar responses
• Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
• Reflexes can be normal, decreased/abolished, or brisk.
• Positive Romberg and dysmetria worsened by eye closure
• Normal muscle bulk, strength, and tone
• Flexor plantar responses
• Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
• Reflexes can be normal, decreased/abolished, or brisk.
• Positive Romberg and dysmetria worsened by eye closure
• Normal muscle bulk, strength, and tone
• Flexor plantar responses
• Symptoms include oscillopsia.
• Examination reveals bilateral vestibular hypofunction:
• Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
• Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
• Note: Vertigo, defined as an abnormal sensation of motion in which the individual or the individual's surroundings seem to whirl dizzily, stemming from a subacute/acute imbalance of vestibular inputs,
• Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
• Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
• Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
• Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
• Symptoms include dysarthria, dysphagia.
• Examination reveals abnormal eye movements (downbeat, horizontal, rotatory gaze-evoked nystagmus, broken pursuits, dysmetric saccades), dysdiadokokinesia, normal/reduced muscle tone.
• Symptoms include postural hypotension; erectile dysfunction; urinary dysfunction; chronic constipation and/or diarrhea; nausea, vomiting or bloating after a small meal; anhidrosis or increased sweating; dry mouth/eyes.
• Examination includes autonomic testing (in some cases) for sympathetic dysfunction (measuring blood pressure response to change in posture and handgrip and sympathetic skin response) and/or parasympathetic dysfunction (ECG monitoring of heart rate variation during Valsalva maneuver, deep breathing and standing).
• Reduced or absent sensory action potential (SAP). When the individual already has a clear ataxic gait, SAPs are often absent throughout.
• Usually normal motor study
• Abnormal blink reflex (trigeminal neuronopathy), preserved H–reflex (Hoffmann reflex)
• Bilaterally abnormal video head impulse test
• Bilaterally reduced caloric response
• Vestibulo-ocular reflex gain tested using a rotatory chair
• Brain MRI shows cerebellar atrophy (vermian atrophy, crus I atrophy).
• Spine MRI shows cord atrophy and T
• Nerve ultrasound shows reduced cross-sectional area of upper and lower limb nerves (reported by 1 group) [
• Consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity)
• Family history may alternatively be consistent with pseudodominant inheritance (i.e., the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) due to the high heterozygote carrier frequency of
• Absence of a known family history does not preclude the diagnosis.
## Clinical Findings
Symptoms include unsteadiness (imbalance, dizziness), falls, clumsiness of hands.
Examination reveals progressive ataxia of gait and limb dysmetria.
Symptoms include unsteadiness, loss of feeling, pins and needles, pain and cramps.
On examination:
Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
Reflexes can be normal, decreased/abolished, or brisk.
Positive Romberg and dysmetria worsened by eye closure
Normal muscle bulk, strength, and tone
Flexor plantar responses
Symptoms include oscillopsia.
Examination reveals bilateral vestibular hypofunction:
Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
Note: Vertigo, defined as an abnormal sensation of motion in which the individual or the individual's surroundings seem to whirl dizzily, stemming from a subacute/acute imbalance of vestibular inputs,
Symptoms include dysarthria, dysphagia.
Examination reveals abnormal eye movements (downbeat, horizontal, rotatory gaze-evoked nystagmus, broken pursuits, dysmetric saccades), dysdiadokokinesia, normal/reduced muscle tone.
Symptoms include postural hypotension; erectile dysfunction; urinary dysfunction; chronic constipation and/or diarrhea; nausea, vomiting or bloating after a small meal; anhidrosis or increased sweating; dry mouth/eyes.
Examination includes autonomic testing (in some cases) for sympathetic dysfunction (measuring blood pressure response to change in posture and handgrip and sympathetic skin response) and/or parasympathetic dysfunction (ECG monitoring of heart rate variation during Valsalva maneuver, deep breathing and standing).
• Symptoms include unsteadiness (imbalance, dizziness), falls, clumsiness of hands.
• Examination reveals progressive ataxia of gait and limb dysmetria.
• Symptoms include unsteadiness, loss of feeling, pins and needles, pain and cramps.
• On examination:
• Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
• Reflexes can be normal, decreased/abolished, or brisk.
• Positive Romberg and dysmetria worsened by eye closure
• Normal muscle bulk, strength, and tone
• Flexor plantar responses
• Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
• Reflexes can be normal, decreased/abolished, or brisk.
• Positive Romberg and dysmetria worsened by eye closure
• Normal muscle bulk, strength, and tone
• Flexor plantar responses
• Altered sensation (pinprick, vibration, position sense) in all limbs in either a length-dependent (distal extremities worse) or non-length-dependent pattern
• Reflexes can be normal, decreased/abolished, or brisk.
• Positive Romberg and dysmetria worsened by eye closure
• Normal muscle bulk, strength, and tone
• Flexor plantar responses
• Symptoms include oscillopsia.
• Examination reveals bilateral vestibular hypofunction:
• Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
• Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
• Note: Vertigo, defined as an abnormal sensation of motion in which the individual or the individual's surroundings seem to whirl dizzily, stemming from a subacute/acute imbalance of vestibular inputs,
• Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
• Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
• Absent/reduced vestibulo-ocular reflex at bedside on head impulse test
• Impaired visually enhanced vestibulo-ocular reflexes (indicating the coexistence of vestibular and cerebellar pathology)
• Symptoms include dysarthria, dysphagia.
• Examination reveals abnormal eye movements (downbeat, horizontal, rotatory gaze-evoked nystagmus, broken pursuits, dysmetric saccades), dysdiadokokinesia, normal/reduced muscle tone.
• Symptoms include postural hypotension; erectile dysfunction; urinary dysfunction; chronic constipation and/or diarrhea; nausea, vomiting or bloating after a small meal; anhidrosis or increased sweating; dry mouth/eyes.
• Examination includes autonomic testing (in some cases) for sympathetic dysfunction (measuring blood pressure response to change in posture and handgrip and sympathetic skin response) and/or parasympathetic dysfunction (ECG monitoring of heart rate variation during Valsalva maneuver, deep breathing and standing).
## Supportive Findings
Reduced or absent sensory action potential (SAP). When the individual already has a clear ataxic gait, SAPs are often absent throughout.
Usually normal motor study
Abnormal blink reflex (trigeminal neuronopathy), preserved H–reflex (Hoffmann reflex)
Electromyography is usually normal.
Bilaterally abnormal video head impulse test
Bilaterally reduced caloric response
Vestibulo-ocular reflex gain tested using a rotatory chair
Brain MRI shows cerebellar atrophy (vermian atrophy, crus I atrophy).
Spine MRI shows cord atrophy and T
Nerve ultrasound shows reduced cross-sectional area of upper and lower limb nerves (reported by 1 group) [
Consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity)
Family history may alternatively be consistent with pseudodominant inheritance (i.e., the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) due to the high heterozygote carrier frequency of
Absence of a known family history does not preclude the diagnosis.
• Reduced or absent sensory action potential (SAP). When the individual already has a clear ataxic gait, SAPs are often absent throughout.
• Usually normal motor study
• Abnormal blink reflex (trigeminal neuronopathy), preserved H–reflex (Hoffmann reflex)
• Bilaterally abnormal video head impulse test
• Bilaterally reduced caloric response
• Vestibulo-ocular reflex gain tested using a rotatory chair
• Brain MRI shows cerebellar atrophy (vermian atrophy, crus I atrophy).
• Spine MRI shows cord atrophy and T
• Nerve ultrasound shows reduced cross-sectional area of upper and lower limb nerves (reported by 1 group) [
• Consistent with autosomal recessive inheritance (e.g., affected sibs and/or parental consanguinity)
• Family history may alternatively be consistent with pseudodominant inheritance (i.e., the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) due to the high heterozygote carrier frequency of
• Absence of a known family history does not preclude the diagnosis.
## Establishing the Diagnosis
The diagnosis of
Note: Pathogenic AAGGG repeat expansions in
AAAAG
AAAAG
AAAGG
Most commonly AAGGG repeat expansion, most frequently ranging from 400 to more than 2000 repeats (maximum number of repeats in Authors' series = 2750) (allele frequency = 0.01-0.04)
Additional pathogenic repeat expansions recently identified in specific populations:
ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
(AAAGG)
Molecular Genetic Testing Used in
See
See
After exclusion of biallelic AAGGG expansions, targeted analysis for ACAGG repeats can also be advised in typical CANVAS cases of Asian and Asian Pacific origin, based on current and evolving knowledge.
• AAAAG
• AAAAG
• AAAGG
• Most commonly AAGGG repeat expansion, most frequently ranging from 400 to more than 2000 repeats (maximum number of repeats in Authors' series = 2750) (allele frequency = 0.01-0.04)
• Additional pathogenic repeat expansions recently identified in specific populations:
• ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
• (AAAGG)
• ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
• (AAAGG)
• ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
• (AAAGG)
## Repeat Sizes
AAAAG
AAAAG
AAAGG
Most commonly AAGGG repeat expansion, most frequently ranging from 400 to more than 2000 repeats (maximum number of repeats in Authors' series = 2750) (allele frequency = 0.01-0.04)
Additional pathogenic repeat expansions recently identified in specific populations:
ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
(AAAGG)
Molecular Genetic Testing Used in
See
See
After exclusion of biallelic AAGGG expansions, targeted analysis for ACAGG repeats can also be advised in typical CANVAS cases of Asian and Asian Pacific origin, based on current and evolving knowledge.
• AAAAG
• AAAAG
• AAAGG
• Most commonly AAGGG repeat expansion, most frequently ranging from 400 to more than 2000 repeats (maximum number of repeats in Authors' series = 2750) (allele frequency = 0.01-0.04)
• Additional pathogenic repeat expansions recently identified in specific populations:
• ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
• (AAAGG)
• ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
• (AAAGG)
• ACAGG repeat expansion (~1000 repeats) in two Asia-Pacific families and one Japanese individual [
• (AAAGG)
## Clinical Characteristics
The phenotypic spectrum associated with biallelic
Before its molecular basis was known, CANVAS was characterized as cerebellar dysfunction with predominant vermian atrophy, spinal and cranial sensory neuronopathy, and bilateral vestibular areflexia [
To date, more than 200 individuals – either simplex cases (i.e., a single occurrence in a family) or having a family history consistent with autosomal recessive inheritance – have been identified with biallelic AAGGG repeat expansions in
After ten years of disease duration:
Clinical features of CANVAS were seen in two thirds of affected individuals;
A complex sensory ataxia with cerebellar or vestibular involvement was identified in 16 and six individuals, respectively;
A sensory neuropathy was the only clinically detectable diasease manifestation in 15 individuals.
Based on 100 individuals with
CANVAS =
In the series of
No genotype-phenotype correlations have been identified.
The heterozygote carrier frequency of
Therefore, the estimated prevalence of
• Clinical features of CANVAS were seen in two thirds of affected individuals;
• A complex sensory ataxia with cerebellar or vestibular involvement was identified in 16 and six individuals, respectively;
• A sensory neuropathy was the only clinically detectable diasease manifestation in 15 individuals.
## Clinical Description
The phenotypic spectrum associated with biallelic
Before its molecular basis was known, CANVAS was characterized as cerebellar dysfunction with predominant vermian atrophy, spinal and cranial sensory neuronopathy, and bilateral vestibular areflexia [
To date, more than 200 individuals – either simplex cases (i.e., a single occurrence in a family) or having a family history consistent with autosomal recessive inheritance – have been identified with biallelic AAGGG repeat expansions in
After ten years of disease duration:
Clinical features of CANVAS were seen in two thirds of affected individuals;
A complex sensory ataxia with cerebellar or vestibular involvement was identified in 16 and six individuals, respectively;
A sensory neuropathy was the only clinically detectable diasease manifestation in 15 individuals.
Based on 100 individuals with
CANVAS =
In the series of
• Clinical features of CANVAS were seen in two thirds of affected individuals;
• A complex sensory ataxia with cerebellar or vestibular involvement was identified in 16 and six individuals, respectively;
• A sensory neuropathy was the only clinically detectable diasease manifestation in 15 individuals.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Prevalence
The heterozygote carrier frequency of
Therefore, the estimated prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
AAGGG expansions in
AAGGG expansions in
Given the multisystem involvement of
Genetic causes of inherited ataxia (see
Genetic causes of inherited neuropathy (see
Mitochondrial disorders that can manifest with ataxia, neuropathy and (more occasionally) bilateral vestibular areflexia (see
Selected genes and disorders of interest are summarized in
Genes of Interest in the Differential Diagnosis of
Progressive cerebellar ataxia
Sensory loss
Bilateral vestibular areflexia
Because MJD is a late-onset disorder (5th-7th decade) & pyramidal/ extrapyramidal signs may be absent, MJD may mimic
Frequent assoc of dystonic-rigid extrapyramidal syndrome &/or peripheral amyotrophy
Sensorimotor neuropathy (vs pure sensory neuropathy typical of
In some, addl clinical signs incl PEO, dystonia, action-induced facial & lingual fasciculation-like movements, & bulging eyes
Sensory neuronopathy
Cerebellar dysfunction
Bilateral vestibular areflexia is possible.
Late-onset FRDA can be clinically indistinguishable from
Typical age of onset: <25 yrs
Frequent muscle weakness, pyramidal involvement (Babinski signs) & skeletal deformities (pes cavus, scoliosis)
Assoc cardiomyopathy & diabetes
Vision & hearing loss
Ataxia
Neuropathy
Bilateral vestibular areflexia (reported in assoc w/m.3243A>G)
Earlier onset
Chronic PEO
Hearing & vision loss
Weakness
Extraneurologic involvement
Sensory neuronopathy
Cerebellar dysfunction
Onset 2nd-4th decade
Chronic PEO
Multisystem involvement
Neuropathy
Ataxia
Autonomic failure
Dementia
More rapid decline
Sensory neuronopathy
Bilateral vestibular areflexia
Adult onset
Normal cerebellar function
SAPs can be normal.
AD = autosomal dominant; AR = autosomal recessive; CANVAS = cerebellar ataxia, neuropathy, vestibular areflexia syndrome; DiffDx = differential diagnosis; Mat = maternal transmission; MELAS = mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes; MIDD = maternally inherited diabetes and deafness; MJD = Machado-Joseph disease; MOI = mode of inheritance; NARP = neuropathy, ataxia, and retinitis pigmentosa; PEO = progressive external ophthalmoplegia; SANDO = sensory ataxic neuropathy, dysarthria, and ophthalmoparesis; SAP = sensory action potential; SCA = spinocerebellar ataxia
m.8993T>G or m.8993T>C in MT-ATP6; m.3243A>G in MT-TL1
As sensory neuronopathy was identified in all individuals with genetically confirmed diagnoses and tends to appear early in the disease course, the differential diagnosis should initially encompass causes of acquired sensory neuronopathy including:
Paraneoplastic syndrome
Sjogren syndrome
Acute and chronic immune-mediated disorders
Metabolic disorders (diabetes mellitus, vitamin B
Toxins (alcohol, pyridoxine, platinum derivatives, pyridoxine intoxication)
The average time from first manifestations to death in MSA is 9.3 years, while disease progression in
Unlike
Autonomic dysfunction, a common and highly debilitating feature of MSA, is usually mild in
Presence of additional features that favor an MSA diagnosis include rapid eye movement sleep behavior disorder, parkinsonism, and MRI pattern (putaminal, pontine, and middle cerebellar peduncle atrophy and "hot cross-bun" sign cruciform T
The differential diagnosis of bilateral vestibular areflexia includes (among other conditions) aminoglycoside ototoxicity, Meniere's disease, bilateral vestibular neuritis, tumors compressing both vestibular nerves (e.g., bilateral schwannomas in neurofibromatosis 2), and infectious and/or inflammatory systemic disorders.
Bilateral vestibular hypofunction can be observed in several hereditary neurodegenerative conditions including spinocerebellar ataxia (
When bilateral vestibular hypofunction occurs with hearing and visual loss,
• Genetic causes of inherited ataxia (see
• Genetic causes of inherited neuropathy (see
• Mitochondrial disorders that can manifest with ataxia, neuropathy and (more occasionally) bilateral vestibular areflexia (see
• Progressive cerebellar ataxia
• Sensory loss
• Bilateral vestibular areflexia
• Because MJD is a late-onset disorder (5th-7th decade) & pyramidal/ extrapyramidal signs may be absent, MJD may mimic
• Frequent assoc of dystonic-rigid extrapyramidal syndrome &/or peripheral amyotrophy
• Sensorimotor neuropathy (vs pure sensory neuropathy typical of
• In some, addl clinical signs incl PEO, dystonia, action-induced facial & lingual fasciculation-like movements, & bulging eyes
• Sensory neuronopathy
• Cerebellar dysfunction
• Bilateral vestibular areflexia is possible.
• Late-onset FRDA can be clinically indistinguishable from
• Typical age of onset: <25 yrs
• Frequent muscle weakness, pyramidal involvement (Babinski signs) & skeletal deformities (pes cavus, scoliosis)
• Assoc cardiomyopathy & diabetes
• Vision & hearing loss
• Ataxia
• Neuropathy
• Bilateral vestibular areflexia (reported in assoc w/m.3243A>G)
• Earlier onset
• Chronic PEO
• Hearing & vision loss
• Weakness
• Extraneurologic involvement
• Sensory neuronopathy
• Cerebellar dysfunction
• Onset 2nd-4th decade
• Chronic PEO
• Multisystem involvement
• Neuropathy
• Ataxia
• Autonomic failure
• Dementia
• More rapid decline
• Sensory neuronopathy
• Bilateral vestibular areflexia
• Adult onset
• Normal cerebellar function
• SAPs can be normal.
• Paraneoplastic syndrome
• Sjogren syndrome
• Acute and chronic immune-mediated disorders
• Metabolic disorders (diabetes mellitus, vitamin B
• Toxins (alcohol, pyridoxine, platinum derivatives, pyridoxine intoxication)
• The average time from first manifestations to death in MSA is 9.3 years, while disease progression in
• Unlike
• Autonomic dysfunction, a common and highly debilitating feature of MSA, is usually mild in
• Presence of additional features that favor an MSA diagnosis include rapid eye movement sleep behavior disorder, parkinsonism, and MRI pattern (putaminal, pontine, and middle cerebellar peduncle atrophy and "hot cross-bun" sign cruciform T
## Sensory Neuronopathy
As sensory neuronopathy was identified in all individuals with genetically confirmed diagnoses and tends to appear early in the disease course, the differential diagnosis should initially encompass causes of acquired sensory neuronopathy including:
Paraneoplastic syndrome
Sjogren syndrome
Acute and chronic immune-mediated disorders
Metabolic disorders (diabetes mellitus, vitamin B
Toxins (alcohol, pyridoxine, platinum derivatives, pyridoxine intoxication)
• Paraneoplastic syndrome
• Sjogren syndrome
• Acute and chronic immune-mediated disorders
• Metabolic disorders (diabetes mellitus, vitamin B
• Toxins (alcohol, pyridoxine, platinum derivatives, pyridoxine intoxication)
## Late-Onset Cerebellar Ataxia
The average time from first manifestations to death in MSA is 9.3 years, while disease progression in
Unlike
Autonomic dysfunction, a common and highly debilitating feature of MSA, is usually mild in
Presence of additional features that favor an MSA diagnosis include rapid eye movement sleep behavior disorder, parkinsonism, and MRI pattern (putaminal, pontine, and middle cerebellar peduncle atrophy and "hot cross-bun" sign cruciform T
• The average time from first manifestations to death in MSA is 9.3 years, while disease progression in
• Unlike
• Autonomic dysfunction, a common and highly debilitating feature of MSA, is usually mild in
• Presence of additional features that favor an MSA diagnosis include rapid eye movement sleep behavior disorder, parkinsonism, and MRI pattern (putaminal, pontine, and middle cerebellar peduncle atrophy and "hot cross-bun" sign cruciform T
## Bilateral Vestibular Areflexia
The differential diagnosis of bilateral vestibular areflexia includes (among other conditions) aminoglycoside ototoxicity, Meniere's disease, bilateral vestibular neuritis, tumors compressing both vestibular nerves (e.g., bilateral schwannomas in neurofibromatosis 2), and infectious and/or inflammatory systemic disorders.
Bilateral vestibular hypofunction can be observed in several hereditary neurodegenerative conditions including spinocerebellar ataxia (
When bilateral vestibular hypofunction occurs with hearing and visual loss,
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Prevention of falls
Adaptive devices (cane, walker, wheelchair)
PT
Nutritional status;
Aspiration risk.
Respiratory function testing, esp in non-ambulant individuals;
A sleep study if sleep apnea is suspected.
Use of community or
Need for social work involvement for caregiver support.
CMTNS = Charcot-Marie-Tooth Neuropathy Score; EMG = electromyogram; MOI = mode of inheritance; NCS = nerve conduction study; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
The goals of treatment are to maximize function and reduce complications. Depending on the clinical manifestations, each affected individual should be managed by a multidisciplinary team of relevant specialists including neurologists, occupational therapists, physical therapists, physiatrists, and (depending on individual needs) speech therapists, respiratory therapists, nutritionists, and gastroenterologists.
Treatment of Manifestations in Individuals with
Consider adaptive devices to maintain/improve 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
Inpatient rehab w/OT/PT may improve ataxia & functional abilities in patients w/degenerative ataxias.
Consider vestibular rehab.
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Exercise w/in patient's capability
Weight control to avoid obesity
Advice on injury avoidance
Consider pain treatment (rarely required).
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist
While 4-aminopyridine (used for the treatment of episodic ataxia type 2,
Recommended Surveillance for Individuals with
Neurologic assessment for progression of ataxia; sensory impairment; vestibular dysfunction; dysautonomia
No validated clinical scale exists for
CMTNS = Charcot-Marie-Tooth Neuropathy Score; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
Medications of known toxicity for peripheral nerves (e.g., neurotoxic chemotherapy agents, pyridoxine), the cerebellum (e.g., phenytoin), or the vestibular system (e.g., aminoglycosides) as well as chronic alcohol consumption may worsen the condition.
See
Search
• Prevention of falls
• Adaptive devices (cane, walker, wheelchair)
• PT
• Nutritional status;
• Aspiration risk.
• Respiratory function testing, esp in non-ambulant individuals;
• A sleep study if sleep apnea is suspected.
• Use of community or
• Need for social work involvement for caregiver support.
• Consider adaptive devices to maintain/improve 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
• Inpatient rehab w/OT/PT may improve ataxia & functional abilities in patients w/degenerative ataxias.
• Consider vestibular rehab.
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Exercise w/in patient's capability
• Weight control to avoid obesity
• Advice on injury avoidance
• Consider pain treatment (rarely required).
• Neurologic assessment for progression of ataxia; sensory impairment; vestibular dysfunction; dysautonomia
• No validated clinical scale exists for
## 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
Prevention of falls
Adaptive devices (cane, walker, wheelchair)
PT
Nutritional status;
Aspiration risk.
Respiratory function testing, esp in non-ambulant individuals;
A sleep study if sleep apnea is suspected.
Use of community or
Need for social work involvement for caregiver support.
CMTNS = Charcot-Marie-Tooth Neuropathy Score; EMG = electromyogram; MOI = mode of inheritance; NCS = nerve conduction study; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Prevention of falls
• Adaptive devices (cane, walker, wheelchair)
• PT
• Nutritional status;
• Aspiration risk.
• Respiratory function testing, esp in non-ambulant individuals;
• A sleep study if sleep apnea is suspected.
• Use of community or
• Need for social work involvement for caregiver support.
## Treatment of Manifestations
The goals of treatment are to maximize function and reduce complications. Depending on the clinical manifestations, each affected individual should be managed by a multidisciplinary team of relevant specialists including neurologists, occupational therapists, physical therapists, physiatrists, and (depending on individual needs) speech therapists, respiratory therapists, nutritionists, and gastroenterologists.
Treatment of Manifestations in Individuals with
Consider adaptive devices to maintain/improve 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
Inpatient rehab w/OT/PT may improve ataxia & functional abilities in patients w/degenerative ataxias.
Consider vestibular rehab.
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Exercise w/in patient's capability
Weight control to avoid obesity
Advice on injury avoidance
Consider pain treatment (rarely required).
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist
While 4-aminopyridine (used for the treatment of episodic ataxia type 2,
• Consider adaptive devices to maintain/improve 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
• Inpatient rehab w/OT/PT may improve ataxia & functional abilities in patients w/degenerative ataxias.
• Consider vestibular rehab.
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Exercise w/in patient's capability
• Weight control to avoid obesity
• Advice on injury avoidance
• Consider pain treatment (rarely required).
## Surveillance
Recommended Surveillance for Individuals with
Neurologic assessment for progression of ataxia; sensory impairment; vestibular dysfunction; dysautonomia
No validated clinical scale exists for
CMTNS = Charcot-Marie-Tooth Neuropathy Score; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
• Neurologic assessment for progression of ataxia; sensory impairment; vestibular dysfunction; dysautonomia
• No validated clinical scale exists for
## Agents/Circumstances to Avoid
Medications of known toxicity for peripheral nerves (e.g., neurotoxic chemotherapy agents, pyridoxine), the cerebellum (e.g., phenytoin), or the vestibular system (e.g., aminoglycosides) as well as chronic alcohol consumption may worsen the condition.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Pseudodominance (the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) may be observed in
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing of the parents can be used to confirm that both parents are heterozygous for an
To date, all reported heterozygotes (carriers) are asymptomatic and are presumed not to be at risk of developing the disorder (additional long-term testing is needed to confirm this observation).
If both parents are known to be heterozygous for an
To date, all reported heterozygotes (carriers) are asymptomatic and are presumed not to be at risk of developing the disorder (additional long-term testing is needed to confirm this observation).
Once 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 young adults who are affected, are carriers, or are at risk of being carriers.
Once biallelic
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 of the parents can be used to confirm that both parents are heterozygous for an
• To date, all reported heterozygotes (carriers) are asymptomatic and are presumed not to be at risk of developing the disorder (additional long-term testing is needed to confirm this observation).
• If both parents are known to be heterozygous for an
• To date, all reported heterozygotes (carriers) are asymptomatic and are presumed not to be at risk of developing the disorder (additional long-term testing is needed to confirm this observation).
• 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
Pseudodominance (the occurrence of an autosomal recessive disorder in two generations of a family without consanguinity) may be observed in
The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
Molecular genetic testing of the parents can be used to confirm that both parents are heterozygous for an
To date, all reported heterozygotes (carriers) are asymptomatic and are presumed not to be at risk of developing the disorder (additional long-term testing is needed to confirm this observation).
If both parents are known to be heterozygous for an
To date, all reported heterozygotes (carriers) are asymptomatic and are presumed not to be at risk of developing the disorder (additional long-term testing is needed to confirm this observation).
• The parents of an affected individual are obligate heterozygotes (i.e., presumed to be carriers of one
• Molecular genetic testing of the parents can be used to confirm that both parents are heterozygous for an
• To date, all reported heterozygotes (carriers) are asymptomatic and are presumed not to be at risk of developing the disorder (additional long-term testing is needed to confirm this observation).
• If both parents are known to be heterozygous for an
• To date, all reported heterozygotes (carriers) are asymptomatic and are presumed not to be at risk of developing the disorder (additional long-term testing is needed to confirm this observation).
## Carrier Detection
Once 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 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 biallelic
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
United Kingdom
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## Molecular Genetics
RFC1 CANVAS / Spectrum Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for RFC1 CANVAS / Spectrum Disorder (
Absence of PCR amplifiable product on flanking PCR
Presence of a saw-tooth decremental pattern on repeat-primed PCR (RP-PCR) for the pathogenic AAGGG pentanucleotide expansion
Optional: Absence of a saw-tooth decremental pattern on repeat-primed PCR for non-pathogenic repeat expansions of (e.g.,) AAAAG, AAAGG, and other possible configurations [
These expansions can be large enough to prevent amplification of a PCR product on standard flanking PCR conditions.
PCR = polymerase chain reaction
Recently, biallelic ACAGG repeat expansions were identified in one Japanese individual with typical CANVAS who did not have the common AAGGG repeat expansion [
Other techniques, including long-read sequencing [
Notable
Variants listed in the table have been provided by the authors.
Not available, but reported to be in the same range as AAGGG expansions [Author, personal observation]
In 13 affected individuals of New Zealand Māori and Cook Island ancestry, the core AAGGG expansion was identified to be flanked by short AAAGG expansion arms, resulting in the configuration (AAAGG)10-25(AAGGG)exp (AAAGG)4-6 [
• Absence of PCR amplifiable product on flanking PCR
• Presence of a saw-tooth decremental pattern on repeat-primed PCR (RP-PCR) for the pathogenic AAGGG pentanucleotide expansion
• Optional: Absence of a saw-tooth decremental pattern on repeat-primed PCR for non-pathogenic repeat expansions of (e.g.,) AAAAG, AAAGG, and other possible configurations [
• These expansions can be large enough to prevent amplification of a PCR product on standard flanking PCR conditions.
## Molecular Pathogenesis
Absence of PCR amplifiable product on flanking PCR
Presence of a saw-tooth decremental pattern on repeat-primed PCR (RP-PCR) for the pathogenic AAGGG pentanucleotide expansion
Optional: Absence of a saw-tooth decremental pattern on repeat-primed PCR for non-pathogenic repeat expansions of (e.g.,) AAAAG, AAAGG, and other possible configurations [
These expansions can be large enough to prevent amplification of a PCR product on standard flanking PCR conditions.
PCR = polymerase chain reaction
Recently, biallelic ACAGG repeat expansions were identified in one Japanese individual with typical CANVAS who did not have the common AAGGG repeat expansion [
Other techniques, including long-read sequencing [
Notable
Variants listed in the table have been provided by the authors.
Not available, but reported to be in the same range as AAGGG expansions [Author, personal observation]
In 13 affected individuals of New Zealand Māori and Cook Island ancestry, the core AAGGG expansion was identified to be flanked by short AAAGG expansion arms, resulting in the configuration (AAAGG)10-25(AAGGG)exp (AAAGG)4-6 [
• Absence of PCR amplifiable product on flanking PCR
• Presence of a saw-tooth decremental pattern on repeat-primed PCR (RP-PCR) for the pathogenic AAGGG pentanucleotide expansion
• Optional: Absence of a saw-tooth decremental pattern on repeat-primed PCR for non-pathogenic repeat expansions of (e.g.,) AAAAG, AAAGG, and other possible configurations [
• These expansions can be large enough to prevent amplification of a PCR product on standard flanking PCR conditions.
## Chapter Notes
Andrea Cortese's work focuses on genetic discovery, functional modeling, and treatment of neuromuscular diseases and other hereditary neurodegenerative conditions. A major area of his research focuses on understanding how
Andrea Cortese thanks the Medical Research Council (MR/T001712/1), Fondazione CARIPLO (2019-1836), Italian Ministry of Healthy (Ricerca Corrente 2020), and the Inherited Neuropathy Consortium for grant support.
25 November 2020 (bp) Review posted live
14 April 2020 (ac) Original submission
• 25 November 2020 (bp) Review posted live
• 14 April 2020 (ac) Original submission
## Author Notes
Andrea Cortese's work focuses on genetic discovery, functional modeling, and treatment of neuromuscular diseases and other hereditary neurodegenerative conditions. A major area of his research focuses on understanding how
## Acknowledgments
Andrea Cortese thanks the Medical Research Council (MR/T001712/1), Fondazione CARIPLO (2019-1836), Italian Ministry of Healthy (Ricerca Corrente 2020), and the Inherited Neuropathy Consortium for grant support.
## Revision History
25 November 2020 (bp) Review posted live
14 April 2020 (ac) Original submission
• 25 November 2020 (bp) Review posted live
• 14 April 2020 (ac) Original submission
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] |
25/11/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
riboflavin-tn
|
riboflavin-tn
|
[
"Solute carrier family 52, riboflavin transporter, member 1",
"Solute carrier family 52, riboflavin transporter, member 2",
"Solute carrier family 52, riboflavin transporter, member 3",
"SLC52A1",
"SLC52A2",
"SLC52A3",
"Riboflavin Transporter Deficiency"
] |
Riboflavin Transporter Deficiency
|
Elisa Cali, Natalia Dominik, Andreea Manole, Henry Houlden
|
Summary Riboflavin transporter deficiency (RTD), comprising RTD2 and RTD3 (caused by biallelic pathogenic variants in In the majority of affected individuals, the initial finding is sensorineural hearing loss, which is usually progressive and severe. The time between the onset of hearing loss and the development of other manifestations varies but is usually one to two years. In some individuals an intercurrent event, usually an injury or infection, appears to precipitate the initial manifestations or worsen existing findings. One case report (which requires additional confirmation) suggests that biallelic expression of pathogenic variants in The diagnosis of RTD2 and RTD3 is established in an individual with suggestive findings and biallelic pathogenic variants in either Because oral riboflavin supplementation is effective (and possibly lifesaving), it should begin as soon as a riboflavin transporter deficiency is suspected and continued lifelong unless molecular genetic testing fails to identify biallelic pathogenic variants in either Supportive care includes respiratory support; physiotherapy to avoid contractures; occupational therapy to support activities of daily living; orthotics for limb and trunk bracing; speech and language therapy to avoid choking and respiratory problems; wheelchair as needed; low vision aids as needed; routine management of scoliosis to avoid long-term respiratory problems; and routine management of depression. RTD caused by biallelic pathogenic variants in either
|
Riboflavin transporter deficiency (RTD), comprising RTD2 and RTD3 (caused by biallelic pathogenic variants in
One case report (which requires additional confirmation) suggests that biallelic expression of pathogenic variants in
## Diagnosis
Very frequently affecting cranial nerves II (optic atrophy with bilateral symmetric optic nerve pallor, variably associated nystagmus) and VIII (sensorineural hearing loss is one of the initial findings)
Frequently affecting cranial nerves IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)
Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)
Affecting upper limbs more than lower limbs, resulting in weakness involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent
Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up
Resulting in paralysis of the diaphragm, which can result in respiratory insufficiency
Cognition is usually preserved.
Electromyogram shows chronic partial denervation.
Nerve conduction studies show a sensory > motor axonal neuronopathy. Motor nerve conduction velocities are usually normal.
Sensory nerve action potentials are often absent.
Visual evoked potentials are frequently abnormal.
Brain stem audiometry evoked response has universally shown sensorineural deafness.
EEG (electroencephalogram) may show an excess of theta activity or slow waves [
Acylcarnitine profile in blood is abnormal with accumulation of short- and medium-chain (and sometimes long-chain) acylcarnitine in some but not all individuals with molecularly confirmed RTD [
Note: Even in children with RTD diagnosed in the first months of life with abnormal acylcarnitine profiles, newborn screening bloodspots demonstrated normal acylcarnitine profiles, probably due to sufficient maternal riboflavin supply to the unborn infant [
The diagnosis of riboflavin transporter deficiency (RTD)
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
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Riboflavin Transporter Deficiency (RTD)
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 gene-targeted microarray designed to detect single-exon deletions or duplications.
No large deletions/duplications have been identified using chromosome microarray analysis (CMA) [
• Very frequently affecting cranial nerves II (optic atrophy with bilateral symmetric optic nerve pallor, variably associated nystagmus) and VIII (sensorineural hearing loss is one of the initial findings)
• Frequently affecting cranial nerves IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)
• Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)
• Very frequently affecting cranial nerves II (optic atrophy with bilateral symmetric optic nerve pallor, variably associated nystagmus) and VIII (sensorineural hearing loss is one of the initial findings)
• Frequently affecting cranial nerves IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)
• Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)
• Affecting upper limbs more than lower limbs, resulting in weakness involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent
• Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up
• Resulting in paralysis of the diaphragm, which can result in respiratory insufficiency
• Affecting upper limbs more than lower limbs, resulting in weakness involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent
• Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up
• Resulting in paralysis of the diaphragm, which can result in respiratory insufficiency
• Very frequently affecting cranial nerves II (optic atrophy with bilateral symmetric optic nerve pallor, variably associated nystagmus) and VIII (sensorineural hearing loss is one of the initial findings)
• Frequently affecting cranial nerves IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)
• Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)
• Affecting upper limbs more than lower limbs, resulting in weakness involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent
• Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up
• Resulting in paralysis of the diaphragm, which can result in respiratory insufficiency
• Electromyogram shows chronic partial denervation.
• Nerve conduction studies show a sensory > motor axonal neuronopathy. Motor nerve conduction velocities are usually normal.
• Sensory nerve action potentials are often absent.
• Visual evoked potentials are frequently abnormal.
• Brain stem audiometry evoked response has universally shown sensorineural deafness.
• EEG (electroencephalogram) may show an excess of theta activity or slow waves [
• Acylcarnitine profile in blood is abnormal with accumulation of short- and medium-chain (and sometimes long-chain) acylcarnitine in some but not all individuals with molecularly confirmed RTD [
• Note: Even in children with RTD diagnosed in the first months of life with abnormal acylcarnitine profiles, newborn screening bloodspots demonstrated normal acylcarnitine profiles, probably due to sufficient maternal riboflavin supply to the unborn infant [
## Suggestive Findings
Very frequently affecting cranial nerves II (optic atrophy with bilateral symmetric optic nerve pallor, variably associated nystagmus) and VIII (sensorineural hearing loss is one of the initial findings)
Frequently affecting cranial nerves IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)
Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)
Affecting upper limbs more than lower limbs, resulting in weakness involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent
Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up
Resulting in paralysis of the diaphragm, which can result in respiratory insufficiency
Cognition is usually preserved.
Electromyogram shows chronic partial denervation.
Nerve conduction studies show a sensory > motor axonal neuronopathy. Motor nerve conduction velocities are usually normal.
Sensory nerve action potentials are often absent.
Visual evoked potentials are frequently abnormal.
Brain stem audiometry evoked response has universally shown sensorineural deafness.
EEG (electroencephalogram) may show an excess of theta activity or slow waves [
Acylcarnitine profile in blood is abnormal with accumulation of short- and medium-chain (and sometimes long-chain) acylcarnitine in some but not all individuals with molecularly confirmed RTD [
Note: Even in children with RTD diagnosed in the first months of life with abnormal acylcarnitine profiles, newborn screening bloodspots demonstrated normal acylcarnitine profiles, probably due to sufficient maternal riboflavin supply to the unborn infant [
• Very frequently affecting cranial nerves II (optic atrophy with bilateral symmetric optic nerve pallor, variably associated nystagmus) and VIII (sensorineural hearing loss is one of the initial findings)
• Frequently affecting cranial nerves IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)
• Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)
• Very frequently affecting cranial nerves II (optic atrophy with bilateral symmetric optic nerve pallor, variably associated nystagmus) and VIII (sensorineural hearing loss is one of the initial findings)
• Frequently affecting cranial nerves IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)
• Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)
• Affecting upper limbs more than lower limbs, resulting in weakness involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent
• Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up
• Resulting in paralysis of the diaphragm, which can result in respiratory insufficiency
• Affecting upper limbs more than lower limbs, resulting in weakness involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent
• Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up
• Resulting in paralysis of the diaphragm, which can result in respiratory insufficiency
• Very frequently affecting cranial nerves II (optic atrophy with bilateral symmetric optic nerve pallor, variably associated nystagmus) and VIII (sensorineural hearing loss is one of the initial findings)
• Frequently affecting cranial nerves IX and X (bulbar palsy), and XII (tongue fasciculations, weakness, and atrophy)
• Occasionally affecting cranial nerves III (ptosis) and VII (facial weakness)
• Affecting upper limbs more than lower limbs, resulting in weakness involving proximal and distal limb musculature, often with severe distal wasting. Deep tendon reflexes are consistently absent
• Resulting in axial weakness, manifest as severe trunk and neck weakness requiring trunk bracing and difficulty with holding the head up
• Resulting in paralysis of the diaphragm, which can result in respiratory insufficiency
• Electromyogram shows chronic partial denervation.
• Nerve conduction studies show a sensory > motor axonal neuronopathy. Motor nerve conduction velocities are usually normal.
• Sensory nerve action potentials are often absent.
• Visual evoked potentials are frequently abnormal.
• Brain stem audiometry evoked response has universally shown sensorineural deafness.
• EEG (electroencephalogram) may show an excess of theta activity or slow waves [
• Acylcarnitine profile in blood is abnormal with accumulation of short- and medium-chain (and sometimes long-chain) acylcarnitine in some but not all individuals with molecularly confirmed RTD [
• Note: Even in children with RTD diagnosed in the first months of life with abnormal acylcarnitine profiles, newborn screening bloodspots demonstrated normal acylcarnitine profiles, probably due to sufficient maternal riboflavin supply to the unborn infant [
## Establishing the Diagnosis
The diagnosis of riboflavin transporter deficiency (RTD)
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
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Riboflavin Transporter Deficiency (RTD)
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 gene-targeted microarray designed to detect single-exon deletions or duplications.
No large deletions/duplications have been identified using chromosome microarray analysis (CMA) [
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Riboflavin Transporter Deficiency (RTD)
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 gene-targeted microarray designed to detect single-exon deletions or duplications.
No large deletions/duplications have been identified using chromosome microarray analysis (CMA) [
## Clinical Characteristics
Riboflavin transporter deficiency 2 (caused by biallelic
In contrast, RTD1 (possibly caused by biallelic
While most individuals with RTD2 or RTD3 (caused by biallelic pathogenic variants in
Riboflavin Transporter Deficiency 2 and 3: Select Features
Based on
RTD2 = riboflavin transporter deficiency caused by biallelic
The phenotype of individuals with riboflavin deficiency 2 and 3 at onset usually includes hearing impairment and/or sensory ataxia, followed by progressive upper limb weakness, optic atrophy, bulbar weakness, and respiratory failure.The time between the disease onset and the development of other manifestations varies but is usually one to two years. In some individuals an intercurrent event, usually an injury or infection, appears to precipitate the initial manifestations or worsen existing findings [
Note: When the onset occurs in infancy, after a symptom-free first few weeks (or in some cases months) of life, infants become floppy with failure to thrive and rapidly developing respiratory insufficiency due to paralysis of the diaphragm, followed (in order of appearance) by:
Infantile- or early childhood-onset nystagmus
Early childhood-onset sensory (gait) ataxia
Early-childhood onset progressive and severe sensorineural hearing loss
Weakness and atrophy of the upper limbs (first distally then proximally)
Weakness of neck extensors and later trunk muscles
Tongue fasciculations and atrophy with increased swallowing problems
Respiratory insufficiency due to muscle weakness
Other initial presenting features can include stridor, slurring of speech, and facial weakness. Visual problems due to optic atrophy are common [
Electrophysiologic studies, when performed, were suggestive of peripheral neuropathy in most individuals with RTD, showing chronic denervation and anterior horn dysfunction. Nerve conduction studies suggest an axonal rather than demyelinating neuropathy.
When present, torsional/horizontal nystagmus is one of the early signs of optic atrophy prior to vision loss; thus, RTD should be considered in children with new-onset nystagmus [
Other features variably seen:
While the RTD2 and RTD3 phenotypes are difficult to differentiate, in RTD2 early-onset weakness in the upper limbs and neck is almost invariable, in contrast to RTD3 or genetically unclassified Brown-Vialetto-Van Laere (BVVL) syndrome, in which the onset of weakness is often more generalized [
Previous data suggest that in 70% of individuals receiving riboflavin supplementation, muscle strength, motor abilities, respiratory function, and cranial nerve deficits improve [
With improved disease management and riboflavin treatment (see
See
Other terms used to refer to riboflavin transporter deficiency:
Brown-Vialetto-Van Laere (BVVL) syndrome (corresponding with either
Although riboflavin transporter deficiency (RTD) is relatively rare, the advent of molecular genetic testing has improved diagnostic capabilities, making RTD appear more prevalent than previously thought [
It is difficult to establish the prevalence of RTD. It may be underdiagnosed and misdiagnosed; however, it is estimated that RTD affects one in 1,000,000 people in the general population.
• Infantile- or early childhood-onset nystagmus
• Early childhood-onset sensory (gait) ataxia
• Early-childhood onset progressive and severe sensorineural hearing loss
• Weakness and atrophy of the upper limbs (first distally then proximally)
• Weakness of neck extensors and later trunk muscles
• Tongue fasciculations and atrophy with increased swallowing problems
• Respiratory insufficiency due to muscle weakness
• Brown-Vialetto-Van Laere (BVVL) syndrome (corresponding with either
## Clinical Description
Riboflavin transporter deficiency 2 (caused by biallelic
In contrast, RTD1 (possibly caused by biallelic
While most individuals with RTD2 or RTD3 (caused by biallelic pathogenic variants in
Riboflavin Transporter Deficiency 2 and 3: Select Features
Based on
RTD2 = riboflavin transporter deficiency caused by biallelic
The phenotype of individuals with riboflavin deficiency 2 and 3 at onset usually includes hearing impairment and/or sensory ataxia, followed by progressive upper limb weakness, optic atrophy, bulbar weakness, and respiratory failure.The time between the disease onset and the development of other manifestations varies but is usually one to two years. In some individuals an intercurrent event, usually an injury or infection, appears to precipitate the initial manifestations or worsen existing findings [
Note: When the onset occurs in infancy, after a symptom-free first few weeks (or in some cases months) of life, infants become floppy with failure to thrive and rapidly developing respiratory insufficiency due to paralysis of the diaphragm, followed (in order of appearance) by:
Infantile- or early childhood-onset nystagmus
Early childhood-onset sensory (gait) ataxia
Early-childhood onset progressive and severe sensorineural hearing loss
Weakness and atrophy of the upper limbs (first distally then proximally)
Weakness of neck extensors and later trunk muscles
Tongue fasciculations and atrophy with increased swallowing problems
Respiratory insufficiency due to muscle weakness
Other initial presenting features can include stridor, slurring of speech, and facial weakness. Visual problems due to optic atrophy are common [
Electrophysiologic studies, when performed, were suggestive of peripheral neuropathy in most individuals with RTD, showing chronic denervation and anterior horn dysfunction. Nerve conduction studies suggest an axonal rather than demyelinating neuropathy.
When present, torsional/horizontal nystagmus is one of the early signs of optic atrophy prior to vision loss; thus, RTD should be considered in children with new-onset nystagmus [
Other features variably seen:
While the RTD2 and RTD3 phenotypes are difficult to differentiate, in RTD2 early-onset weakness in the upper limbs and neck is almost invariable, in contrast to RTD3 or genetically unclassified Brown-Vialetto-Van Laere (BVVL) syndrome, in which the onset of weakness is often more generalized [
Previous data suggest that in 70% of individuals receiving riboflavin supplementation, muscle strength, motor abilities, respiratory function, and cranial nerve deficits improve [
With improved disease management and riboflavin treatment (see
• Infantile- or early childhood-onset nystagmus
• Early childhood-onset sensory (gait) ataxia
• Early-childhood onset progressive and severe sensorineural hearing loss
• Weakness and atrophy of the upper limbs (first distally then proximally)
• Weakness of neck extensors and later trunk muscles
• Tongue fasciculations and atrophy with increased swallowing problems
• Respiratory insufficiency due to muscle weakness
## Riboflavin Deficiency 2 and 3
While most individuals with RTD2 or RTD3 (caused by biallelic pathogenic variants in
Riboflavin Transporter Deficiency 2 and 3: Select Features
Based on
RTD2 = riboflavin transporter deficiency caused by biallelic
The phenotype of individuals with riboflavin deficiency 2 and 3 at onset usually includes hearing impairment and/or sensory ataxia, followed by progressive upper limb weakness, optic atrophy, bulbar weakness, and respiratory failure.The time between the disease onset and the development of other manifestations varies but is usually one to two years. In some individuals an intercurrent event, usually an injury or infection, appears to precipitate the initial manifestations or worsen existing findings [
Note: When the onset occurs in infancy, after a symptom-free first few weeks (or in some cases months) of life, infants become floppy with failure to thrive and rapidly developing respiratory insufficiency due to paralysis of the diaphragm, followed (in order of appearance) by:
Infantile- or early childhood-onset nystagmus
Early childhood-onset sensory (gait) ataxia
Early-childhood onset progressive and severe sensorineural hearing loss
Weakness and atrophy of the upper limbs (first distally then proximally)
Weakness of neck extensors and later trunk muscles
Tongue fasciculations and atrophy with increased swallowing problems
Respiratory insufficiency due to muscle weakness
Other initial presenting features can include stridor, slurring of speech, and facial weakness. Visual problems due to optic atrophy are common [
Electrophysiologic studies, when performed, were suggestive of peripheral neuropathy in most individuals with RTD, showing chronic denervation and anterior horn dysfunction. Nerve conduction studies suggest an axonal rather than demyelinating neuropathy.
When present, torsional/horizontal nystagmus is one of the early signs of optic atrophy prior to vision loss; thus, RTD should be considered in children with new-onset nystagmus [
Other features variably seen:
While the RTD2 and RTD3 phenotypes are difficult to differentiate, in RTD2 early-onset weakness in the upper limbs and neck is almost invariable, in contrast to RTD3 or genetically unclassified Brown-Vialetto-Van Laere (BVVL) syndrome, in which the onset of weakness is often more generalized [
Previous data suggest that in 70% of individuals receiving riboflavin supplementation, muscle strength, motor abilities, respiratory function, and cranial nerve deficits improve [
With improved disease management and riboflavin treatment (see
• Infantile- or early childhood-onset nystagmus
• Early childhood-onset sensory (gait) ataxia
• Early-childhood onset progressive and severe sensorineural hearing loss
• Weakness and atrophy of the upper limbs (first distally then proximally)
• Weakness of neck extensors and later trunk muscles
• Tongue fasciculations and atrophy with increased swallowing problems
• Respiratory insufficiency due to muscle weakness
## Genotype-Phenotype Correlations
See
## Nomenclature
Other terms used to refer to riboflavin transporter deficiency:
Brown-Vialetto-Van Laere (BVVL) syndrome (corresponding with either
• Brown-Vialetto-Van Laere (BVVL) syndrome (corresponding with either
## Prevalence
Although riboflavin transporter deficiency (RTD) is relatively rare, the advent of molecular genetic testing has improved diagnostic capabilities, making RTD appear more prevalent than previously thought [
It is difficult to establish the prevalence of RTD. It may be underdiagnosed and misdiagnosed; however, it is estimated that RTD affects one in 1,000,000 people in the general population.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Sporadic tumors (including esophageal squamous cell carcinomas) occurring as single tumors in the absence of any other findings of riboflavin transporter deficiency frequently harbor somatic pathogenic variants in
## Differential Diagnosis
Genes and Disorders of Interest in the Differential Diagnosis of Riboflavin Transporter Deficiency
Progressive, fatal, neurodegenerative disease involving both brain & spinal cord. Death most often results from failure of respiratory muscles. RTD has been described as an AR juvenile form of ALS since both RTD & ALS have bulbar & LMN involvement.
AD = autosomal dominant; ALS = amyotrophic lateral sclerosis; AR = autosomal recessive; LMN = lower motor neuron; MOI = mode of inheritance; RTD = riboflavin transporter deficiency; XL = X-linked
Of note, a
The ALS-related genes that have been identified and that account for at least half of ALS that occurs in families with a history of more than one affected relative. Thirty genes have been associated with genetic ALS;
Determination of the mode of inheritance is based on family history and molecular genetic testing.
## Management
No clinical practice guidelines for riboflavin transporter deficiency have been published.
Note: Because
When riboflavin transporter deficiency is suspected during the diagnostic evaluation, begin oral riboflavin supplementation (see
To establish the extent of disease and needs in an individual diagnosed with riboflavin transporter deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Riboflavin Transporter Deficiency 2 and 3
Gross motor & fine motor skills
Spine for scoliosis
Mobility, ADL, & need for bracing &/or adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
ABRs to confirm pathology & provide baseline
Evoked OAEs to identify type of hearing impairment
Speech discrimination tests
Behavioral tests
Community or
Social work involvement for parental support;
Home nursing referral.
ABR = auditory evoked brain stem response; ADL = activities of daily living; MOI = mode of inheritance; OAE = otoacoustic emission; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
High-dose supplementation of riboflavin (10-50 mg/kg/day) has been effective in individuals with molecularly confirmed riboflavin transporter deficiency and, also in some individuals in whom the genetic basis of riboflavin transporter deficiency has not been established.
The amount of riboflavin given varies depending on the severity and response of the individual to the treatment. It has been reported that doses <10 mg/kg/day are ineffective [
Oral riboflavin supplementation should be given in gradually increasing doses in order to establish the optimal dose:
Riboflavin 10 mg/kg/day in 3 doses for 1 month
Riboflavin 20 mg/kg/day in 3 doses for 1 month
Riboflavin 30 mg/kg/day in 3 doses for 1 month
Riboflavin 40 mg/kg/day in 3 doses for 1 month
Riboflavin 50 mg/kg/day in 3 doses for 1 month
Note: Theoretically, parenteral administration of riboflavin may increase uptake and effect [
Side effects reported after high-dose riboflavin supplementation, when present, can include diarrhea, increased urination, and urine discoloration. Allergic reactions have been described rarely. Side effects, problems, or deterioration at any point require discussion with the treating clinician.
Open-label studies have reported improvement of motor symptoms or neurophysiologic measurements or hearing level in a third of individuals treated with up to 500 mg riboflavin three times per day. However, no randomized controlled trials have been performed [
Positive clinical response to the treatment could occur with some latency; thus, riboflavin therapy should be continued in all suspected or genetically diagnosed RTD cases even when there is no apparent initial clinical improvement [
Better response to the treatment is reported when given earlier in life or in the disease course. Adulthood-onset or late treatment are frequently associated with non-improvement, likely reflecting neuronal damage.
Supportive Care for Individuals with Riboflavin Transporter Deficiency 2 and 3
Determine exact cause of swallowing malfunction; modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.
Attn to oral hygiene & dental care, as dysphagia may → impaired clearance of organisms & pathogenic colonization
Many ASMs may be effective; no one ASM has been demonstrated effective specifically for RTD.
Education of parents/caregivers
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; SNHL = sensorineural hearing loss
See
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.
Recommended Surveillance for Individuals with Riboflavin Transporter Deficiency 2 and 3
Discussion of any problems w/riboflavin supplementation
Blood sample for riboflavin/FAD/FMN; acylcarnitine analysis (if previous/y abnormal) to determine if they are normalizing
Orthopedic eval of spine/scoliosis
Physical medicine & rehab; OT/PT eval of fine & gross motor skills, ADL
ADL = activities of daily living; FAD = flavin adenine dinucleotide; FMN = flavin mononucleotide; OT = occupational therapy; PT = physical therapy
Avoid dietary restriction of riboflavin and consume riboflavin-rich foods such as meat, eggs, and milk.
Metabolic stress caused by increased physical activity can decrease levels of riboflavin; therefore, excessive exercise should be limited.
When the
If the pathogenic variants are not known, riboflavin should be administered for both diagnostic and therapeutic purposes if a younger sib of a proband presents with typical symptoms or signs of RTD.
See
See
Transient neonatal riboflavin deficiency (see
Although no data are available, heterozygous females may be at increased risk of developing symptoms due to an increased demand for riboflavin during pregnancy.
Few studies have evaluated for adverse fetal outcomes after excessive maternal riboflavin intake during pregnancy. Riboflavin deficiency during pregnancy, however, has been associated with an increased risk of maternal preeclampsia and preterm delivery [
Search
• Gross motor & fine motor skills
• Spine for scoliosis
• Mobility, ADL, & need for bracing &/or adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• ABRs to confirm pathology & provide baseline
• Evoked OAEs to identify type of hearing impairment
• Speech discrimination tests
• Behavioral tests
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Riboflavin 10 mg/kg/day in 3 doses for 1 month
• Riboflavin 20 mg/kg/day in 3 doses for 1 month
• Riboflavin 30 mg/kg/day in 3 doses for 1 month
• Riboflavin 40 mg/kg/day in 3 doses for 1 month
• Riboflavin 50 mg/kg/day in 3 doses for 1 month
• Determine exact cause of swallowing malfunction; modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.
• Attn to oral hygiene & dental care, as dysphagia may → impaired clearance of organisms & pathogenic colonization
• Many ASMs may be effective; no one ASM has been demonstrated effective specifically for RTD.
• 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 whether any changes are needed.
• Special education law requires that children participating in 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.
• Discussion of any problems w/riboflavin supplementation
• Blood sample for riboflavin/FAD/FMN; acylcarnitine analysis (if previous/y abnormal) to determine if they are normalizing
• Orthopedic eval of spine/scoliosis
• Physical medicine & rehab; OT/PT eval of fine & gross motor skills, ADL
• Transient neonatal riboflavin deficiency (see
• Although no data are available, heterozygous females may be at increased risk of developing symptoms due to an increased demand for riboflavin during pregnancy.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with riboflavin transporter deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Riboflavin Transporter Deficiency 2 and 3
Gross motor & fine motor skills
Spine for scoliosis
Mobility, ADL, & need for bracing &/or adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
ABRs to confirm pathology & provide baseline
Evoked OAEs to identify type of hearing impairment
Speech discrimination tests
Behavioral tests
Community or
Social work involvement for parental support;
Home nursing referral.
ABR = auditory evoked brain stem response; ADL = activities of daily living; MOI = mode of inheritance; OAE = otoacoustic emission; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Gross motor & fine motor skills
• Spine for scoliosis
• Mobility, ADL, & need for bracing &/or adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• ABRs to confirm pathology & provide baseline
• Evoked OAEs to identify type of hearing impairment
• Speech discrimination tests
• Behavioral tests
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
High-dose supplementation of riboflavin (10-50 mg/kg/day) has been effective in individuals with molecularly confirmed riboflavin transporter deficiency and, also in some individuals in whom the genetic basis of riboflavin transporter deficiency has not been established.
The amount of riboflavin given varies depending on the severity and response of the individual to the treatment. It has been reported that doses <10 mg/kg/day are ineffective [
Oral riboflavin supplementation should be given in gradually increasing doses in order to establish the optimal dose:
Riboflavin 10 mg/kg/day in 3 doses for 1 month
Riboflavin 20 mg/kg/day in 3 doses for 1 month
Riboflavin 30 mg/kg/day in 3 doses for 1 month
Riboflavin 40 mg/kg/day in 3 doses for 1 month
Riboflavin 50 mg/kg/day in 3 doses for 1 month
Note: Theoretically, parenteral administration of riboflavin may increase uptake and effect [
Side effects reported after high-dose riboflavin supplementation, when present, can include diarrhea, increased urination, and urine discoloration. Allergic reactions have been described rarely. Side effects, problems, or deterioration at any point require discussion with the treating clinician.
Open-label studies have reported improvement of motor symptoms or neurophysiologic measurements or hearing level in a third of individuals treated with up to 500 mg riboflavin three times per day. However, no randomized controlled trials have been performed [
Positive clinical response to the treatment could occur with some latency; thus, riboflavin therapy should be continued in all suspected or genetically diagnosed RTD cases even when there is no apparent initial clinical improvement [
Better response to the treatment is reported when given earlier in life or in the disease course. Adulthood-onset or late treatment are frequently associated with non-improvement, likely reflecting neuronal damage.
Supportive Care for Individuals with Riboflavin Transporter Deficiency 2 and 3
Determine exact cause of swallowing malfunction; modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.
Attn to oral hygiene & dental care, as dysphagia may → impaired clearance of organisms & pathogenic colonization
Many ASMs may be effective; no one ASM has been demonstrated effective specifically for RTD.
Education of parents/caregivers
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; SNHL = sensorineural hearing loss
See
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.
• Riboflavin 10 mg/kg/day in 3 doses for 1 month
• Riboflavin 20 mg/kg/day in 3 doses for 1 month
• Riboflavin 30 mg/kg/day in 3 doses for 1 month
• Riboflavin 40 mg/kg/day in 3 doses for 1 month
• Riboflavin 50 mg/kg/day in 3 doses for 1 month
• Determine exact cause of swallowing malfunction; modify food types & consistency, head positioning during swallowing, & exercises to improve swallowing.
• Attn to oral hygiene & dental care, as dysphagia may → impaired clearance of organisms & pathogenic colonization
• Many ASMs may be effective; no one ASM has been demonstrated effective specifically for RTD.
• 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 whether any changes are needed.
• Special education law requires that children participating in 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.
## Educational Services for Those with Motor and Language Disabilities
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.
## Surveillance
Recommended Surveillance for Individuals with Riboflavin Transporter Deficiency 2 and 3
Discussion of any problems w/riboflavin supplementation
Blood sample for riboflavin/FAD/FMN; acylcarnitine analysis (if previous/y abnormal) to determine if they are normalizing
Orthopedic eval of spine/scoliosis
Physical medicine & rehab; OT/PT eval of fine & gross motor skills, ADL
ADL = activities of daily living; FAD = flavin adenine dinucleotide; FMN = flavin mononucleotide; OT = occupational therapy; PT = physical therapy
• Discussion of any problems w/riboflavin supplementation
• Blood sample for riboflavin/FAD/FMN; acylcarnitine analysis (if previous/y abnormal) to determine if they are normalizing
• Orthopedic eval of spine/scoliosis
• Physical medicine & rehab; OT/PT eval of fine & gross motor skills, ADL
## Agents/Circumstances to Avoid
Avoid dietary restriction of riboflavin and consume riboflavin-rich foods such as meat, eggs, and milk.
Metabolic stress caused by increased physical activity can decrease levels of riboflavin; therefore, excessive exercise should be limited.
## Evaluation of Relatives at Risk
When the
If the pathogenic variants are not known, riboflavin should be administered for both diagnostic and therapeutic purposes if a younger sib of a proband presents with typical symptoms or signs of RTD.
See
See
## Pregnancy Management
Transient neonatal riboflavin deficiency (see
Although no data are available, heterozygous females may be at increased risk of developing symptoms due to an increased demand for riboflavin during pregnancy.
Few studies have evaluated for adverse fetal outcomes after excessive maternal riboflavin intake during pregnancy. Riboflavin deficiency during pregnancy, however, has been associated with an increased risk of maternal preeclampsia and preterm delivery [
• Transient neonatal riboflavin deficiency (see
• Although no data are available, heterozygous females may be at increased risk of developing symptoms due to an increased demand for riboflavin during pregnancy.
## Therapies Under Investigation
Search
## Genetic Counseling
Riboflavin transporter deficiency 2 (RTD2) and RTD3 – caused by biallelic pathogenic variants in
Preliminary data from a single case report suggests that RTD1 is caused by biallelic pathogenic variants in
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.
Most heterozygous individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see
If both parents are known to be heterozygous for an
Most heterozygous individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see
Carrier testing for at-risk relatives requires prior identification of the
See Management,
Young women with RTD should receive counseling regarding riboflavin supplementation both before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the fetus and infant (see
Women found to be heterozygous (carriers) 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 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.
• Most heterozygous individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (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
• Most heterozygous individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see
• Young women with RTD should receive counseling regarding riboflavin supplementation both before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the fetus and infant (see
• Women found to be heterozygous (carriers) 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 carriers or are at risk of being carriers.
## Mode of Inheritance
Riboflavin transporter deficiency 2 (RTD2) and RTD3 – caused by biallelic pathogenic variants in
Preliminary data from a single case report suggests that RTD1 is caused by biallelic pathogenic variants in
## 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.
Most heterozygous individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see
If both parents are known to be heterozygous for an
Most heterozygous individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see
• 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.
• Most heterozygous individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (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
• Most heterozygous individuals do not have manifestations of RTD. Theoretically, heterozygotes may have manifestations of RTD if other conditions that lead to riboflavin depletion (e.g., dietary restriction, malnourishment, pregnancy, and/or illness) co-occur (see
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
See Management,
Young women with RTD should receive counseling regarding riboflavin supplementation both before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the fetus and infant (see
Women found to be heterozygous (carriers) 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 carriers or are at risk of being carriers.
• Young women with RTD should receive counseling regarding riboflavin supplementation both before and during pregnancy and when breast feeding to avoid inducing riboflavin deficiency in the fetus and infant (see
• Women found to be heterozygous (carriers) 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 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
Riboflavin Transporter Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Riboflavin Transporter Deficiency (
Riboflavin Transporter Deficiency: Gene-Specific Laboratory Technical Considerations
RTD1 = riboflavin transporter deficiency 1; RTD2 = RTD caused by biallelic
Riboflavin Transporter Deficiency: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Riboflavin Transporter Deficiency: Gene-Specific Laboratory Technical Considerations
RTD1 = riboflavin transporter deficiency 1; RTD2 = RTD caused by biallelic
Riboflavin Transporter Deficiency: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
## Chapter Notes
The authors are interested in neuromuscular diseases, channelopathies, and neurodevelopmental disorders; their work involves both the genetics and the functional aspects of these disorders.
Emails for correspondence:
The authors would like to thank the patients and their families for their essential help with this work. This study was supported by the Medical Research Council UK, the Wellcome Trust, and the Brain Research Trust (BRT). This study was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR-UCLH-BRC).
8 April 2021 (bp) Comprehensive update posted live
11 June 2015 (me) Review posted live
2 September 2014 (am) Original submission
• 8 April 2021 (bp) Comprehensive update posted live
• 11 June 2015 (me) Review posted live
• 2 September 2014 (am) Original submission
## Author Notes
The authors are interested in neuromuscular diseases, channelopathies, and neurodevelopmental disorders; their work involves both the genetics and the functional aspects of these disorders.
Emails for correspondence:
## Acknowledgments
The authors would like to thank the patients and their families for their essential help with this work. This study was supported by the Medical Research Council UK, the Wellcome Trust, and the Brain Research Trust (BRT). This study was also supported by the National Institute for Health Research University College London Hospitals Biomedical Research Centre (NIHR-UCLH-BRC).
## Revision History
8 April 2021 (bp) Comprehensive update posted live
11 June 2015 (me) Review posted live
2 September 2014 (am) Original submission
• 8 April 2021 (bp) Comprehensive update posted live
• 11 June 2015 (me) Review posted live
• 2 September 2014 (am) Original submission
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"P Anderson, S Schaefer, L Henderson, IA Bruce. Cochlear implantation in children with auditory neuropathy: lessons from Brown-Vialetto-Van Laere syndrome.. Cochlear Implants International 2019;20:31-8",
"M Babanejad, OA Adeli, N Nikzat, M Beheshtian, H Azarafra, F Sadeghnia, M Mohseni, H Najmabadi, K Kahrizi. SLC52A2 mutations cause SCABD2 phenotype: a second report.. Int J Pediatr Otorhinolaryngol. 2018;104:195-9",
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"AM Bosch, NG Abeling, L Ijlst, H Knoester, WL van der Pol, AE Stroomer, RJ Wanders, G Visser, FA Wijburg, M Duran, HR Waterham. Brown-Vialetto-Van Laere and Fazio Londe syndrome is associated with a riboflavin transporter defect mimicking mild MADD: a new inborn error of metabolism with potential treatment.. J Inherit Metab Dis. 2011;34:159-64",
"AM Bosch, K Stroek, NG Abeling, HR Waterham, L Ijlst, RJ Wanders. The Brown-Vialetto-Van Laere and Fazio Londe syndrome revisited: natural history, genetics, treatment and future perspectives.. Orphanet J Rare Dis. 2012;7:83",
"SL Carmichael, W Yang, GM Shaw. National Birth Defects Prevention Study: maternal dietary nutrient intake and risk of preterm delivery.. Am J Perinatol. 2013;30:579-88",
"C Carreau, C Benoit, G Ahle, C Cauquil, A Roubertie, T Lenglet, J Cosgrove, I Meunier, A Veauville-Merllié, C Acquaviva-Bourdain, Y Nadjar. Late-onset riboflavin transporter deficiency: a treatable mimic of various motor neuropathy aetiologies.. J Neurol Neurosurg Psychiatry. 2020",
"ME Flokas, M Tomani, L Agdere, B Brown. Triple A syndrome (Allgrove syndrome): improving outcomes with a multidisciplinary approach.. Pediatric Health Med Ther. 2019;10:99-106",
"AR Foley, MP Menezes, A Pandraud, MA Gonzalez, A Al-Odaib, AJ Abrams, K Sugano, A Yonezawa, AY Manzur, J Burns, I Hughes, BG McCullagh, H Jungbluth, MJ Lim, JP Lin, A Megarbane, JA Urtizberea, AH Shah, J Antony, R Webster, A Broomfield, J Ng, AA Mathew, JJ O'Byrne, E Forman, M Scoto, M Prasad, K O'Brien, S Olpin, M Oppenheim, I Hargreaves, JM Land, MX Wang, K Carpenter, R Horvath, V Straub, M Lek, W Gold, MO Farrell, S Brandner, R Phadke, K Matsubara, ML McGarvey, SS Scherer, PS Baxter, MD King, P Clayton, S Rahman, MM Reilly, RA Ouvrier, J Christodoulou, S Züchner, F Muntoni, H Houlden. Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2.. Brain. 2014;137:44-56",
"M Garg, SD Kulkarni, AU Hegde, KN Shah. Riboflavin treatment in genetically proven Brown-Vialetto-Van Laere syndrome.. J Pediatr Neurosci. 2018;13:471-3",
"S Gayathri, VK Gowda, T Udhayabanu, B O'Callaghan, S Efthymiou, P Varalakshmi, N Benakappa, H Houlden, B Ashokkumar. Brown-Vialetto-Van Laere and Fazio-Londe syndromes: SLC52A3 mutations with puzzling phenotypes and inheritance.. Eur J Neurol. 2021;28:945-54",
"P González-Pérez, Y Lu, RJ Chian, PC Sapp, RE Tanzi, L Bertram, D McKenna-Yasek, FB Gao, RH Brown. Association of UBQLN1 mutation with Brown-Vialetto-Van Laere syndrome but not typical ALS.. Neurobiol Dis. 2012;48:391-8",
"S Gorcenco, FM Vaz, A Tracewska-Siemiatkowska, L Tranebjærg, FPM Cremers, E Ygland, J Kicsi, ND Rendtorff, C Möller, U Kjellström, S Andréasson, A Puschmann. Oral therapy for riboflavin transporter deficiency - what is the regimen of choice?. Parkinsonism Relat Disord. 2019;61:245-7",
"P Green, M Wiseman, YJ Crow, H Houlden, S Riphagen, JP Lin, FL Raymond, AM Childs, E Sheridan, S Edwards, DJ Josifova. Brown-Vialetto-Van Laere syndrome, a ponto-bulbar palsy with deafness, is caused by mutations in c20orf54.. Am J Hum Genet. 2010;86:485-9",
"TB Haack, C Makowski, Y Yao, E Graf, M Hempel, T Wieland, U Tauer, U Ahting, JA Mayr, P Freisinger, H Yoshimatsu, K Inui, TM Strom, T Meitinger, A Yonezawa, H Prokisch. Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome.. J Inherit Metab Dis. 2012;35:943-8",
"G Ho, A Yonezawa, S Masuda, K Inui, KG Sim, K Carpenter, RK Olsen, JJ Mitchell, WJ Rhead, G Peters, J Christodoulou. Maternal riboflavin deficiency, resulting in transient neonatal-onset glutaric aciduria Type 2, is caused by a microdeletion in the riboflavin transporter gene GPR172B.. Hum Mutat. 2011;32:E1976-84",
"R. Horvath. Update on clinical aspects and treatment of selected vitamin-responsive disorders II (riboflavin and CoQ 10).. J Inherit Metab Dis. 2012;35:679-87",
"B Jaeger, AM Bosch. Clinical presentation and outcome of riboflavin transporter deficiency: mini review after five years of experience.. J Inherit Metab Dis. 2016;39:559-64",
"JO Johnson, JR Gibbs, A Megarbane, JA Urtizberea, DG Hernandez, AR Foley, S Arepalli, A Pandraud, J Simón-Sánchez, P Clayton, MM Reilly, F Muntoni, Y Abramzon, H Houlden, AB Singleton. Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease.. Brain. 2012;135:2875-82",
"JO Johnson, JR Gibbs, L Van Maldergem, H Houlden, AB Singleton. Exome sequencing in Brown-Vialetto-van Laere syndrome.. Am J Hum Genet. 2010;87:567-9",
"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",
"U Kang, DH Yang, SO Nam, Y-J Lee, GM Yeon. Riboflavin transporter 1 deficiency caused by a homozygous single exonal deletion of SLC52A1.. Ann Child Neurol 2020;28:160-3",
"M Khani, H Shamshiri, H Taheri, J Hardy, JT Bras, S Carmona, H Moazzeni, A Alavi, A Heshmati, P Taghizadeh, Y Nilipour, T Ghazanfari, M Shahabi, AA Okhovat, M Rohani, G Valle, R Boostani, S Abdi, S Eshghi, S Nafissi, E Elahi. BVVL/ FL: features caused by SLC52A3 mutations; WDFY4 and TNFSF13B may be novel causative genes.. Neurobiol Aging. 2021;99:102.e1-102.e10",
"P Kranthi, BR Garuda, S Gopi, TS Kumar. Brown-Vialetto-Van Laere syndrome: a rare case report of MND mimic.. Neurol India. 2020;68:1217-9",
"A Manole, P Fratta, H Houlden. Recent advances in bulbar syndromes: genetic causes and disease mechanisms.. Curr Opin Neurol. 2014;27:506-14",
"A Manole, Z Jaunmuktane, I Hargreaves, MHR Ludtmann, V Salpietro, OD Bello, S Pope, A Pandraud, A Horga, RS Scalco, A Li, B Ashokkumar, CM Lourenço, S Heales, R Horvath, PF Chinnery, C Toro, AB Singleton, TS Jacques, AY Abramov, F Muntoni, MG Hanna, MM Reilly, T Revesz, DM Kullmann, JEC Jepson, H Houlden. Clinical, pathological and functional characterization of riboflavin-responsive neuropathy.. Brain. 2017;140:2820-37",
"S Mosegaard, GH Bruun, KF Flyvbjerg, YT Bliksrud, N Gregersen, M Dembic, E Annexstad, T Tangeraas, RKJ Olsen, BS Andresen. An intronic variation in SLC52A1 causes exon skipping and transient riboflavin-responsive multiple acyl-CoA dehydrogenation deficiency.. Mol Genet Metab. 2017;122:182-8",
"S Mosegaard, G Dipace, P Bross, J Carlsen, N Gregersen, RKJ Olsen. Riboflavin deficiency-implications for general human health and inborn errors of metabolism.. Int J Mol Sci. 2020;21:3847",
"B Mutlu, MT Topçu, A Çiprut. A case with Brown-Vialetto-Van Laere syndrome: a sudden onset auditory neuropathy spectrum disorder.. Turk Arch Otorhinolaryngol. 2019;57:201-5",
"A Nalini, A Pandraud, K Mok, H Houlden. Madras motor neuron disease (MMND) is distinct from the riboflavin transporter genetic defects that cause Brown-Vialetto-Van Laere syndrome.. J Neurol Sci. 2013;334:119-22",
"B O'Callaghan, AM Bosch, H Houlden. An update on the genetics, clinical presentation, and pathomechanisms of human riboflavin transporter deficiency.. J Inherit Metab Dis. 2019;42:598-607",
"NR Pillai, H Amin, C Gijavanekar, N Liu, N Issaq, KA Broniowska, AA Bertuch, VR Sutton, SH Elsea, F Scaglia. Hematologic presentation and the role of untargeted metabolomics analysis in monitoring treatment for riboflavin transporter deficiency.. Am J Med Genet A. 2020;182:2781-7",
"WBVR Pinto, FGM Naylor, MAT Chieia, PVS de Souza, ASB Oliveira. New findings in facial-onset sensory and motor neuronopathy (FOSMN) syndrome.. Rev Neurol (Paris) 2019;175:238-46",
"B Rabbani, MK Bakhshandeh, MR Navaeifar, A Abbaskhanian, M Soveizi, S Geravandpoor, N Mahdieh. Brown-Vialetto-Van Laere syndrome and Fazio-Londe syndrome: a novel mutation and in silico analyses.. J Clin Neurosci. 2020;72:342-9",
"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",
"S Rosemberg, CL Lancellotti, F Arita, C Campos, NP de Castro. Progressive bulbar paralysis of childhood (Fazio-Londe disease) with deafness. Case report with clinicopathologic correlation.. Eur Neurol. 1982;21:84-9",
"AM Rossor, B Kalmar, L Greensmith, MM Reilly. The distal hereditary motor neuropathies.. J Neurol Neurosurg Psychiatry. 2012;83:6-14",
"M Saladini, M Nizzardo, A Govoni, M Taiana, N Bresolin, GP Comi, S Corti. Spinal muscular atrophy with respiratory distress type 1: clinical phenotypes, molecular pathogenesis and therapeutic insights.. J Cell Mol Med. 2020;24:1169-78",
"K Shi, Z Shi, H Yan, X Wang, Y Yang, H Xiong, Q Gu, Y Wu, Y Jiang, J. Wang. A Chinese pedigree with Brown-Vialetto-Van Laere syndrome due to two novel mutations of SLC52A2 gene: clinical course and response to riboflavin.. BMC Med Genet. 2019;20:76",
"C Spagnoli, MC Pitt, S Rahman, C de Sousa. Brown-Vialetto-van Laere syndrome: a riboflavin responsive neuronopathy of infancy with singular features.. Eur J Paediatr Neurol. 2014;18:231-4",
"M Srour, ML Putorti, J Schwartzentruber, V Bolduc, MI Shevell, C Poulin, E O'ferrall, D Buhas, J Majewski, B Brais. Mutations in riboflavin transporter present with severe sensory loss and deafness in childhood.. Muscle Nerve. 2014;50:775-9",
"VS Subramanian, R Kapadia, A Ghosal, HM Said. Identification of residues/sequences in the human riboflavin transporter-2 that is important for function and cell biology.. Nutr Metab (Lond) 2015;12:13",
"T Udhayabanu, VS Subramanian, T Teafatiller, VK Gowda, VS Raghavan, P Varalakshmi, HM Said, B Ashokkumar. SLC52A2 [p.P141T] and SLC52A3 [p.N21S] causing Brown-Vialetto-Van Laere syndrome in an Indian patient: first genetically proven case with mutations in two riboflavin transporters.. Clin Chim Acta. 2016;462:210-4",
"VS Yedavalli, A Patil, P Shah. Amyotrophic lateral sclerosis and its mimics/variants: a comprehensive review.. J Clin Imaging Sci. 2018;8:53"
] |
11/6/2015
|
8/4/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
rickets-xlh
|
rickets-xlh
|
[
"X-Linked Hypophosphatemic Rickets (XLHR)",
"X-Linked Vitamin D-Resistant Rickets",
"Hypophosphatemic Rickets, PHEX-Related",
"X-Linked Vitamin D-Resistant Rickets",
"X-Linked Hypophosphatemic Rickets (XLHR)",
"Hypophosphatemic Rickets, PHEX-Related",
"Phosphate-regulating neutral endopeptidase PHEX",
"PHEX",
"X-Linked Hypophosphatemia"
] |
X-Linked Hypophosphatemia
|
Michaël R Laurent, Pol Harvengt, Geert R Mortier, Detlef Böckenhauer
|
Summary The phenotypic spectrum of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to severe lower extremity bowing and/or craniosynostosis, usually involving the sagittal suture with consequent scaphocephaly. XLH typically manifests in the first two years of life with lower extremity bowing due to the onset of weight-bearing; however, it sometimes does not manifest until adulthood, as previously unevaluated short stature. Adults may present with calcification of the tendons, ligaments, and joint capsules, joint pain, fatigue, insufficiency fractures, and impaired mobility. Persons with XLH are prone to spontaneous dental abscesses; sensorineural hearing loss has also been reported. Rarely, individuals with XLH can suffer from spinal stenosis, Chiari I malformation, syringomyelia, and/or raised intracranial pressure. The diagnosis is established in a proband with characteristic clinical, biochemical, and radiographic findings by identification of a hemizygous XLH is inherited in an X-linked manner; hemizygous males and heterozygous females are similarly affected. Affected males transmit the
|
## Diagnosis
For the purposes of this
X-linked hypophosphatemia (XLH)
Clinical signs of rickets resistant to treatment with regular vitamin D
Progressive lower extremity bowing
Decrease in height velocity after the child starts ambulating
Epiphyseal swelling
Harrison groove (a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward)
Rachitic rosary (visibly prominent costochondral joints)
Craniosynostosis and/or craniotabes (softening of the skull bone)
Dental abscesses
Short stature, sometimes disproportionate with short legs
Joint pain, enthesopathy, and decreased joint mobility, particularly at the hips, spine (which may cause spinal stenosis), and shoulders
Insufficiency fractures
Dental abscesses
Fatigue, chronic pain, muscle atrophy, weakness [
Sensorineural hearing loss
Chiari I malformations (mostly asymptomatic in children)
Rickets in growing children. Metaphyses may be widened, frayed, or cupped (most often affecting lower limbs, but any metaphysis can be involved); excessive limb bowing in adults may indicate presence of rickets during skeletal growth.
Rachitic rosary or beading of the ribs from poor skeletal mineralization leading to overgrowth of the costochondral joint cartilage
Insufficiency fractures
Looser zones or pseudofractures
Calcification of the tendons, ligaments, and joint capsules in adults
Radiographically dense bones (in contrast to nutritional, calcipenic, or vitamin D deficiency-related rickets, or osteomalacia). Diffuse osteosclerosis may be seen particularly in the axial skeleton at the late stage.
Low serum phosphate concentration for age (although individuals with milder manifestations may be normophosphatemic [
High alkaline phosphatase (ALP) for age (bone-specific ALP or total ALP in the absence of liver disease) is a biochemical indicator of rickets/osteomalacia.
TRP = 1 - [(urine phosphate ÷ plasma phosphate) x (plasma creatinine ÷ urine creatinine)]
In those with TRP <0.86, the TmP/GFR can be calculated directly as follows:
TmP/GFR = TRP x plasma phosphate
Note: Historically, the nomogram-based method described by
Age-Related Normal Range of TmP/GFR
Based on
Note: For the calculation of TRP the urine should be collected as an untimed urine after an overnight fast.
Normal serum calcium and 25-hydroxyvitamin D. Note: If the serum 25-hydroxyvitamin D concentration is low, vitamin D levels need to be replete before the diagnosis of XLH can be confirmed by laboratory testing.
Lack of hypercalciuria (in untreated individuals with XLH). While TmP/GFR is calculated from paired plasma and urine samples, 24-hour urine collections are recommended to assess urinary calcium excretion in continent individuals [
Inappropriately normal serum calcitriol (1,25-dihydroxyvitamin D) concentration in the presence of hypophosphatemia
Secondary hyperparathyroidism (i.e., without hypercalcemia). In one large cohort, 25% of individuals with XLH had secondary hyperparathyroidism [
Absence of hypouricemia, glycosuria, bicarbonaturia, low molecular weight (tubular) proteinuria, or aminoaciduria (presence of any of these should raise suspicion of renal Fanconi syndrome). However, in long-standing XLH, particularly when complicated by nephrocalcinosis, some degree of renal tubular acidosis may be acquired [
Fibroblast growth factor 23 (FGF23) is usually increased in individuals with XLH. However, there is a lack of standardization of FGF23 assays, and results should be interpreted with caution due to preanalytic and analytic issues. Reference ranges are also not universally established, and higher cutoff values are associated with poor sensitivity [
The diagnosis of XLH
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 comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Hypophosphatemia
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 [
Deep intronic pathogenic variants may be identified by RNA-based analyses (e.g., sequence analysis of PCR-amplified RNA from urine-derived 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. 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 signs of rickets resistant to treatment with regular vitamin D
• Progressive lower extremity bowing
• Decrease in height velocity after the child starts ambulating
• Epiphyseal swelling
• Harrison groove (a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward)
• Rachitic rosary (visibly prominent costochondral joints)
• Progressive lower extremity bowing
• Decrease in height velocity after the child starts ambulating
• Epiphyseal swelling
• Harrison groove (a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward)
• Rachitic rosary (visibly prominent costochondral joints)
• Craniosynostosis and/or craniotabes (softening of the skull bone)
• Dental abscesses
• Progressive lower extremity bowing
• Decrease in height velocity after the child starts ambulating
• Epiphyseal swelling
• Harrison groove (a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward)
• Rachitic rosary (visibly prominent costochondral joints)
• Short stature, sometimes disproportionate with short legs
• Joint pain, enthesopathy, and decreased joint mobility, particularly at the hips, spine (which may cause spinal stenosis), and shoulders
• Insufficiency fractures
• Dental abscesses
• Fatigue, chronic pain, muscle atrophy, weakness [
• Sensorineural hearing loss
• Chiari I malformations (mostly asymptomatic in children)
• Rickets in growing children. Metaphyses may be widened, frayed, or cupped (most often affecting lower limbs, but any metaphysis can be involved); excessive limb bowing in adults may indicate presence of rickets during skeletal growth.
• Rachitic rosary or beading of the ribs from poor skeletal mineralization leading to overgrowth of the costochondral joint cartilage
• Insufficiency fractures
• Looser zones or pseudofractures
• Calcification of the tendons, ligaments, and joint capsules in adults
• Radiographically dense bones (in contrast to nutritional, calcipenic, or vitamin D deficiency-related rickets, or osteomalacia). Diffuse osteosclerosis may be seen particularly in the axial skeleton at the late stage.
• Low serum phosphate concentration for age (although individuals with milder manifestations may be normophosphatemic [
• High alkaline phosphatase (ALP) for age (bone-specific ALP or total ALP in the absence of liver disease) is a biochemical indicator of rickets/osteomalacia.
• TRP = 1 - [(urine phosphate ÷ plasma phosphate) x (plasma creatinine ÷ urine creatinine)]
• In those with TRP <0.86, the TmP/GFR can be calculated directly as follows:
• TmP/GFR = TRP x plasma phosphate
• Note: Historically, the nomogram-based method described by
• TRP = 1 - [(urine phosphate ÷ plasma phosphate) x (plasma creatinine ÷ urine creatinine)]
• TmP/GFR = TRP x plasma phosphate
• TRP = 1 - [(urine phosphate ÷ plasma phosphate) x (plasma creatinine ÷ urine creatinine)]
• TmP/GFR = TRP x plasma phosphate
• Normal serum calcium and 25-hydroxyvitamin D. Note: If the serum 25-hydroxyvitamin D concentration is low, vitamin D levels need to be replete before the diagnosis of XLH can be confirmed by laboratory testing.
• Lack of hypercalciuria (in untreated individuals with XLH). While TmP/GFR is calculated from paired plasma and urine samples, 24-hour urine collections are recommended to assess urinary calcium excretion in continent individuals [
• Inappropriately normal serum calcitriol (1,25-dihydroxyvitamin D) concentration in the presence of hypophosphatemia
• Secondary hyperparathyroidism (i.e., without hypercalcemia). In one large cohort, 25% of individuals with XLH had secondary hyperparathyroidism [
• Absence of hypouricemia, glycosuria, bicarbonaturia, low molecular weight (tubular) proteinuria, or aminoaciduria (presence of any of these should raise suspicion of renal Fanconi syndrome). However, in long-standing XLH, particularly when complicated by nephrocalcinosis, some degree of renal tubular acidosis may be acquired [
• Fibroblast growth factor 23 (FGF23) is usually increased in individuals with XLH. However, there is a lack of standardization of FGF23 assays, and results should be interpreted with caution due to preanalytic and analytic issues. Reference ranges are also not universally established, and higher cutoff values are associated with poor sensitivity [
## Suggestive Findings
X-linked hypophosphatemia (XLH)
Clinical signs of rickets resistant to treatment with regular vitamin D
Progressive lower extremity bowing
Decrease in height velocity after the child starts ambulating
Epiphyseal swelling
Harrison groove (a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward)
Rachitic rosary (visibly prominent costochondral joints)
Craniosynostosis and/or craniotabes (softening of the skull bone)
Dental abscesses
Short stature, sometimes disproportionate with short legs
Joint pain, enthesopathy, and decreased joint mobility, particularly at the hips, spine (which may cause spinal stenosis), and shoulders
Insufficiency fractures
Dental abscesses
Fatigue, chronic pain, muscle atrophy, weakness [
Sensorineural hearing loss
Chiari I malformations (mostly asymptomatic in children)
Rickets in growing children. Metaphyses may be widened, frayed, or cupped (most often affecting lower limbs, but any metaphysis can be involved); excessive limb bowing in adults may indicate presence of rickets during skeletal growth.
Rachitic rosary or beading of the ribs from poor skeletal mineralization leading to overgrowth of the costochondral joint cartilage
Insufficiency fractures
Looser zones or pseudofractures
Calcification of the tendons, ligaments, and joint capsules in adults
Radiographically dense bones (in contrast to nutritional, calcipenic, or vitamin D deficiency-related rickets, or osteomalacia). Diffuse osteosclerosis may be seen particularly in the axial skeleton at the late stage.
Low serum phosphate concentration for age (although individuals with milder manifestations may be normophosphatemic [
High alkaline phosphatase (ALP) for age (bone-specific ALP or total ALP in the absence of liver disease) is a biochemical indicator of rickets/osteomalacia.
TRP = 1 - [(urine phosphate ÷ plasma phosphate) x (plasma creatinine ÷ urine creatinine)]
In those with TRP <0.86, the TmP/GFR can be calculated directly as follows:
TmP/GFR = TRP x plasma phosphate
Note: Historically, the nomogram-based method described by
Age-Related Normal Range of TmP/GFR
Based on
Note: For the calculation of TRP the urine should be collected as an untimed urine after an overnight fast.
Normal serum calcium and 25-hydroxyvitamin D. Note: If the serum 25-hydroxyvitamin D concentration is low, vitamin D levels need to be replete before the diagnosis of XLH can be confirmed by laboratory testing.
Lack of hypercalciuria (in untreated individuals with XLH). While TmP/GFR is calculated from paired plasma and urine samples, 24-hour urine collections are recommended to assess urinary calcium excretion in continent individuals [
Inappropriately normal serum calcitriol (1,25-dihydroxyvitamin D) concentration in the presence of hypophosphatemia
Secondary hyperparathyroidism (i.e., without hypercalcemia). In one large cohort, 25% of individuals with XLH had secondary hyperparathyroidism [
Absence of hypouricemia, glycosuria, bicarbonaturia, low molecular weight (tubular) proteinuria, or aminoaciduria (presence of any of these should raise suspicion of renal Fanconi syndrome). However, in long-standing XLH, particularly when complicated by nephrocalcinosis, some degree of renal tubular acidosis may be acquired [
Fibroblast growth factor 23 (FGF23) is usually increased in individuals with XLH. However, there is a lack of standardization of FGF23 assays, and results should be interpreted with caution due to preanalytic and analytic issues. Reference ranges are also not universally established, and higher cutoff values are associated with poor sensitivity [
• Clinical signs of rickets resistant to treatment with regular vitamin D
• Progressive lower extremity bowing
• Decrease in height velocity after the child starts ambulating
• Epiphyseal swelling
• Harrison groove (a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward)
• Rachitic rosary (visibly prominent costochondral joints)
• Progressive lower extremity bowing
• Decrease in height velocity after the child starts ambulating
• Epiphyseal swelling
• Harrison groove (a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward)
• Rachitic rosary (visibly prominent costochondral joints)
• Craniosynostosis and/or craniotabes (softening of the skull bone)
• Dental abscesses
• Progressive lower extremity bowing
• Decrease in height velocity after the child starts ambulating
• Epiphyseal swelling
• Harrison groove (a horizontal channel at the lower end of the chest caused by the diaphragm pulling the osteomalacic bone inward)
• Rachitic rosary (visibly prominent costochondral joints)
• Short stature, sometimes disproportionate with short legs
• Joint pain, enthesopathy, and decreased joint mobility, particularly at the hips, spine (which may cause spinal stenosis), and shoulders
• Insufficiency fractures
• Dental abscesses
• Fatigue, chronic pain, muscle atrophy, weakness [
• Sensorineural hearing loss
• Chiari I malformations (mostly asymptomatic in children)
• Rickets in growing children. Metaphyses may be widened, frayed, or cupped (most often affecting lower limbs, but any metaphysis can be involved); excessive limb bowing in adults may indicate presence of rickets during skeletal growth.
• Rachitic rosary or beading of the ribs from poor skeletal mineralization leading to overgrowth of the costochondral joint cartilage
• Insufficiency fractures
• Looser zones or pseudofractures
• Calcification of the tendons, ligaments, and joint capsules in adults
• Radiographically dense bones (in contrast to nutritional, calcipenic, or vitamin D deficiency-related rickets, or osteomalacia). Diffuse osteosclerosis may be seen particularly in the axial skeleton at the late stage.
• Low serum phosphate concentration for age (although individuals with milder manifestations may be normophosphatemic [
• High alkaline phosphatase (ALP) for age (bone-specific ALP or total ALP in the absence of liver disease) is a biochemical indicator of rickets/osteomalacia.
• TRP = 1 - [(urine phosphate ÷ plasma phosphate) x (plasma creatinine ÷ urine creatinine)]
• In those with TRP <0.86, the TmP/GFR can be calculated directly as follows:
• TmP/GFR = TRP x plasma phosphate
• Note: Historically, the nomogram-based method described by
• TRP = 1 - [(urine phosphate ÷ plasma phosphate) x (plasma creatinine ÷ urine creatinine)]
• TmP/GFR = TRP x plasma phosphate
• TRP = 1 - [(urine phosphate ÷ plasma phosphate) x (plasma creatinine ÷ urine creatinine)]
• TmP/GFR = TRP x plasma phosphate
• Normal serum calcium and 25-hydroxyvitamin D. Note: If the serum 25-hydroxyvitamin D concentration is low, vitamin D levels need to be replete before the diagnosis of XLH can be confirmed by laboratory testing.
• Lack of hypercalciuria (in untreated individuals with XLH). While TmP/GFR is calculated from paired plasma and urine samples, 24-hour urine collections are recommended to assess urinary calcium excretion in continent individuals [
• Inappropriately normal serum calcitriol (1,25-dihydroxyvitamin D) concentration in the presence of hypophosphatemia
• Secondary hyperparathyroidism (i.e., without hypercalcemia). In one large cohort, 25% of individuals with XLH had secondary hyperparathyroidism [
• Absence of hypouricemia, glycosuria, bicarbonaturia, low molecular weight (tubular) proteinuria, or aminoaciduria (presence of any of these should raise suspicion of renal Fanconi syndrome). However, in long-standing XLH, particularly when complicated by nephrocalcinosis, some degree of renal tubular acidosis may be acquired [
• Fibroblast growth factor 23 (FGF23) is usually increased in individuals with XLH. However, there is a lack of standardization of FGF23 assays, and results should be interpreted with caution due to preanalytic and analytic issues. Reference ranges are also not universally established, and higher cutoff values are associated with poor sensitivity [
## Establishing the Diagnosis
The diagnosis of XLH
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 comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Hypophosphatemia
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 [
Deep intronic pathogenic variants may be identified by RNA-based analyses (e.g., sequence analysis of PCR-amplified RNA from urine-derived 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. 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.
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in X-Linked Hypophosphatemia
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 [
Deep intronic pathogenic variants may be identified by RNA-based analyses (e.g., sequence analysis of PCR-amplified RNA from urine-derived 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. 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 presentation of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to craniosynostosis and/or severe lower extremity bowing. The diagnosis is typically made in the first two years of life, when lower extremity bowing becomes evident with the onset of weight-bearing; however, because of the extremely variable presentation, the diagnosis is sometimes not made until adulthood. Overall, XLH significantly impairs health-related quality of life (more so than, for example, axial spondylarthritis [
X-Linked Hypophosphatemia: Frequency of Select Features
Incl insufficiency & pseudofractures
Fractures are not typical in children.
Based on
Individuals with XLH commonly present with short stature and lower extremity bowing (valgus or varus deformities). Joint pain and impaired mobility associated with enthesopathy, osteophyte formation, or other radiologic findings can occur.
Adults with XLH have a significantly reduced final height (1.9 SD below the mean). Individuals appear disproportionate, with leg length scores (2.7 SD below the mean) being significantly lower than those for sitting height (1.1 SD below the mean) [
Lower extremity torsion and rotation may also be seen, particularly at the femur but also at the tibia [
Insufficient pharmacologic therapy during childhood and adolescence may lead to persistent lower extremity deformities. In addition, some individuals have persistent lower extremity bowing and torsion despite what appears to be adequate pharmacologic therapy. In these individuals, surgical treatment is frequently pursued for misalignment.
Calcification of vertebral ligaments has been reported [
Increased osteophyte formation with spinal hyperostosis and arthritis or fusion of the sacroiliac joints can also lead to pain and compromised mobility. This often mimics ankylosing spondylitis [
Looser zones or pseudofractures that may be symptomatic or asymptomatic are commonly seen and have been reported to occur at any age.
Lower limb muscle power and functional capacity are reduced in adults with XLH and are associated with low levels of physical activity [
Cranial abnormalities include frontal bossing, craniosynostosis, and Chiari I malformations. A detailed cephalometric study revealed increased head length, decreased occipital breadth, and a low mean cephalic index (the ratio of the maximum width of the head multiplied by 100 divided by its maximum length) [
A retrospective study of 44 children reported that 59% had partial or complete fusion of the sagittal suture, 25% showed protrusion of the cerebellar tonsils, although only 5% had neurologic symptoms, and 9% received neurosurgery [
The presentation of craniosynostosis in individuals with XLH tends to manifest slightly later than congenital craniosynostosis and can vary in severity and appearance, making diagnosis difficult and resulting in inconsistent clinical outcomes [
Persons with XLH are prone to spontaneous dental abscesses, which have been attributed to changes in the dentin component of teeth. Irregular spaces with defective mineralization in the tooth dentin have been described [
Sensorineural hearing loss and tinnitus are reported in adults and children; the actual prevalence of hearing loss is not known [
Nephrocalcinosis and nephrolithiasis typically develop as a complication of treatment with phosphate and active vitamin D analogs rather than as a primary complication of XLH. Nephrocalcinosis is reported in 25%-60% of individuals with XLH, and nephrolithiasis in about 10%. With the expanding use of burosumab treatment, it is expected that these complications will become less prevalent [
One study reported an increased risk of mortality in older adults with XLH (hazard ratio: 2.93; 95% confidence interval: 1.24-6.91) [
Several studies have evaluated genotype-phenotype correlations in XLH. Overall, however, there is little consistent evidence for genotype-phenotype correlations in XLH.
One study involving 59 persons correlated dental and hearing defects with pathogenic variants in exons near the 5' end of
Some studies suggested a correlation between more severe bone disease (defined by the severity of bowing and a history of osteotomies) and truncating variants [
A study by
Penetrance is 100%. There is no difference between penetrance in males and females.
The designated term for X-linked hypophosphatemia in the 2023 revision of the Nosology of Genetic Skeletal Disorders is hypophosphatemic rickets,
X-linked dominant hypophosphatemic rickets (XLHR)
X-linked rickets (XLR)
Vitamin D-resistant rickets
Hypophosphatemic vitamin D-resistant rickets (HPDR)
Phosphate diabetes (a more general term referring to renal phosphate wasting conditions)
Familial hypophosphatemic rickets
The incidence of XLH is 3.9-5 in 100,000 live births [
• Incl insufficiency & pseudofractures
• Fractures are not typical in children.
• One study involving 59 persons correlated dental and hearing defects with pathogenic variants in exons near the 5' end of
• Some studies suggested a correlation between more severe bone disease (defined by the severity of bowing and a history of osteotomies) and truncating variants [
• A study by
• X-linked dominant hypophosphatemic rickets (XLHR)
• X-linked rickets (XLR)
• Vitamin D-resistant rickets
• Hypophosphatemic vitamin D-resistant rickets (HPDR)
• Phosphate diabetes (a more general term referring to renal phosphate wasting conditions)
• Familial hypophosphatemic rickets
## Clinical Description
The clinical presentation of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to craniosynostosis and/or severe lower extremity bowing. The diagnosis is typically made in the first two years of life, when lower extremity bowing becomes evident with the onset of weight-bearing; however, because of the extremely variable presentation, the diagnosis is sometimes not made until adulthood. Overall, XLH significantly impairs health-related quality of life (more so than, for example, axial spondylarthritis [
X-Linked Hypophosphatemia: Frequency of Select Features
Incl insufficiency & pseudofractures
Fractures are not typical in children.
Based on
Individuals with XLH commonly present with short stature and lower extremity bowing (valgus or varus deformities). Joint pain and impaired mobility associated with enthesopathy, osteophyte formation, or other radiologic findings can occur.
Adults with XLH have a significantly reduced final height (1.9 SD below the mean). Individuals appear disproportionate, with leg length scores (2.7 SD below the mean) being significantly lower than those for sitting height (1.1 SD below the mean) [
Lower extremity torsion and rotation may also be seen, particularly at the femur but also at the tibia [
Insufficient pharmacologic therapy during childhood and adolescence may lead to persistent lower extremity deformities. In addition, some individuals have persistent lower extremity bowing and torsion despite what appears to be adequate pharmacologic therapy. In these individuals, surgical treatment is frequently pursued for misalignment.
Calcification of vertebral ligaments has been reported [
Increased osteophyte formation with spinal hyperostosis and arthritis or fusion of the sacroiliac joints can also lead to pain and compromised mobility. This often mimics ankylosing spondylitis [
Looser zones or pseudofractures that may be symptomatic or asymptomatic are commonly seen and have been reported to occur at any age.
Lower limb muscle power and functional capacity are reduced in adults with XLH and are associated with low levels of physical activity [
Cranial abnormalities include frontal bossing, craniosynostosis, and Chiari I malformations. A detailed cephalometric study revealed increased head length, decreased occipital breadth, and a low mean cephalic index (the ratio of the maximum width of the head multiplied by 100 divided by its maximum length) [
A retrospective study of 44 children reported that 59% had partial or complete fusion of the sagittal suture, 25% showed protrusion of the cerebellar tonsils, although only 5% had neurologic symptoms, and 9% received neurosurgery [
The presentation of craniosynostosis in individuals with XLH tends to manifest slightly later than congenital craniosynostosis and can vary in severity and appearance, making diagnosis difficult and resulting in inconsistent clinical outcomes [
Persons with XLH are prone to spontaneous dental abscesses, which have been attributed to changes in the dentin component of teeth. Irregular spaces with defective mineralization in the tooth dentin have been described [
Sensorineural hearing loss and tinnitus are reported in adults and children; the actual prevalence of hearing loss is not known [
Nephrocalcinosis and nephrolithiasis typically develop as a complication of treatment with phosphate and active vitamin D analogs rather than as a primary complication of XLH. Nephrocalcinosis is reported in 25%-60% of individuals with XLH, and nephrolithiasis in about 10%. With the expanding use of burosumab treatment, it is expected that these complications will become less prevalent [
One study reported an increased risk of mortality in older adults with XLH (hazard ratio: 2.93; 95% confidence interval: 1.24-6.91) [
• Incl insufficiency & pseudofractures
• Fractures are not typical in children.
## Skeletal Abnormalities
Individuals with XLH commonly present with short stature and lower extremity bowing (valgus or varus deformities). Joint pain and impaired mobility associated with enthesopathy, osteophyte formation, or other radiologic findings can occur.
Adults with XLH have a significantly reduced final height (1.9 SD below the mean). Individuals appear disproportionate, with leg length scores (2.7 SD below the mean) being significantly lower than those for sitting height (1.1 SD below the mean) [
Lower extremity torsion and rotation may also be seen, particularly at the femur but also at the tibia [
Insufficient pharmacologic therapy during childhood and adolescence may lead to persistent lower extremity deformities. In addition, some individuals have persistent lower extremity bowing and torsion despite what appears to be adequate pharmacologic therapy. In these individuals, surgical treatment is frequently pursued for misalignment.
Calcification of vertebral ligaments has been reported [
Increased osteophyte formation with spinal hyperostosis and arthritis or fusion of the sacroiliac joints can also lead to pain and compromised mobility. This often mimics ankylosing spondylitis [
Looser zones or pseudofractures that may be symptomatic or asymptomatic are commonly seen and have been reported to occur at any age.
Lower limb muscle power and functional capacity are reduced in adults with XLH and are associated with low levels of physical activity [
## Cranial Structures
Cranial abnormalities include frontal bossing, craniosynostosis, and Chiari I malformations. A detailed cephalometric study revealed increased head length, decreased occipital breadth, and a low mean cephalic index (the ratio of the maximum width of the head multiplied by 100 divided by its maximum length) [
A retrospective study of 44 children reported that 59% had partial or complete fusion of the sagittal suture, 25% showed protrusion of the cerebellar tonsils, although only 5% had neurologic symptoms, and 9% received neurosurgery [
The presentation of craniosynostosis in individuals with XLH tends to manifest slightly later than congenital craniosynostosis and can vary in severity and appearance, making diagnosis difficult and resulting in inconsistent clinical outcomes [
## Dental Abnormalities
Persons with XLH are prone to spontaneous dental abscesses, which have been attributed to changes in the dentin component of teeth. Irregular spaces with defective mineralization in the tooth dentin have been described [
## Hearing Loss
Sensorineural hearing loss and tinnitus are reported in adults and children; the actual prevalence of hearing loss is not known [
## Nephrocalcinosis
Nephrocalcinosis and nephrolithiasis typically develop as a complication of treatment with phosphate and active vitamin D analogs rather than as a primary complication of XLH. Nephrocalcinosis is reported in 25%-60% of individuals with XLH, and nephrolithiasis in about 10%. With the expanding use of burosumab treatment, it is expected that these complications will become less prevalent [
## Prognosis
One study reported an increased risk of mortality in older adults with XLH (hazard ratio: 2.93; 95% confidence interval: 1.24-6.91) [
## Genotype-Phenotype Correlations
Several studies have evaluated genotype-phenotype correlations in XLH. Overall, however, there is little consistent evidence for genotype-phenotype correlations in XLH.
One study involving 59 persons correlated dental and hearing defects with pathogenic variants in exons near the 5' end of
Some studies suggested a correlation between more severe bone disease (defined by the severity of bowing and a history of osteotomies) and truncating variants [
A study by
• One study involving 59 persons correlated dental and hearing defects with pathogenic variants in exons near the 5' end of
• Some studies suggested a correlation between more severe bone disease (defined by the severity of bowing and a history of osteotomies) and truncating variants [
• A study by
## Penetrance
Penetrance is 100%. There is no difference between penetrance in males and females.
## Nomenclature
The designated term for X-linked hypophosphatemia in the 2023 revision of the Nosology of Genetic Skeletal Disorders is hypophosphatemic rickets,
X-linked dominant hypophosphatemic rickets (XLHR)
X-linked rickets (XLR)
Vitamin D-resistant rickets
Hypophosphatemic vitamin D-resistant rickets (HPDR)
Phosphate diabetes (a more general term referring to renal phosphate wasting conditions)
Familial hypophosphatemic rickets
• X-linked dominant hypophosphatemic rickets (XLHR)
• X-linked rickets (XLR)
• Vitamin D-resistant rickets
• Hypophosphatemic vitamin D-resistant rickets (HPDR)
• Phosphate diabetes (a more general term referring to renal phosphate wasting conditions)
• Familial hypophosphatemic rickets
## Prevalence
The incidence of XLH is 3.9-5 in 100,000 live births [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
In vitamin D-deficient rickets, the 25-hydroxyvitamin D serum concentration is low and the calcium concentration may be low or normal.
In hypophosphatemic rickets, serum concentrations of 25-hydroxyvitamin D and calcium are normal. Concomitant vitamin D deficiency should be corrected before establishing a diagnosis of XLH.
Note: Genetic disorders of vitamin D metabolism that may mimic nutritional rickets clinically, radiographically, and biochemically (but can be distinguished from XLH on all three domains) include those associated with pathogenic variants in
Hereditary Disorders with Renal Phosphate Wasting in the Differential Diagnosis of X-Linked Hypophosphatemia
Hypophosphatemia & hypercalciuria
Suppressed FGF23
1,25-dihydroxyvitamin D may be ↑, normal, or low due to proximal tubular dysfunction.
Low molecular weight proteinuria
Renal phosphate wasting w/o hypercalciuria
Extremely rare
Hypophosphatemia
↓ DMP1 activity leads to ↑ FGF23 production.
Osteosclerotic skeletal changes
Renal phosphate wasting w/o hypercalciuria
Onset can be delayed; rarely, phosphate wasting resolves later in life.
The full-length active form of the protein is stabilized, leading to prolonged or enhanced FGF23 action.
ADHR is much rarer than XLH.
Severe skeletal dysplasia
Hypophosphatemia & lower than expected 1,25-dihydroxyvitamin D levels
↑ FGF23 production from abnormal bone
Hypophosphatemic rickets
Fibrous dysplasia of the bone; precocious puberty; café au lait macules
Overproduction of FGF23 by the fibrous dysplastic bone results in renal phosphate wasting.
Hypophosphatemia is frequent & biochemically indistinguishable from that seen in XLH.
Multiple cutaneous nevi; radiologic evidence of fibrous dysplasia
FGF23 is the cause of the phosphate wasting.
Hypophosphatemia; inappropriately normal 1,25-dihydroxyvitamin D level
Hyperparathyroidism
↑ alpha-klotho & ↑ FGF23
Very short stature, more pronounced skeletal dysplasia
Hypophosphatemia; hypercalciuria
↑ 1,25-dihydroxyvitamin D
Osteopenia, prominent nephrolithiasis/nephrocalcinosis
Hypophosphatemia; hypercalciuria
↑ 1,25-dihydroxyvitamin D
Osteopenia, prominent nephrolithiasis/nephrocalcinosis
AD = autosomal dominant; AR = autosomal recessive; FGF23 = fibroblast growth factor 23; MOI = mode of inheritance; XL = X-linked
Caused by postzygotic somatic activating variants
Also referred to as Schimmelpenning-Feuerstein-Mims syndrome, linear sebaceous nevus syndrome, or epidermal nevus syndrome
In addition to the genes listed in
Two studies reported an association between heterozygous variants in
• In vitamin D-deficient rickets, the 25-hydroxyvitamin D serum concentration is low and the calcium concentration may be low or normal.
• In hypophosphatemic rickets, serum concentrations of 25-hydroxyvitamin D and calcium are normal. Concomitant vitamin D deficiency should be corrected before establishing a diagnosis of XLH.
• Hypophosphatemia & hypercalciuria
• Suppressed FGF23
• 1,25-dihydroxyvitamin D may be ↑, normal, or low due to proximal tubular dysfunction.
• Low molecular weight proteinuria
• Renal phosphate wasting w/o hypercalciuria
• Extremely rare
• Hypophosphatemia
• ↓ DMP1 activity leads to ↑ FGF23 production.
• Osteosclerotic skeletal changes
• Renal phosphate wasting w/o hypercalciuria
• Onset can be delayed; rarely, phosphate wasting resolves later in life.
• The full-length active form of the protein is stabilized, leading to prolonged or enhanced FGF23 action.
• ADHR is much rarer than XLH.
• Severe skeletal dysplasia
• Hypophosphatemia & lower than expected 1,25-dihydroxyvitamin D levels
• ↑ FGF23 production from abnormal bone
• Hypophosphatemic rickets
• Fibrous dysplasia of the bone; precocious puberty; café au lait macules
• Overproduction of FGF23 by the fibrous dysplastic bone results in renal phosphate wasting.
• Hypophosphatemia is frequent & biochemically indistinguishable from that seen in XLH.
• Multiple cutaneous nevi; radiologic evidence of fibrous dysplasia
• FGF23 is the cause of the phosphate wasting.
• Hypophosphatemia; inappropriately normal 1,25-dihydroxyvitamin D level
• Hyperparathyroidism
• ↑ alpha-klotho & ↑ FGF23
• Very short stature, more pronounced skeletal dysplasia
• Hypophosphatemia; hypercalciuria
• ↑ 1,25-dihydroxyvitamin D
• Osteopenia, prominent nephrolithiasis/nephrocalcinosis
• Hypophosphatemia; hypercalciuria
• ↑ 1,25-dihydroxyvitamin D
• Osteopenia, prominent nephrolithiasis/nephrocalcinosis
## Management
To establish the extent of disease and needs of an individual diagnosed with X-linked hypophosphatemia (XLH), the evaluations summarized in
X-Linked Hypophosphatemia: Recommended Evaluations Following Initial Diagnosis
Serum & urine calcium & phosphate
PTH, 25-hydroxyvitamin D, creatinine, & alkaline phosphatase (total or bone specific)
Assess growth.
Lower extremity radiograph (teleroentgenogram) & radiograph of the wrists to assess extent of skeletal disease
Consider bone age radiograph to evaluate growth potential.
Craniofacial exam for manifestations of craniosynostosis
Clinical assessment of joint mobility & pain
Skeletal radiograph survey, esp of skeletal sites w/reported pain or restricted mobility, to assess for joint calcifications &/or insufficiency or pseudofractures
MOI = mode of inheritance; PTH = parathyroid hormone; XLH = X-linked hypophosphatemia
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Current guidelines recommend multidisciplinary team evaluation and management at tertiary referral centers for persons with XLH, with appropriate attention to transitioning from pediatric to adult care [
The aim of targeted therapy is to improve osteomalacia and rickets (including pseudofractures), improve pain, promote fracture healing in those with fractures or undergoing (planned or unplanned) surgery, or – in children – to stimulate growth and correct/prevent bone deformation [
Targeted Treatment of Manifestations in Individuals with X-Linked Hypophosphatemia
In clinical trials, burosumab improved radiographic signs of rickets, lower limb deformity, & height z scores in children compared to phosphate w/active vitamin D supplementation.
In adults, burosumab compared to placebo improved joint stiffness & physical function & improved healing of pseudofractures as well as histologic signs of osteomalacia.
Referred to as conventional therapy (although superiority of burosumab compared to phosphate w/active vitamin D has now been demonstrated in children).
Aim of therapy is to improve growth & rickets in children. In adults, this treatment may be considered in case of pseudofractures, bone pain, other symptoms (incl dental abscesses), &/or planned surgery.
Biochemically, aim of therapy is to improve circulating phosphate, 1,25-dihydroxyvitamin D levels, & secondary hyperparathyroidism; however, oral phosphate w/active vitamin D analogues aggravates renal phosphate wasting, ↑ urinary calcium excretion w/risk of nephrocalcinosis, & further ↑ FGF23.
FGF23 = fibroblast growth factor 23
In clinical trials, burosumab improved radiographic signs of rickets, lower limb deformity, and height z scores in children compared to phosphate with active vitamin D supplementation [
Any oral phosphate and active vitamin D analog should be discontinued at least one week before starting burosumab, to avoid excessive hyperphosphatemia and ectopic calcifications. Fasting serum phosphate should be targeted in the lower end of the normal reference range for age.
The recommended starting dose in
In
Injection site reactions may occur. Burosumab is not recommended in individuals with XLH with severe kidney insufficiency, which is commonly characterized by decreased urinary phosphate excretion and consequent normalization of phosphatemia.
There are insufficient human data to support the safety of burosumab in pregnant women. Moreover, in animal studies, mineralization of the placenta, shortening of gestation, and premature birth have been observed. Burosumab was detected in offspring serum, indicating that it crosses the placenta, but there were no teratogenic effects. Still, given these findings, its use during pregnancy is discouraged. It is unknown whether burosumab or its metabolites are present in breast milk. Also, in animal toxicity studies with burosumab, ectopic mineralization due to hyperphosphatemia was observed in multiple tissues and organs, including the kidney, aorta, heart, lung, and the seminiferous tubules of the testes. The clinical relevance of these findings remains unknown. Both pregnancy and burosumab increase 1,25-dihydroxyvitamin D levels, increasing the risk of hypercalcemia and nephrolithiasis.
Burosumab treatment has been associated with increased PTH levels in some individuals; therefore, monitoring PTH levels may be considered. Coadministration of burosumab with calcimimetics is contraindicated due to the risk of hypocalcemia. Individuals receiving burosumab may develop anti-drug antibodies, which may be associated with declining phosphate levels and may require increased dosing.
In
Doses are adjusted based on (1) evidence of therapeutic success, including reduction in serum ALP activity, improvements in bone deformities, improvement in radiographic rachitic changes and/or pseudofractures, and (in those with open growth plates) improved growth velocity; and (2) evidence of therapeutic complications including secondary hyperparathyroidism, hypercalciuria, and nephrocalcinosis. Note: Normalization of the serum phosphate concentration is not a therapeutic goal with oral phosphate and vitamin D analogs, as normal serum phosphate concentration frequently indicates overtreatment and increases the risk for treatment-related complications. Phosphate levels will also vary with timing of the blood test in relation to the latest phosphate dose. Spreading out the dose in multiple aliquots over the day (or adding it to the drinking water bottle) may help to achieve more stable and sustained phosphate levels.
Initially, during healing of rickets, ALP levels may paradoxically increase. After growth is complete, lower doses of the medications can be used to reach the treatment goals.
Response to oral phosphate and calcitriol treatment is variable.
A healthy diet with sufficient fluid intake, as well as nutritional calcium intake from dairy products, is recommended. In fact, a pilot randomized control trial in children showed that dairy products in equimolar doses may be more effective and safer than phosphate tablets [
In
The doses that are frequently employed in adults are in the range of 0.50 to 0.75 µg of calcitriol and 1 to 1.5 µg of alfacalcidol daily; the phosphate is given is 750-1,000 mg per day, ideally in three to four divided doses. As with children, the phosphate dose is slowly titrated to avoid gastrointestinal side effects, starting at 250 mg per day and titrating up by 250 mg per day each week until the final dose is reached.
Phosphate supplements can be used in various formulations (e.g., Joulie solution, magistral or commercially available capsules, effervescent tablets). Choice of formulation should be determined by the affected individual rather than prescriber preference. Vitamin D analogs can be considered as monotherapy in individuals unwilling to take phosphate. Conversely, the use of phosphate without vitamin D is contraindicated, because phosphate without vitamin D analogs worsens secondary hyperparathyroidism.
A small clinical trial and several case reports have investigated the use of cinacalcet in adults with XLH who have secondary hyperparathyroidism [
Ectopic calcifications have been reported in individuals on conventional therapy, in the absence of hypercalcemia, hyperphosphatemia, or elevations in the product of calcium x phosphate (phosphocalcic product) [
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
X-Linked Hypophosphatemia: Treatment of Manifestations
"Guided growth" using stapling or toggle plate insertion in prepubertal children prior to peak growth velocity (generally age <10 yrs)
Consider as a minimally invasive method of reversible hemiepiphysiodesis.
Note: The risk w/this procedure is prematurely stopping growth.
Surgical treatment may be used in older children & adults w/misalignment.
Treatments may incl distraction osteogenesis (incl Ilizarov surgery) by external fixation, acute correction by external fixation w/intramedullary nailing, internal fixation w/intramedullary nailing, & acute correction by intramedullary nailing.
There are no controlled trials of the various surgical techniques; the literature consists of case series.
Complications of orthopedic surgery are common.
Evaluate underlying causes (e.g., osteoarthritis, insufficiency fractures, osteophytes).
Rehab, physiotherapy, analgesics (paracetamol/acetaminophen, non-steroidal anti-inflammatory drugs, &/or opioids per standard practices in pain medicine)
See
If tertiary hyperparathyroidism is identified, surgical eval (parathyroidectomy w/ or w/o auto-reimplantation) is warranted.
Good oral hygiene w/flossing, regular dental care, & fluoride treatments
Pit & fissure sealants
Pit & fissure sealants have not been well studied.
Treatment in adults w/phosphate & active vitamin D analogs may improve severity of dental disease.
Education on XLH, psychosocial support, referral to XLH organizations
Consider dietary counseling.
Consider treatment w/physical medicine & rehab.
Analgesics as needed
Consider sleep studies for suspected central or obstructive sleep apnea.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
X-Linked Hypophosphatemia: Recommended Surveillance
Serum phosphate, calcium, & creatinine, ALP, intact PTH
Note: The adequacy of treatment is indicated by normal ALP, intact PTH, & normal (or near-normal) phosphate levels (using age-specific reference values).
Radiographs of painful areas to assess for calcifications, pseudofractures, &/or insufficiency fractures
Note: Knee MRI has shown promise as a tool to monitor disease activity & skeletal response to treatment, which avoids radiation exposure of serial radiographs.
ALP = alkaline phosphatase; PTH = parathyroid hormone; TmP/GFR = tubular resorption of phosphate corrected for glomerular filtration rate
It is recommended that treatment with unopposed phosphate (without 1,25-dihydroxyvitamin D) be avoided as this may increase the risk for secondary hyperparathyroidism.
Although 1,25-dihydroxyvitamin D has been used as a single agent, this may increase the risk for hypercalcemia, hypercalciuria, and nephrocalcinosis.
In individuals with fractures, there is no rationale for bisphosphonates or osteoporosis medications, which may cause deterioration of osteomalacia in some individuals [
Laboratory measurements of FGF23 may only be considered for diagnostic purposes but are not useful for follow up.
Testing of at-risk first-degree relatives (male and female infants, children, and/or parents) is warranted to ensure early diagnosis and early treatment for optimal outcome. Evaluation can be accomplished by:
Molecular genetic testing if the
Clinical evaluation and biochemical testing consisting of serum phosphorus, creatinine, calcium, ALP, intact PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D concentrations and urine phosphorus and creatinine concentrations. Infants with initially normal test results require reevaluation every two to three months until at least age one year.
See
There is no consensus on the use of active vitamin D analogs and phosphate in women during pregnancy. Most women with XLH who are on this therapy at the time of conception are continued on treatment throughout the pregnancy with vigilant monitoring (every 1-2 months) of urinary calcium-to-creatinine ratios to detect hypercalciuria early in order to modify treatment accordingly. Since 1,25-dihydroxvitamin D rises during pregnancy, the risk of hypercalcemia, hypercalciuria, and urolithiasis increases. Those individuals who are not on therapy at the time of conception are generally not started on treatment during pregnancy. While pregnancy and lactation are accompanied by transfer of phosphorus from maternal stores to the fetus and a consequent decline in phosphate levels, the available clinical evidence from untreated mothers is reassuring [
A randomized controlled trial of calcitriol monotherapy (without phosphate) in children is ongoing (
Randomized trials are evaluating self-adhesive sealants to prevent dental abscesses in XLH (
In both growing and adult
Studies have evaluated calcitonin to suppress FGF23. However, randomized trials have been disappointing [
Search
• Serum & urine calcium & phosphate
• PTH, 25-hydroxyvitamin D, creatinine, & alkaline phosphatase (total or bone specific)
• Assess growth.
• Lower extremity radiograph (teleroentgenogram) & radiograph of the wrists to assess extent of skeletal disease
• Consider bone age radiograph to evaluate growth potential.
• Craniofacial exam for manifestations of craniosynostosis
• Clinical assessment of joint mobility & pain
• Skeletal radiograph survey, esp of skeletal sites w/reported pain or restricted mobility, to assess for joint calcifications &/or insufficiency or pseudofractures
• In clinical trials, burosumab improved radiographic signs of rickets, lower limb deformity, & height z scores in children compared to phosphate w/active vitamin D supplementation.
• In adults, burosumab compared to placebo improved joint stiffness & physical function & improved healing of pseudofractures as well as histologic signs of osteomalacia.
• Referred to as conventional therapy (although superiority of burosumab compared to phosphate w/active vitamin D has now been demonstrated in children).
• Aim of therapy is to improve growth & rickets in children. In adults, this treatment may be considered in case of pseudofractures, bone pain, other symptoms (incl dental abscesses), &/or planned surgery.
• Biochemically, aim of therapy is to improve circulating phosphate, 1,25-dihydroxyvitamin D levels, & secondary hyperparathyroidism; however, oral phosphate w/active vitamin D analogues aggravates renal phosphate wasting, ↑ urinary calcium excretion w/risk of nephrocalcinosis, & further ↑ FGF23.
• A small clinical trial and several case reports have investigated the use of cinacalcet in adults with XLH who have secondary hyperparathyroidism [
• Ectopic calcifications have been reported in individuals on conventional therapy, in the absence of hypercalcemia, hyperphosphatemia, or elevations in the product of calcium x phosphate (phosphocalcic product) [
• Consider as a minimally invasive method of reversible hemiepiphysiodesis.
• Note: The risk w/this procedure is prematurely stopping growth.
• Surgical treatment may be used in older children & adults w/misalignment.
• Treatments may incl distraction osteogenesis (incl Ilizarov surgery) by external fixation, acute correction by external fixation w/intramedullary nailing, internal fixation w/intramedullary nailing, & acute correction by intramedullary nailing.
• There are no controlled trials of the various surgical techniques; the literature consists of case series.
• Complications of orthopedic surgery are common.
• Evaluate underlying causes (e.g., osteoarthritis, insufficiency fractures, osteophytes).
• Rehab, physiotherapy, analgesics (paracetamol/acetaminophen, non-steroidal anti-inflammatory drugs, &/or opioids per standard practices in pain medicine)
• See
• If tertiary hyperparathyroidism is identified, surgical eval (parathyroidectomy w/ or w/o auto-reimplantation) is warranted.
• Good oral hygiene w/flossing, regular dental care, & fluoride treatments
• Pit & fissure sealants
• Pit & fissure sealants have not been well studied.
• Treatment in adults w/phosphate & active vitamin D analogs may improve severity of dental disease.
• Education on XLH, psychosocial support, referral to XLH organizations
• Consider dietary counseling.
• Consider treatment w/physical medicine & rehab.
• Analgesics as needed
• Consider sleep studies for suspected central or obstructive sleep apnea.
• Serum phosphate, calcium, & creatinine, ALP, intact PTH
• Note: The adequacy of treatment is indicated by normal ALP, intact PTH, & normal (or near-normal) phosphate levels (using age-specific reference values).
• Radiographs of painful areas to assess for calcifications, pseudofractures, &/or insufficiency fractures
• Note: Knee MRI has shown promise as a tool to monitor disease activity & skeletal response to treatment, which avoids radiation exposure of serial radiographs.
• Molecular genetic testing if the
• Clinical evaluation and biochemical testing consisting of serum phosphorus, creatinine, calcium, ALP, intact PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D concentrations and urine phosphorus and creatinine concentrations. Infants with initially normal test results require reevaluation every two to three months until at least age one year.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with X-linked hypophosphatemia (XLH), the evaluations summarized in
X-Linked Hypophosphatemia: Recommended Evaluations Following Initial Diagnosis
Serum & urine calcium & phosphate
PTH, 25-hydroxyvitamin D, creatinine, & alkaline phosphatase (total or bone specific)
Assess growth.
Lower extremity radiograph (teleroentgenogram) & radiograph of the wrists to assess extent of skeletal disease
Consider bone age radiograph to evaluate growth potential.
Craniofacial exam for manifestations of craniosynostosis
Clinical assessment of joint mobility & pain
Skeletal radiograph survey, esp of skeletal sites w/reported pain or restricted mobility, to assess for joint calcifications &/or insufficiency or pseudofractures
MOI = mode of inheritance; PTH = parathyroid hormone; XLH = X-linked hypophosphatemia
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Serum & urine calcium & phosphate
• PTH, 25-hydroxyvitamin D, creatinine, & alkaline phosphatase (total or bone specific)
• Assess growth.
• Lower extremity radiograph (teleroentgenogram) & radiograph of the wrists to assess extent of skeletal disease
• Consider bone age radiograph to evaluate growth potential.
• Craniofacial exam for manifestations of craniosynostosis
• Clinical assessment of joint mobility & pain
• Skeletal radiograph survey, esp of skeletal sites w/reported pain or restricted mobility, to assess for joint calcifications &/or insufficiency or pseudofractures
## Treatment of Manifestations
Current guidelines recommend multidisciplinary team evaluation and management at tertiary referral centers for persons with XLH, with appropriate attention to transitioning from pediatric to adult care [
The aim of targeted therapy is to improve osteomalacia and rickets (including pseudofractures), improve pain, promote fracture healing in those with fractures or undergoing (planned or unplanned) surgery, or – in children – to stimulate growth and correct/prevent bone deformation [
Targeted Treatment of Manifestations in Individuals with X-Linked Hypophosphatemia
In clinical trials, burosumab improved radiographic signs of rickets, lower limb deformity, & height z scores in children compared to phosphate w/active vitamin D supplementation.
In adults, burosumab compared to placebo improved joint stiffness & physical function & improved healing of pseudofractures as well as histologic signs of osteomalacia.
Referred to as conventional therapy (although superiority of burosumab compared to phosphate w/active vitamin D has now been demonstrated in children).
Aim of therapy is to improve growth & rickets in children. In adults, this treatment may be considered in case of pseudofractures, bone pain, other symptoms (incl dental abscesses), &/or planned surgery.
Biochemically, aim of therapy is to improve circulating phosphate, 1,25-dihydroxyvitamin D levels, & secondary hyperparathyroidism; however, oral phosphate w/active vitamin D analogues aggravates renal phosphate wasting, ↑ urinary calcium excretion w/risk of nephrocalcinosis, & further ↑ FGF23.
FGF23 = fibroblast growth factor 23
In clinical trials, burosumab improved radiographic signs of rickets, lower limb deformity, and height z scores in children compared to phosphate with active vitamin D supplementation [
Any oral phosphate and active vitamin D analog should be discontinued at least one week before starting burosumab, to avoid excessive hyperphosphatemia and ectopic calcifications. Fasting serum phosphate should be targeted in the lower end of the normal reference range for age.
The recommended starting dose in
In
Injection site reactions may occur. Burosumab is not recommended in individuals with XLH with severe kidney insufficiency, which is commonly characterized by decreased urinary phosphate excretion and consequent normalization of phosphatemia.
There are insufficient human data to support the safety of burosumab in pregnant women. Moreover, in animal studies, mineralization of the placenta, shortening of gestation, and premature birth have been observed. Burosumab was detected in offspring serum, indicating that it crosses the placenta, but there were no teratogenic effects. Still, given these findings, its use during pregnancy is discouraged. It is unknown whether burosumab or its metabolites are present in breast milk. Also, in animal toxicity studies with burosumab, ectopic mineralization due to hyperphosphatemia was observed in multiple tissues and organs, including the kidney, aorta, heart, lung, and the seminiferous tubules of the testes. The clinical relevance of these findings remains unknown. Both pregnancy and burosumab increase 1,25-dihydroxyvitamin D levels, increasing the risk of hypercalcemia and nephrolithiasis.
Burosumab treatment has been associated with increased PTH levels in some individuals; therefore, monitoring PTH levels may be considered. Coadministration of burosumab with calcimimetics is contraindicated due to the risk of hypocalcemia. Individuals receiving burosumab may develop anti-drug antibodies, which may be associated with declining phosphate levels and may require increased dosing.
In
Doses are adjusted based on (1) evidence of therapeutic success, including reduction in serum ALP activity, improvements in bone deformities, improvement in radiographic rachitic changes and/or pseudofractures, and (in those with open growth plates) improved growth velocity; and (2) evidence of therapeutic complications including secondary hyperparathyroidism, hypercalciuria, and nephrocalcinosis. Note: Normalization of the serum phosphate concentration is not a therapeutic goal with oral phosphate and vitamin D analogs, as normal serum phosphate concentration frequently indicates overtreatment and increases the risk for treatment-related complications. Phosphate levels will also vary with timing of the blood test in relation to the latest phosphate dose. Spreading out the dose in multiple aliquots over the day (or adding it to the drinking water bottle) may help to achieve more stable and sustained phosphate levels.
Initially, during healing of rickets, ALP levels may paradoxically increase. After growth is complete, lower doses of the medications can be used to reach the treatment goals.
Response to oral phosphate and calcitriol treatment is variable.
A healthy diet with sufficient fluid intake, as well as nutritional calcium intake from dairy products, is recommended. In fact, a pilot randomized control trial in children showed that dairy products in equimolar doses may be more effective and safer than phosphate tablets [
In
The doses that are frequently employed in adults are in the range of 0.50 to 0.75 µg of calcitriol and 1 to 1.5 µg of alfacalcidol daily; the phosphate is given is 750-1,000 mg per day, ideally in three to four divided doses. As with children, the phosphate dose is slowly titrated to avoid gastrointestinal side effects, starting at 250 mg per day and titrating up by 250 mg per day each week until the final dose is reached.
Phosphate supplements can be used in various formulations (e.g., Joulie solution, magistral or commercially available capsules, effervescent tablets). Choice of formulation should be determined by the affected individual rather than prescriber preference. Vitamin D analogs can be considered as monotherapy in individuals unwilling to take phosphate. Conversely, the use of phosphate without vitamin D is contraindicated, because phosphate without vitamin D analogs worsens secondary hyperparathyroidism.
A small clinical trial and several case reports have investigated the use of cinacalcet in adults with XLH who have secondary hyperparathyroidism [
Ectopic calcifications have been reported in individuals on conventional therapy, in the absence of hypercalcemia, hyperphosphatemia, or elevations in the product of calcium x phosphate (phosphocalcic product) [
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
X-Linked Hypophosphatemia: Treatment of Manifestations
"Guided growth" using stapling or toggle plate insertion in prepubertal children prior to peak growth velocity (generally age <10 yrs)
Consider as a minimally invasive method of reversible hemiepiphysiodesis.
Note: The risk w/this procedure is prematurely stopping growth.
Surgical treatment may be used in older children & adults w/misalignment.
Treatments may incl distraction osteogenesis (incl Ilizarov surgery) by external fixation, acute correction by external fixation w/intramedullary nailing, internal fixation w/intramedullary nailing, & acute correction by intramedullary nailing.
There are no controlled trials of the various surgical techniques; the literature consists of case series.
Complications of orthopedic surgery are common.
Evaluate underlying causes (e.g., osteoarthritis, insufficiency fractures, osteophytes).
Rehab, physiotherapy, analgesics (paracetamol/acetaminophen, non-steroidal anti-inflammatory drugs, &/or opioids per standard practices in pain medicine)
See
If tertiary hyperparathyroidism is identified, surgical eval (parathyroidectomy w/ or w/o auto-reimplantation) is warranted.
Good oral hygiene w/flossing, regular dental care, & fluoride treatments
Pit & fissure sealants
Pit & fissure sealants have not been well studied.
Treatment in adults w/phosphate & active vitamin D analogs may improve severity of dental disease.
Education on XLH, psychosocial support, referral to XLH organizations
Consider dietary counseling.
Consider treatment w/physical medicine & rehab.
Analgesics as needed
Consider sleep studies for suspected central or obstructive sleep apnea.
• In clinical trials, burosumab improved radiographic signs of rickets, lower limb deformity, & height z scores in children compared to phosphate w/active vitamin D supplementation.
• In adults, burosumab compared to placebo improved joint stiffness & physical function & improved healing of pseudofractures as well as histologic signs of osteomalacia.
• Referred to as conventional therapy (although superiority of burosumab compared to phosphate w/active vitamin D has now been demonstrated in children).
• Aim of therapy is to improve growth & rickets in children. In adults, this treatment may be considered in case of pseudofractures, bone pain, other symptoms (incl dental abscesses), &/or planned surgery.
• Biochemically, aim of therapy is to improve circulating phosphate, 1,25-dihydroxyvitamin D levels, & secondary hyperparathyroidism; however, oral phosphate w/active vitamin D analogues aggravates renal phosphate wasting, ↑ urinary calcium excretion w/risk of nephrocalcinosis, & further ↑ FGF23.
• A small clinical trial and several case reports have investigated the use of cinacalcet in adults with XLH who have secondary hyperparathyroidism [
• Ectopic calcifications have been reported in individuals on conventional therapy, in the absence of hypercalcemia, hyperphosphatemia, or elevations in the product of calcium x phosphate (phosphocalcic product) [
• Consider as a minimally invasive method of reversible hemiepiphysiodesis.
• Note: The risk w/this procedure is prematurely stopping growth.
• Surgical treatment may be used in older children & adults w/misalignment.
• Treatments may incl distraction osteogenesis (incl Ilizarov surgery) by external fixation, acute correction by external fixation w/intramedullary nailing, internal fixation w/intramedullary nailing, & acute correction by intramedullary nailing.
• There are no controlled trials of the various surgical techniques; the literature consists of case series.
• Complications of orthopedic surgery are common.
• Evaluate underlying causes (e.g., osteoarthritis, insufficiency fractures, osteophytes).
• Rehab, physiotherapy, analgesics (paracetamol/acetaminophen, non-steroidal anti-inflammatory drugs, &/or opioids per standard practices in pain medicine)
• See
• If tertiary hyperparathyroidism is identified, surgical eval (parathyroidectomy w/ or w/o auto-reimplantation) is warranted.
• Good oral hygiene w/flossing, regular dental care, & fluoride treatments
• Pit & fissure sealants
• Pit & fissure sealants have not been well studied.
• Treatment in adults w/phosphate & active vitamin D analogs may improve severity of dental disease.
• Education on XLH, psychosocial support, referral to XLH organizations
• Consider dietary counseling.
• Consider treatment w/physical medicine & rehab.
• Analgesics as needed
• Consider sleep studies for suspected central or obstructive sleep apnea.
## Targeted Therapies
The aim of targeted therapy is to improve osteomalacia and rickets (including pseudofractures), improve pain, promote fracture healing in those with fractures or undergoing (planned or unplanned) surgery, or – in children – to stimulate growth and correct/prevent bone deformation [
Targeted Treatment of Manifestations in Individuals with X-Linked Hypophosphatemia
In clinical trials, burosumab improved radiographic signs of rickets, lower limb deformity, & height z scores in children compared to phosphate w/active vitamin D supplementation.
In adults, burosumab compared to placebo improved joint stiffness & physical function & improved healing of pseudofractures as well as histologic signs of osteomalacia.
Referred to as conventional therapy (although superiority of burosumab compared to phosphate w/active vitamin D has now been demonstrated in children).
Aim of therapy is to improve growth & rickets in children. In adults, this treatment may be considered in case of pseudofractures, bone pain, other symptoms (incl dental abscesses), &/or planned surgery.
Biochemically, aim of therapy is to improve circulating phosphate, 1,25-dihydroxyvitamin D levels, & secondary hyperparathyroidism; however, oral phosphate w/active vitamin D analogues aggravates renal phosphate wasting, ↑ urinary calcium excretion w/risk of nephrocalcinosis, & further ↑ FGF23.
FGF23 = fibroblast growth factor 23
In clinical trials, burosumab improved radiographic signs of rickets, lower limb deformity, and height z scores in children compared to phosphate with active vitamin D supplementation [
Any oral phosphate and active vitamin D analog should be discontinued at least one week before starting burosumab, to avoid excessive hyperphosphatemia and ectopic calcifications. Fasting serum phosphate should be targeted in the lower end of the normal reference range for age.
The recommended starting dose in
In
Injection site reactions may occur. Burosumab is not recommended in individuals with XLH with severe kidney insufficiency, which is commonly characterized by decreased urinary phosphate excretion and consequent normalization of phosphatemia.
There are insufficient human data to support the safety of burosumab in pregnant women. Moreover, in animal studies, mineralization of the placenta, shortening of gestation, and premature birth have been observed. Burosumab was detected in offspring serum, indicating that it crosses the placenta, but there were no teratogenic effects. Still, given these findings, its use during pregnancy is discouraged. It is unknown whether burosumab or its metabolites are present in breast milk. Also, in animal toxicity studies with burosumab, ectopic mineralization due to hyperphosphatemia was observed in multiple tissues and organs, including the kidney, aorta, heart, lung, and the seminiferous tubules of the testes. The clinical relevance of these findings remains unknown. Both pregnancy and burosumab increase 1,25-dihydroxyvitamin D levels, increasing the risk of hypercalcemia and nephrolithiasis.
Burosumab treatment has been associated with increased PTH levels in some individuals; therefore, monitoring PTH levels may be considered. Coadministration of burosumab with calcimimetics is contraindicated due to the risk of hypocalcemia. Individuals receiving burosumab may develop anti-drug antibodies, which may be associated with declining phosphate levels and may require increased dosing.
In
Doses are adjusted based on (1) evidence of therapeutic success, including reduction in serum ALP activity, improvements in bone deformities, improvement in radiographic rachitic changes and/or pseudofractures, and (in those with open growth plates) improved growth velocity; and (2) evidence of therapeutic complications including secondary hyperparathyroidism, hypercalciuria, and nephrocalcinosis. Note: Normalization of the serum phosphate concentration is not a therapeutic goal with oral phosphate and vitamin D analogs, as normal serum phosphate concentration frequently indicates overtreatment and increases the risk for treatment-related complications. Phosphate levels will also vary with timing of the blood test in relation to the latest phosphate dose. Spreading out the dose in multiple aliquots over the day (or adding it to the drinking water bottle) may help to achieve more stable and sustained phosphate levels.
Initially, during healing of rickets, ALP levels may paradoxically increase. After growth is complete, lower doses of the medications can be used to reach the treatment goals.
Response to oral phosphate and calcitriol treatment is variable.
A healthy diet with sufficient fluid intake, as well as nutritional calcium intake from dairy products, is recommended. In fact, a pilot randomized control trial in children showed that dairy products in equimolar doses may be more effective and safer than phosphate tablets [
In
The doses that are frequently employed in adults are in the range of 0.50 to 0.75 µg of calcitriol and 1 to 1.5 µg of alfacalcidol daily; the phosphate is given is 750-1,000 mg per day, ideally in three to four divided doses. As with children, the phosphate dose is slowly titrated to avoid gastrointestinal side effects, starting at 250 mg per day and titrating up by 250 mg per day each week until the final dose is reached.
Phosphate supplements can be used in various formulations (e.g., Joulie solution, magistral or commercially available capsules, effervescent tablets). Choice of formulation should be determined by the affected individual rather than prescriber preference. Vitamin D analogs can be considered as monotherapy in individuals unwilling to take phosphate. Conversely, the use of phosphate without vitamin D is contraindicated, because phosphate without vitamin D analogs worsens secondary hyperparathyroidism.
A small clinical trial and several case reports have investigated the use of cinacalcet in adults with XLH who have secondary hyperparathyroidism [
Ectopic calcifications have been reported in individuals on conventional therapy, in the absence of hypercalcemia, hyperphosphatemia, or elevations in the product of calcium x phosphate (phosphocalcic product) [
• In clinical trials, burosumab improved radiographic signs of rickets, lower limb deformity, & height z scores in children compared to phosphate w/active vitamin D supplementation.
• In adults, burosumab compared to placebo improved joint stiffness & physical function & improved healing of pseudofractures as well as histologic signs of osteomalacia.
• Referred to as conventional therapy (although superiority of burosumab compared to phosphate w/active vitamin D has now been demonstrated in children).
• Aim of therapy is to improve growth & rickets in children. In adults, this treatment may be considered in case of pseudofractures, bone pain, other symptoms (incl dental abscesses), &/or planned surgery.
• Biochemically, aim of therapy is to improve circulating phosphate, 1,25-dihydroxyvitamin D levels, & secondary hyperparathyroidism; however, oral phosphate w/active vitamin D analogues aggravates renal phosphate wasting, ↑ urinary calcium excretion w/risk of nephrocalcinosis, & further ↑ FGF23.
• A small clinical trial and several case reports have investigated the use of cinacalcet in adults with XLH who have secondary hyperparathyroidism [
• Ectopic calcifications have been reported in individuals on conventional therapy, in the absence of hypercalcemia, hyperphosphatemia, or elevations in the product of calcium x phosphate (phosphocalcic product) [
## 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
X-Linked Hypophosphatemia: Treatment of Manifestations
"Guided growth" using stapling or toggle plate insertion in prepubertal children prior to peak growth velocity (generally age <10 yrs)
Consider as a minimally invasive method of reversible hemiepiphysiodesis.
Note: The risk w/this procedure is prematurely stopping growth.
Surgical treatment may be used in older children & adults w/misalignment.
Treatments may incl distraction osteogenesis (incl Ilizarov surgery) by external fixation, acute correction by external fixation w/intramedullary nailing, internal fixation w/intramedullary nailing, & acute correction by intramedullary nailing.
There are no controlled trials of the various surgical techniques; the literature consists of case series.
Complications of orthopedic surgery are common.
Evaluate underlying causes (e.g., osteoarthritis, insufficiency fractures, osteophytes).
Rehab, physiotherapy, analgesics (paracetamol/acetaminophen, non-steroidal anti-inflammatory drugs, &/or opioids per standard practices in pain medicine)
See
If tertiary hyperparathyroidism is identified, surgical eval (parathyroidectomy w/ or w/o auto-reimplantation) is warranted.
Good oral hygiene w/flossing, regular dental care, & fluoride treatments
Pit & fissure sealants
Pit & fissure sealants have not been well studied.
Treatment in adults w/phosphate & active vitamin D analogs may improve severity of dental disease.
Education on XLH, psychosocial support, referral to XLH organizations
Consider dietary counseling.
Consider treatment w/physical medicine & rehab.
Analgesics as needed
Consider sleep studies for suspected central or obstructive sleep apnea.
• Consider as a minimally invasive method of reversible hemiepiphysiodesis.
• Note: The risk w/this procedure is prematurely stopping growth.
• Surgical treatment may be used in older children & adults w/misalignment.
• Treatments may incl distraction osteogenesis (incl Ilizarov surgery) by external fixation, acute correction by external fixation w/intramedullary nailing, internal fixation w/intramedullary nailing, & acute correction by intramedullary nailing.
• There are no controlled trials of the various surgical techniques; the literature consists of case series.
• Complications of orthopedic surgery are common.
• Evaluate underlying causes (e.g., osteoarthritis, insufficiency fractures, osteophytes).
• Rehab, physiotherapy, analgesics (paracetamol/acetaminophen, non-steroidal anti-inflammatory drugs, &/or opioids per standard practices in pain medicine)
• See
• If tertiary hyperparathyroidism is identified, surgical eval (parathyroidectomy w/ or w/o auto-reimplantation) is warranted.
• Good oral hygiene w/flossing, regular dental care, & fluoride treatments
• Pit & fissure sealants
• Pit & fissure sealants have not been well studied.
• Treatment in adults w/phosphate & active vitamin D analogs may improve severity of dental disease.
• Education on XLH, psychosocial support, referral to XLH organizations
• Consider dietary counseling.
• Consider treatment w/physical medicine & rehab.
• Analgesics as needed
• Consider sleep studies for suspected central or obstructive sleep apnea.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
X-Linked Hypophosphatemia: Recommended Surveillance
Serum phosphate, calcium, & creatinine, ALP, intact PTH
Note: The adequacy of treatment is indicated by normal ALP, intact PTH, & normal (or near-normal) phosphate levels (using age-specific reference values).
Radiographs of painful areas to assess for calcifications, pseudofractures, &/or insufficiency fractures
Note: Knee MRI has shown promise as a tool to monitor disease activity & skeletal response to treatment, which avoids radiation exposure of serial radiographs.
ALP = alkaline phosphatase; PTH = parathyroid hormone; TmP/GFR = tubular resorption of phosphate corrected for glomerular filtration rate
• Serum phosphate, calcium, & creatinine, ALP, intact PTH
• Note: The adequacy of treatment is indicated by normal ALP, intact PTH, & normal (or near-normal) phosphate levels (using age-specific reference values).
• Radiographs of painful areas to assess for calcifications, pseudofractures, &/or insufficiency fractures
• Note: Knee MRI has shown promise as a tool to monitor disease activity & skeletal response to treatment, which avoids radiation exposure of serial radiographs.
## Agents/Circumstances to Avoid
It is recommended that treatment with unopposed phosphate (without 1,25-dihydroxyvitamin D) be avoided as this may increase the risk for secondary hyperparathyroidism.
Although 1,25-dihydroxyvitamin D has been used as a single agent, this may increase the risk for hypercalcemia, hypercalciuria, and nephrocalcinosis.
In individuals with fractures, there is no rationale for bisphosphonates or osteoporosis medications, which may cause deterioration of osteomalacia in some individuals [
Laboratory measurements of FGF23 may only be considered for diagnostic purposes but are not useful for follow up.
## Evaluation of Relatives at Risk
Testing of at-risk first-degree relatives (male and female infants, children, and/or parents) is warranted to ensure early diagnosis and early treatment for optimal outcome. Evaluation can be accomplished by:
Molecular genetic testing if the
Clinical evaluation and biochemical testing consisting of serum phosphorus, creatinine, calcium, ALP, intact PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D concentrations and urine phosphorus and creatinine concentrations. Infants with initially normal test results require reevaluation every two to three months until at least age one year.
See
• Molecular genetic testing if the
• Clinical evaluation and biochemical testing consisting of serum phosphorus, creatinine, calcium, ALP, intact PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D concentrations and urine phosphorus and creatinine concentrations. Infants with initially normal test results require reevaluation every two to three months until at least age one year.
## Pregnancy Management
There is no consensus on the use of active vitamin D analogs and phosphate in women during pregnancy. Most women with XLH who are on this therapy at the time of conception are continued on treatment throughout the pregnancy with vigilant monitoring (every 1-2 months) of urinary calcium-to-creatinine ratios to detect hypercalciuria early in order to modify treatment accordingly. Since 1,25-dihydroxvitamin D rises during pregnancy, the risk of hypercalcemia, hypercalciuria, and urolithiasis increases. Those individuals who are not on therapy at the time of conception are generally not started on treatment during pregnancy. While pregnancy and lactation are accompanied by transfer of phosphorus from maternal stores to the fetus and a consequent decline in phosphate levels, the available clinical evidence from untreated mothers is reassuring [
## Therapies Under Investigation
A randomized controlled trial of calcitriol monotherapy (without phosphate) in children is ongoing (
Randomized trials are evaluating self-adhesive sealants to prevent dental abscesses in XLH (
In both growing and adult
Studies have evaluated calcitonin to suppress FGF23. However, randomized trials have been disappointing [
Search
## Genetic Counseling
By definition, X-linked hypophosphatemia (XLH) is inherited in an X-linked manner; hemizygous males and heterozygous females are similarly affected.
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 the mother of a male proband 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 or have germline mosaicism; or
The mother does not have the
Molecular genetic testing of the mother (or biochemical testing if the
Evaluation of the mother may determine that she is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without biochemical or molecular genetic testing of the mother [
A female proband may have XLH as the result of:
A
A
Molecular genetic testing of the mother and father of the proband (or biochemical testing if the
If the pathogenic variant found in a female proband cannot be detected in either parent and parental identity testing has confirmed biological maternity and paternity, possible explanations include a
Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without biochemical or molecular genetic testing of both parents [
If the father of the proband is affected and/or is known to have a
If the mother of the proband is affected and/or is known to have a
The severity of manifestations can differ among sibs who inherit a
If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental germline 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.
If the
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 the
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote. Note: If the mother of a male proband 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 or have germline mosaicism; or
• The mother does not have the
• The mother may be a heterozygote or have germline mosaicism; or
• The mother does not have the
• Molecular genetic testing of the mother (or biochemical testing if the
• Evaluation of the mother may determine that she is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without biochemical or molecular genetic testing of the mother [
• The mother may be a heterozygote or have germline mosaicism; or
• The mother does not have the
• A female proband may have XLH as the result of:
• A
• A
• A
• A
• Molecular genetic testing of the mother and father of the proband (or biochemical testing if the
• If the pathogenic variant found in a female proband cannot be detected in either parent and parental identity testing has confirmed biological maternity and paternity, possible explanations include a
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without biochemical or molecular genetic testing of both parents [
• A
• A
• If the father of the proband is affected and/or is known to have a
• If the mother of the proband is affected and/or is known to have a
• The severity of manifestations can differ among sibs who inherit a
• If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be low but greater than that of the general population 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.
## Mode of Inheritance
By definition, X-linked hypophosphatemia (XLH) is inherited in an X-linked manner; hemizygous males and heterozygous females are similarly affected.
## 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 the mother of a male proband 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 or have germline mosaicism; or
The mother does not have the
Molecular genetic testing of the mother (or biochemical testing if the
Evaluation of the mother may determine that she is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without biochemical or molecular genetic testing of the mother [
A female proband may have XLH as the result of:
A
A
Molecular genetic testing of the mother and father of the proband (or biochemical testing if the
If the pathogenic variant found in a female proband cannot be detected in either parent and parental identity testing has confirmed biological maternity and paternity, possible explanations include a
Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without biochemical or molecular genetic testing of both parents [
If the father of the proband is affected and/or is known to have a
If the mother of the proband is affected and/or is known to have a
The severity of manifestations can differ among sibs who inherit a
If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental germline mosaicism [
• 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 the mother of a male proband 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 or have germline mosaicism; or
• The mother does not have the
• The mother may be a heterozygote or have germline mosaicism; or
• The mother does not have the
• Molecular genetic testing of the mother (or biochemical testing if the
• Evaluation of the mother may determine that she is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without biochemical or molecular genetic testing of the mother [
• The mother may be a heterozygote or have germline mosaicism; or
• The mother does not have the
• A female proband may have XLH as the result of:
• A
• A
• A
• A
• Molecular genetic testing of the mother and father of the proband (or biochemical testing if the
• If the pathogenic variant found in a female proband cannot be detected in either parent and parental identity testing has confirmed biological maternity and paternity, possible explanations include a
• Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed without biochemical or molecular genetic testing of both parents [
• A
• A
• If the father of the proband is affected and/or is known to have a
• If the mother of the proband is affected and/or is known to have a
• The severity of manifestations can differ among sibs who inherit a
• If the proband represents a simplex case and if the pathogenic variant cannot be detected in the leukocyte DNA of either parent, the risk to sibs is presumed to be low but greater than that of the general population because of the possibility of parental 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
If the
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
•
•
•
•
•
•
## Molecular Genetics
X-Linked Hypophosphatemia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for X-Linked Hypophosphatemia (
The function of the protein produced by
Pathogenic variants in
It has also been hypothesized that pathogenic variants in
Variants listed in the table have been provided by the authors.
Variant designation does not conform to current naming conventions
## Molecular Pathogenesis
The function of the protein produced by
Pathogenic variants in
It has also been hypothesized that pathogenic variants in
Variants listed in the table have been provided by the authors.
Variant designation does not conform to current naming conventions
## Chapter Notes
The authors thank Mary D Ruppe (Methodist Hospital, Houston, TX) for authoring previous versions of this chapter.
Detlef Böckenhauer, MD, PhD (2023-present) Pol Harvengt, PhD (2023-present) Michaël R Laurent, MD, PhD (2023-present) Geert R Mortier MD, PhD (2023-present) Mary D Ruppe, MD; Methodist Hospital, Houston (2012-2023)
14 December 2023 (sw) Comprehensive update posted live
13 April 2017 (ha) Comprehensive update posted live
16 October 2014 (me) Comprehensive update posted live
9 February 2012 (me) Review posted live
1 September 2011 (mr) Initial submission
• 14 December 2023 (sw) Comprehensive update posted live
• 13 April 2017 (ha) Comprehensive update posted live
• 16 October 2014 (me) Comprehensive update posted live
• 9 February 2012 (me) Review posted live
• 1 September 2011 (mr) Initial submission
## Author Notes
## Acknowledgments
The authors thank Mary D Ruppe (Methodist Hospital, Houston, TX) for authoring previous versions of this chapter.
## Author History
Detlef Böckenhauer, MD, PhD (2023-present) Pol Harvengt, PhD (2023-present) Michaël R Laurent, MD, PhD (2023-present) Geert R Mortier MD, PhD (2023-present) Mary D Ruppe, MD; Methodist Hospital, Houston (2012-2023)
## Revision History
14 December 2023 (sw) Comprehensive update posted live
13 April 2017 (ha) Comprehensive update posted live
16 October 2014 (me) Comprehensive update posted live
9 February 2012 (me) Review posted live
1 September 2011 (mr) Initial submission
• 14 December 2023 (sw) Comprehensive update posted live
• 13 April 2017 (ha) Comprehensive update posted live
• 16 October 2014 (me) Comprehensive update posted live
• 9 February 2012 (me) Review posted live
• 1 September 2011 (mr) Initial submission
## Key Sections in this
## References
## Literature Cited
|
[] |
9/2/2012
|
14/12/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
ritscher-schinzel
|
ritscher-schinzel
|
[
"3C Syndrome",
"Cranio-Cerebello-Cardiac Dysplasia",
"3C Syndrome",
"Cranio-Cerebello-Cardiac Dysplasia",
"Coiled-coil domain-containing protein 22",
"WASH complex subunit 5",
"CCDC22",
"WASHC5",
"Ritscher-Schinzel Syndrome"
] |
Ritscher-Schinzel Syndrome
|
Alison M Elliott, Albert Chudley
|
Summary Ritscher-Schinzel syndrome (RSS) is a clinically recognizable condition that includes the cardinal findings of craniofacial features, cerebellar defects, and cardiovascular malformations resulting in the alternate diagnostic name of 3C syndrome. Dysmorphic facial features may include brachycephaly, hypotonic face with protruding tongue, flat appearance of the face on profile view, short midface, widely spaced eyes, downslanted palpebral fissures, low-set ears with overfolding of the upper helix, smooth or short philtrum, and high or cleft palate. Affected individuals also typically have a characteristic metacarpal phalangeal profile showing a consistent wavy pattern on hand radiographs. RSS is associated with variable degrees of developmental delay and intellectual disability. Eye anomalies and hypercholesterolemia may be variably present. The diagnosis of Ritscher-Schinzel syndrome is established in a proband with suggestive clinical findings, including characteristic dysmorphic facial features, and/or by the identification of biallelic pathogenic variants in Once the causative pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
|
## Diagnosis
Consensus clinical diagnostic criteria for Ritscher-Schinzel syndrome (RSS) have not been established.
Congenital heart malformation(s) other than patent ductus arteriosus alone
Dandy-Walker malformation, cerebellar vermis hypoplasia, or enlarged cisterna magna
Cleft palate OR ocular coloboma OR four of the following:
Prominent occiput
Prominent forehead
Downslanted palpebral fissures
Widely-spaced eyes
Depressed nasal bridge
Micrognathia
However, these clinical criteria would exclude affected individuals who may not exhibit cerebellar or cardiac malformations in whom Ritscher-Schinzel syndrome has been molecularly confirmed.
Ritscher-Schinzel syndrome (RSS)
Mild-to-severe intellectual disability
Characteristic dysmorphic facial features
Macrocephaly
Brachycephaly
Flat occiput (prominent occiput in some)
Hypotonic face with a tendency to a protruding tongue
Short midface
Flat appearance of the face on profile view
Highly arched and thick eyebrows
Downslanted palpebral fissures
Widely spaced eyes
Depressed nasal bridge
Low-set ears; overfolding of the upper helix
Smooth or short philtrum
High palate or cleft palate
Short broad neck with a low posterior hair line and webbing
Cardiac malformations (See
Brain MRI
Dandy-Walker malformation
Hypoplasia or dysplasia of the cerebellar vermis
Hydrocephalus
Hand radiographs
Brachydactyly, especially of the second ray
Shortening of the first metacarpal and the fifth distal phalanx
Characteristic metacarpal phalangeal pattern profile (See
The diagnosis of Ritscher-Schinzel 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
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Ritscher-Schinzel syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and radiographic findings suggest the diagnosis of Ritscher-Schinzel syndrome molecular genetic testing approaches can include concurrent or serial single-gene testing, or use of a
If the individual is of First Nations (FN) heritage (indigenous people of Canada who are not Metis or Inuit) or is female, sequence analysis of
If only one or no pathogenic variant is found, gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may be considered.
In a male proband who is not of FN heritage, sequence analysis of
For an introduction to multigene panels click
When the diagnosis of Ritscher-Schinzel syndrome is not considered because an individual has atypical phenotypic features,
Individuals with a chromosome 6p25 deletion have features that can overlap with RSS (see
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Ritscher-Schinzel Syndrome (RSS)
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 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 variant in this gene was reported in two male sibs of Austrian origin [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
This refers to the proportion of affected individuals of First Nations heritage; the proportion of affected individuals of other ethnicities who have biallelic pathogenic variants in
All affected individuals of First Nations heritage from Northern Ontario and Manitoba who were tested for a sequence variant in this gene were found to be homozygous for the c.3335+2T>A variant [
Individuals from a large Colombian kindred identified as having RSS were not identified to have any pathogenic variants in
• Congenital heart malformation(s) other than patent ductus arteriosus alone
• Dandy-Walker malformation, cerebellar vermis hypoplasia, or enlarged cisterna magna
• Cleft palate OR ocular coloboma OR four of the following:
• Prominent occiput
• Prominent forehead
• Downslanted palpebral fissures
• Widely-spaced eyes
• Depressed nasal bridge
• Micrognathia
• Prominent occiput
• Prominent forehead
• Downslanted palpebral fissures
• Widely-spaced eyes
• Depressed nasal bridge
• Micrognathia
• Prominent occiput
• Prominent forehead
• Downslanted palpebral fissures
• Widely-spaced eyes
• Depressed nasal bridge
• Micrognathia
• Mild-to-severe intellectual disability
• Characteristic dysmorphic facial features
• Macrocephaly
• Brachycephaly
• Flat occiput (prominent occiput in some)
• Hypotonic face with a tendency to a protruding tongue
• Short midface
• Flat appearance of the face on profile view
• Highly arched and thick eyebrows
• Downslanted palpebral fissures
• Widely spaced eyes
• Depressed nasal bridge
• Low-set ears; overfolding of the upper helix
• Smooth or short philtrum
• High palate or cleft palate
• Short broad neck with a low posterior hair line and webbing
• Macrocephaly
• Brachycephaly
• Flat occiput (prominent occiput in some)
• Hypotonic face with a tendency to a protruding tongue
• Short midface
• Flat appearance of the face on profile view
• Highly arched and thick eyebrows
• Downslanted palpebral fissures
• Widely spaced eyes
• Depressed nasal bridge
• Low-set ears; overfolding of the upper helix
• Smooth or short philtrum
• High palate or cleft palate
• Short broad neck with a low posterior hair line and webbing
• Macrocephaly
• Brachycephaly
• Flat occiput (prominent occiput in some)
• Hypotonic face with a tendency to a protruding tongue
• Short midface
• Flat appearance of the face on profile view
• Highly arched and thick eyebrows
• Downslanted palpebral fissures
• Widely spaced eyes
• Depressed nasal bridge
• Low-set ears; overfolding of the upper helix
• Smooth or short philtrum
• High palate or cleft palate
• Short broad neck with a low posterior hair line and webbing
• Cardiac malformations (See
• Brain MRI
• Dandy-Walker malformation
• Hypoplasia or dysplasia of the cerebellar vermis
• Hydrocephalus
• Dandy-Walker malformation
• Hypoplasia or dysplasia of the cerebellar vermis
• Hydrocephalus
• Hand radiographs
• Brachydactyly, especially of the second ray
• Shortening of the first metacarpal and the fifth distal phalanx
• Characteristic metacarpal phalangeal pattern profile (See
• Brachydactyly, especially of the second ray
• Shortening of the first metacarpal and the fifth distal phalanx
• Characteristic metacarpal phalangeal pattern profile (See
• Dandy-Walker malformation
• Hypoplasia or dysplasia of the cerebellar vermis
• Hydrocephalus
• Brachydactyly, especially of the second ray
• Shortening of the first metacarpal and the fifth distal phalanx
• Characteristic metacarpal phalangeal pattern profile (See
• If the individual is of First Nations (FN) heritage (indigenous people of Canada who are not Metis or Inuit) or is female, sequence analysis of
• If only one or no pathogenic variant is found, gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may be considered.
• In a male proband who is not of FN heritage, sequence analysis of
## Suggestive Findings
Ritscher-Schinzel syndrome (RSS)
Mild-to-severe intellectual disability
Characteristic dysmorphic facial features
Macrocephaly
Brachycephaly
Flat occiput (prominent occiput in some)
Hypotonic face with a tendency to a protruding tongue
Short midface
Flat appearance of the face on profile view
Highly arched and thick eyebrows
Downslanted palpebral fissures
Widely spaced eyes
Depressed nasal bridge
Low-set ears; overfolding of the upper helix
Smooth or short philtrum
High palate or cleft palate
Short broad neck with a low posterior hair line and webbing
Cardiac malformations (See
Brain MRI
Dandy-Walker malformation
Hypoplasia or dysplasia of the cerebellar vermis
Hydrocephalus
Hand radiographs
Brachydactyly, especially of the second ray
Shortening of the first metacarpal and the fifth distal phalanx
Characteristic metacarpal phalangeal pattern profile (See
• Mild-to-severe intellectual disability
• Characteristic dysmorphic facial features
• Macrocephaly
• Brachycephaly
• Flat occiput (prominent occiput in some)
• Hypotonic face with a tendency to a protruding tongue
• Short midface
• Flat appearance of the face on profile view
• Highly arched and thick eyebrows
• Downslanted palpebral fissures
• Widely spaced eyes
• Depressed nasal bridge
• Low-set ears; overfolding of the upper helix
• Smooth or short philtrum
• High palate or cleft palate
• Short broad neck with a low posterior hair line and webbing
• Macrocephaly
• Brachycephaly
• Flat occiput (prominent occiput in some)
• Hypotonic face with a tendency to a protruding tongue
• Short midface
• Flat appearance of the face on profile view
• Highly arched and thick eyebrows
• Downslanted palpebral fissures
• Widely spaced eyes
• Depressed nasal bridge
• Low-set ears; overfolding of the upper helix
• Smooth or short philtrum
• High palate or cleft palate
• Short broad neck with a low posterior hair line and webbing
• Macrocephaly
• Brachycephaly
• Flat occiput (prominent occiput in some)
• Hypotonic face with a tendency to a protruding tongue
• Short midface
• Flat appearance of the face on profile view
• Highly arched and thick eyebrows
• Downslanted palpebral fissures
• Widely spaced eyes
• Depressed nasal bridge
• Low-set ears; overfolding of the upper helix
• Smooth or short philtrum
• High palate or cleft palate
• Short broad neck with a low posterior hair line and webbing
• Cardiac malformations (See
• Brain MRI
• Dandy-Walker malformation
• Hypoplasia or dysplasia of the cerebellar vermis
• Hydrocephalus
• Dandy-Walker malformation
• Hypoplasia or dysplasia of the cerebellar vermis
• Hydrocephalus
• Hand radiographs
• Brachydactyly, especially of the second ray
• Shortening of the first metacarpal and the fifth distal phalanx
• Characteristic metacarpal phalangeal pattern profile (See
• Brachydactyly, especially of the second ray
• Shortening of the first metacarpal and the fifth distal phalanx
• Characteristic metacarpal phalangeal pattern profile (See
• Dandy-Walker malformation
• Hypoplasia or dysplasia of the cerebellar vermis
• Hydrocephalus
• Brachydactyly, especially of the second ray
• Shortening of the first metacarpal and the fifth distal phalanx
• Characteristic metacarpal phalangeal pattern profile (See
## Establishing the Diagnosis
The diagnosis of Ritscher-Schinzel 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
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because the phenotype of Ritscher-Schinzel syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and radiographic findings suggest the diagnosis of Ritscher-Schinzel syndrome molecular genetic testing approaches can include concurrent or serial single-gene testing, or use of a
If the individual is of First Nations (FN) heritage (indigenous people of Canada who are not Metis or Inuit) or is female, sequence analysis of
If only one or no pathogenic variant is found, gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may be considered.
In a male proband who is not of FN heritage, sequence analysis of
For an introduction to multigene panels click
When the diagnosis of Ritscher-Schinzel syndrome is not considered because an individual has atypical phenotypic features,
Individuals with a chromosome 6p25 deletion have features that can overlap with RSS (see
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Ritscher-Schinzel Syndrome (RSS)
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 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 variant in this gene was reported in two male sibs of Austrian origin [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
This refers to the proportion of affected individuals of First Nations heritage; the proportion of affected individuals of other ethnicities who have biallelic pathogenic variants in
All affected individuals of First Nations heritage from Northern Ontario and Manitoba who were tested for a sequence variant in this gene were found to be homozygous for the c.3335+2T>A variant [
Individuals from a large Colombian kindred identified as having RSS were not identified to have any pathogenic variants in
• If the individual is of First Nations (FN) heritage (indigenous people of Canada who are not Metis or Inuit) or is female, sequence analysis of
• If only one or no pathogenic variant is found, gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may be considered.
• In a male proband who is not of FN heritage, sequence analysis of
## Option 1
When the phenotypic and radiographic findings suggest the diagnosis of Ritscher-Schinzel syndrome molecular genetic testing approaches can include concurrent or serial single-gene testing, or use of a
If the individual is of First Nations (FN) heritage (indigenous people of Canada who are not Metis or Inuit) or is female, sequence analysis of
If only one or no pathogenic variant is found, gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may be considered.
In a male proband who is not of FN heritage, sequence analysis of
For an introduction to multigene panels click
• If the individual is of First Nations (FN) heritage (indigenous people of Canada who are not Metis or Inuit) or is female, sequence analysis of
• If only one or no pathogenic variant is found, gene-targeted deletion/duplication analysis to detect intragenic deletions or duplications may be considered.
• In a male proband who is not of FN heritage, sequence analysis of
## Option 2
When the diagnosis of Ritscher-Schinzel syndrome is not considered because an individual has atypical phenotypic features,
Individuals with a chromosome 6p25 deletion have features that can overlap with RSS (see
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Ritscher-Schinzel Syndrome (RSS)
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 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 variant in this gene was reported in two male sibs of Austrian origin [
No data on detection rate of gene-targeted deletion/duplication analysis are available.
This refers to the proportion of affected individuals of First Nations heritage; the proportion of affected individuals of other ethnicities who have biallelic pathogenic variants in
All affected individuals of First Nations heritage from Northern Ontario and Manitoba who were tested for a sequence variant in this gene were found to be homozygous for the c.3335+2T>A variant [
Individuals from a large Colombian kindred identified as having RSS were not identified to have any pathogenic variants in
## Clinical Characteristics
Ritscher-Schinzel syndrome (RSS) is relatively rare but is a clinically recognizable condition that includes characteristic dysmorphic facial and skeletal features. This disorder is associated with variable degrees of developmental delay and intellectual disability. Malformations have involved many organs and systems including the eye, central nervous system (CNS), and cardiovascular and skeletal systems. Cardinal features include craniofacial features, cerebellar defects, and cardiovascular malformations resulting in the alternate diagnostic name of 3C syndrome.
The following clinical information is based on numerous published reports [
For a concise summary of the timeline from the original description of RSS to the ultimate identification of the underlying molecular mechanisms, click
Individuals with a short neck who are obese are at increased risk of developing obstructive sleep apnea.
While the palate may be highly arched, fewer than 5% of affected individuals have a cleft palate.
About 20% of affected individuals have micrognathia.
Atrioventricular canal defect
Mitral valve anomalies, including cleft mitral valve
Atrial septal defect
Ventricular septal defect
Double-outlet right ventricle
Aortic stenosis
Pulmonary stenosis
Tetralogy of Fallot
Brachydactyly, with the second ray being the most severely affected [
Camptodactyly
Proximally placed thumbs
Abnormalities of the palmar creases
A study by
Most affected individuals achieve ambulation and are able to ultimately feed themselves. Most develop limited but meaningful speech.
Absent ribs
Adrenal hypoplasia
Anal atresia
Congenital glaucoma
Clubbed foot [
Cutis aplasia
Hemangioma
Hemivertebrae
Hypospadias
Inguinal hernia
Malrotation of the gut
Nail hypoplasia
Nipple hypoplasia
"Penis hypoplasia"
Polydactyly, without further description of the location or type
Renal malformations
In one affected individual, humoral immune deficiency was described [
Upslanted palpebral fissures, an uncommon finding in those who are of First Nations heritage [
A more strikingly large, protruding tongue than seen in individuals with variants in
Additional ectodermal findings (nail hypoplasia, abnormal dentition and aplasia cutis congenital).
No genotype-phenotype correlations have been identified; all individuals identified to date with RSS who are of First Nations heritage have the homozygous variant in
RSS is rare and, although individuals have been reported with "3-C syndrome/RSS," not all reports include those who have the characteristic craniofacial features.
For the First Nations cohort (Northern Manitoba and Northwestern Ontario), the carrier frequency is estimated at 1:9 individuals [
• While the palate may be highly arched, fewer than 5% of affected individuals have a cleft palate.
• About 20% of affected individuals have micrognathia.
• Atrioventricular canal defect
• Mitral valve anomalies, including cleft mitral valve
• Atrial septal defect
• Ventricular septal defect
• Double-outlet right ventricle
• Aortic stenosis
• Pulmonary stenosis
• Tetralogy of Fallot
• Brachydactyly, with the second ray being the most severely affected [
• Camptodactyly
• Proximally placed thumbs
• Abnormalities of the palmar creases
• Absent ribs
• Adrenal hypoplasia
• Anal atresia
• Congenital glaucoma
• Clubbed foot [
• Cutis aplasia
• Hemangioma
• Hemivertebrae
• Hypospadias
• Inguinal hernia
• Malrotation of the gut
• Nail hypoplasia
• Nipple hypoplasia
• "Penis hypoplasia"
• Polydactyly, without further description of the location or type
• Renal malformations
• Upslanted palpebral fissures, an uncommon finding in those who are of First Nations heritage [
• A more strikingly large, protruding tongue than seen in individuals with variants in
• Additional ectodermal findings (nail hypoplasia, abnormal dentition and aplasia cutis congenital).
## Clinical Description
Ritscher-Schinzel syndrome (RSS) is relatively rare but is a clinically recognizable condition that includes characteristic dysmorphic facial and skeletal features. This disorder is associated with variable degrees of developmental delay and intellectual disability. Malformations have involved many organs and systems including the eye, central nervous system (CNS), and cardiovascular and skeletal systems. Cardinal features include craniofacial features, cerebellar defects, and cardiovascular malformations resulting in the alternate diagnostic name of 3C syndrome.
The following clinical information is based on numerous published reports [
For a concise summary of the timeline from the original description of RSS to the ultimate identification of the underlying molecular mechanisms, click
Individuals with a short neck who are obese are at increased risk of developing obstructive sleep apnea.
While the palate may be highly arched, fewer than 5% of affected individuals have a cleft palate.
About 20% of affected individuals have micrognathia.
Atrioventricular canal defect
Mitral valve anomalies, including cleft mitral valve
Atrial septal defect
Ventricular septal defect
Double-outlet right ventricle
Aortic stenosis
Pulmonary stenosis
Tetralogy of Fallot
Brachydactyly, with the second ray being the most severely affected [
Camptodactyly
Proximally placed thumbs
Abnormalities of the palmar creases
A study by
Most affected individuals achieve ambulation and are able to ultimately feed themselves. Most develop limited but meaningful speech.
Absent ribs
Adrenal hypoplasia
Anal atresia
Congenital glaucoma
Clubbed foot [
Cutis aplasia
Hemangioma
Hemivertebrae
Hypospadias
Inguinal hernia
Malrotation of the gut
Nail hypoplasia
Nipple hypoplasia
"Penis hypoplasia"
Polydactyly, without further description of the location or type
Renal malformations
In one affected individual, humoral immune deficiency was described [
• While the palate may be highly arched, fewer than 5% of affected individuals have a cleft palate.
• About 20% of affected individuals have micrognathia.
• Atrioventricular canal defect
• Mitral valve anomalies, including cleft mitral valve
• Atrial septal defect
• Ventricular septal defect
• Double-outlet right ventricle
• Aortic stenosis
• Pulmonary stenosis
• Tetralogy of Fallot
• Brachydactyly, with the second ray being the most severely affected [
• Camptodactyly
• Proximally placed thumbs
• Abnormalities of the palmar creases
• Absent ribs
• Adrenal hypoplasia
• Anal atresia
• Congenital glaucoma
• Clubbed foot [
• Cutis aplasia
• Hemangioma
• Hemivertebrae
• Hypospadias
• Inguinal hernia
• Malrotation of the gut
• Nail hypoplasia
• Nipple hypoplasia
• "Penis hypoplasia"
• Polydactyly, without further description of the location or type
• Renal malformations
## Phenotype Correlations by Gene
Upslanted palpebral fissures, an uncommon finding in those who are of First Nations heritage [
A more strikingly large, protruding tongue than seen in individuals with variants in
Additional ectodermal findings (nail hypoplasia, abnormal dentition and aplasia cutis congenital).
• Upslanted palpebral fissures, an uncommon finding in those who are of First Nations heritage [
• A more strikingly large, protruding tongue than seen in individuals with variants in
• Additional ectodermal findings (nail hypoplasia, abnormal dentition and aplasia cutis congenital).
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified; all individuals identified to date with RSS who are of First Nations heritage have the homozygous variant in
## Nomenclature
## Prevalence
RSS is rare and, although individuals have been reported with "3-C syndrome/RSS," not all reports include those who have the characteristic craniofacial features.
For the First Nations cohort (Northern Manitoba and Northwestern Ontario), the carrier frequency is estimated at 1:9 individuals [
## Genetically Related (Allelic) Disorders
Pathogenic variants in
Individuals with X-linked intellectual disability (ID) have been reported to have variants in
## Differential Diagnosis
6p25 deletion can be distinguished from RSS by the presence of the 6p25 deletion on chromosomal microarray analysis and an overall craniofacial gestalt distinct from RSS.
Disorders to Consider in the Differential Diagnosis of Ritscher-Schinzel Syndrome
ID
Hypoplasia of the cerebral vermis
Ocular colobomas
Polydactyly
Retinal dystrophy
Cystic kidneys
Presence of "molar tooth sign" neuroradiologic finding
CHD
Dandy-Walker malformation
Limb & palate anomalies
Polydactyly
Short ribs
Absence of characteristic RSS facial features
ID
CHD
Craniofacial dysmorphisms
Distal limb anomalies
Absence of cerebellar hypoplasia
Characteristic facial features
ID
Dysmorphic facial features
Coloboma
Palate anomalies
CHD
Choanal atresia
Inner-ear dysgenesis
Facial nerve palsies
Pituitary dysfunction
Absence of characteristic RSS facial features
ID
Coloboma
Palate anomalies
Dysmorphic craniofacial features
Characteristic facial features
Persistence of fetal fingertip pads
ID
Dysmorphic craniofacial features
Hypertelorism
Palate anomalies
Distal limb anomalies
Encephalocele
Nasal clefting
Distinctive craniofacial features
ID
Dysmorphic craniofacial features
CHD
Coloboma
Cerebellar vermis hypoplasia
Severe growth restriction
Microphthalmia
Periventricular nodular heterotopia
Chondrodysplasia punctata
Mesomelia of upper extremities
ID
Short stature
Dandy-Walker malformation, cerebellar vermis hypoplasia, & posterior fossa cyst
CHD
Renal anomalies
Distinctive craniofacial features
Ectodermal findings
AD = autosomal dominant; AR = autosomal recessive; CHD = congenital heart defect; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; RSS = Ritscher-Schinzel syndrome; XL = X-linked
See
Joubert syndrome is predominantly inherited in an autosomal recessive manner. Joubert syndrome caused by pathogenic variants in
Typically caused by a
The proportion of Kabuki syndrome caused by
• ID
• Hypoplasia of the cerebral vermis
• Ocular colobomas
• Polydactyly
• Retinal dystrophy
• Cystic kidneys
• Presence of "molar tooth sign" neuroradiologic finding
• CHD
• Dandy-Walker malformation
• Limb & palate anomalies
• Polydactyly
• Short ribs
• Absence of characteristic RSS facial features
• ID
• CHD
• Craniofacial dysmorphisms
• Distal limb anomalies
• Absence of cerebellar hypoplasia
• Characteristic facial features
• ID
• Dysmorphic facial features
• Coloboma
• Palate anomalies
• CHD
• Choanal atresia
• Inner-ear dysgenesis
• Facial nerve palsies
• Pituitary dysfunction
• Absence of characteristic RSS facial features
• ID
• Coloboma
• Palate anomalies
• Dysmorphic craniofacial features
• Characteristic facial features
• Persistence of fetal fingertip pads
• ID
• Dysmorphic craniofacial features
• Hypertelorism
• Palate anomalies
• Distal limb anomalies
• Encephalocele
• Nasal clefting
• Distinctive craniofacial features
• ID
• Dysmorphic craniofacial features
• CHD
• Coloboma
• Cerebellar vermis hypoplasia
• Severe growth restriction
• Microphthalmia
• Periventricular nodular heterotopia
• Chondrodysplasia punctata
• Mesomelia of upper extremities
• ID
• Short stature
• Dandy-Walker malformation, cerebellar vermis hypoplasia, & posterior fossa cyst
• CHD
• Renal anomalies
• Distinctive craniofacial features
• Ectodermal findings
## Management
To establish the extent of disease and needs in an individual diagnosed with Ritscher-Schinzel syndrome (RSS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Ritscher-Schinzel Syndrome
To incl motor, adaptive, cognitive, & speech/ language eval
Eval for early intervention / special education
For persons age >12 mo
Particularly useful at school entry to help formulate an appropriate education plan
In those w/repeated bacterial infections
Consider referral to immunologist.
Community or
Social work involvement for parental support;
Home nursing referral.
Including measurement of total cholesterol, HDL, and LDL cholesterol concentrations. Fasting is not required [
Including serum immunoglobulin levels and assessment of previous immune responses (e.g., measurement of titers from previous immunizations)
Treatment of Manifestations in Individuals with Ritscher-Schinzel Syndrome
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.
Particularly if other cardiovascular risk factors (smoking, diabetes mellitus, hypertension) are identified
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.
Recommended Surveillance for Individuals with Ritscher-Schinzel Syndrome
OT = occupational therapy; PT = physical therapy
Including measurement of total cholesterol, HDL, and LDL cholesterol concentrations
Specific frequency may depend on initial cholesterol levels; in those without elevated cholesterol levels, screening every few years may be appropriate.
See
Search
• To incl motor, adaptive, cognitive, & speech/ language eval
• Eval for early intervention / special education
• For persons age >12 mo
• Particularly useful at school entry to help formulate an appropriate education plan
• In those w/repeated bacterial infections
• Consider referral to immunologist.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• 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.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Ritscher-Schinzel syndrome (RSS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Ritscher-Schinzel Syndrome
To incl motor, adaptive, cognitive, & speech/ language eval
Eval for early intervention / special education
For persons age >12 mo
Particularly useful at school entry to help formulate an appropriate education plan
In those w/repeated bacterial infections
Consider referral to immunologist.
Community or
Social work involvement for parental support;
Home nursing referral.
Including measurement of total cholesterol, HDL, and LDL cholesterol concentrations. Fasting is not required [
Including serum immunoglobulin levels and assessment of previous immune responses (e.g., measurement of titers from previous immunizations)
• To incl motor, adaptive, cognitive, & speech/ language eval
• Eval for early intervention / special education
• For persons age >12 mo
• Particularly useful at school entry to help formulate an appropriate education plan
• In those w/repeated bacterial infections
• Consider referral to immunologist.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Ritscher-Schinzel Syndrome
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.
Particularly if other cardiovascular risk factors (smoking, diabetes mellitus, hypertension) are identified
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.
• 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.
## 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
## Surveillance
Recommended Surveillance for Individuals with Ritscher-Schinzel Syndrome
OT = occupational therapy; PT = physical therapy
Including measurement of total cholesterol, HDL, and LDL cholesterol concentrations
Specific frequency may depend on initial cholesterol levels; in those without elevated cholesterol levels, screening every few years may be appropriate.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Ritscher-Schinzel syndrome (RSS) caused by pathogenic variants in
RSS caused by 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.
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 (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) or the affected male may have a
If the mother of the proband has a
If the proband 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
Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected
Identification of female heterozygotes requires either (a) 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.
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 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 (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) or the affected male may have a
• If the mother of the proband has a
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected
• Identification of female heterozygotes requires either (a) 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.
## Mode of Inheritance
Ritscher-Schinzel syndrome (RSS) caused by pathogenic variants in
RSS caused by 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.
## X-Linked 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 (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) or the affected male may have a
If the mother of the proband has a
If the proband 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
Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected
Identification of female heterozygotes requires either (a) prior identification of 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 (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) or the affected male may have a
• If the mother of the proband has a
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the
• Females who are heterozygous (carriers) for this X-linked disorder will usually not be affected
• Identification of female heterozygotes requires either (a) 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
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
Ritscher-Schinzel Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Ritscher-Schinzel Syndrome (
The genes involved in both autosomal (
An N-terminal conserved domain;
A C-terminal coiled coil domain that is similar to structural maintenance of chromosomes (SMC) proteins.
Multiple transmembrane domains, with the N-terminal region (amino acids 1-240) comprising six α helices and two β strand segments
A central region (amino acids 241-971) comprising spectrin-repeat domains
A C-terminal region (residues 792-1159) demonstrating structural similarity to exportin-5 and importin β-1
The
Western blot analysis revealed that the p.Tyr557Cys variant resulted in a 50% decreased expression of CCDC22 in affected versus control individuals.
The p.Thr17Ala variant resulted in a fivefold decrease in mRNA levels in addition to increased levels of abnormally spliced transcripts retaining intron 1.
The
Notable Ritscher-Schinzel Syndrome Pathogenic Variants by Gene
FN = First Nations; NA = not applicable
Variants listed in the table have been provided by the authors.
Genes from
• An N-terminal conserved domain;
• A C-terminal coiled coil domain that is similar to structural maintenance of chromosomes (SMC) proteins.
• Multiple transmembrane domains, with the N-terminal region (amino acids 1-240) comprising six α helices and two β strand segments
• A central region (amino acids 241-971) comprising spectrin-repeat domains
• A C-terminal region (residues 792-1159) demonstrating structural similarity to exportin-5 and importin β-1
## Molecular Pathogenesis
The genes involved in both autosomal (
An N-terminal conserved domain;
A C-terminal coiled coil domain that is similar to structural maintenance of chromosomes (SMC) proteins.
Multiple transmembrane domains, with the N-terminal region (amino acids 1-240) comprising six α helices and two β strand segments
A central region (amino acids 241-971) comprising spectrin-repeat domains
A C-terminal region (residues 792-1159) demonstrating structural similarity to exportin-5 and importin β-1
The
Western blot analysis revealed that the p.Tyr557Cys variant resulted in a 50% decreased expression of CCDC22 in affected versus control individuals.
The p.Thr17Ala variant resulted in a fivefold decrease in mRNA levels in addition to increased levels of abnormally spliced transcripts retaining intron 1.
The
Notable Ritscher-Schinzel Syndrome Pathogenic Variants by Gene
FN = First Nations; NA = not applicable
Variants listed in the table have been provided by the authors.
Genes from
• An N-terminal conserved domain;
• A C-terminal coiled coil domain that is similar to structural maintenance of chromosomes (SMC) proteins.
• Multiple transmembrane domains, with the N-terminal region (amino acids 1-240) comprising six α helices and two β strand segments
• A central region (amino acids 241-971) comprising spectrin-repeat domains
• A C-terminal region (residues 792-1159) demonstrating structural similarity to exportin-5 and importin β-1
## Chapter Notes
Author's website:
We are grateful to Courtney B Cook, Dr Jill Mwenifumbo, and Dr Alan Rope for assistance.
23 January 2020 (ma) Review posted live
15 April 2019 (ae) Original submission
• 23 January 2020 (ma) Review posted live
• 15 April 2019 (ae) Original submission
## Author Notes
Author's website:
## Acknowledgments
We are grateful to Courtney B Cook, Dr Jill Mwenifumbo, and Dr Alan Rope for assistance.
## Revision History
23 January 2020 (ma) Review posted live
15 April 2019 (ae) Original submission
• 23 January 2020 (ma) Review posted live
• 15 April 2019 (ae) Original submission
## References
## Literature Cited
|
[] |
23/1/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
rnu4atac-dis
|
rnu4atac-dis
|
[
"RNU4ATAC Spectrum Disorder",
"RNU4ATAC Spectrum Disorder",
"Microcephalic Osteodysplastic Primordial Dwarfism Type I/III (MOPDI) / Taybi-Linder Syndrome",
"Roifman Syndrome",
"Lowry-Wood Syndrome",
"N/A (non-coding RNA)",
"RNU4ATAC",
"RNU4atac-opathy"
] |
RNU4atac-opathy
|
Angela Duker, Danita Velasco, Nic Robertson, Andrew Jackson, Magee DeFelice, Michael B Bober
|
Summary RNU4atac-opathy encompasses the phenotypic spectrum of biallelic The diagnosis of RNU4atac-opathy is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in RNU4atac-opathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
With the current widespread use of multigene panels and comprehensive genomic testing, it has become apparent that the phenotypic spectrum of biallelic
The need to evaluate an individual found to have
The importance of counseling families that the finding of biallelic
RNU4atac-opathy: Phenotypic Spectrum Associated with Biallelic
See
Included in the "primordial dwarfism and slender bones" group of the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
• The need to evaluate an individual found to have
• The importance of counseling families that the finding of biallelic
## Diagnosis
No consensus clinical diagnostic criteria for RNU4atac-opathy have been published.
RNU4atac-opathy
Pre- and postnatal growth restriction
Microcephaly. In the most severely affected individuals (clinically designated as MOPDI), the skull is microcephalic and dolichocephalic with prominent occiput and sloping forehead. Ridged metopic suture may be present.
Skeletal dysplasia (see
Developmental delay / cognitive impairment (mild, moderate, or profound)
Facial features (see
Brain anomalies
Individuals at the most severe end of the spectrum (MOPDI) characteristically have significant brain abnormalities.
Brain imaging findings include lissencephaly, abnormal cortical gyral pattern, hypoplastic frontal lobes, intracranial (interhemispheric) cyst, colpocephaly, cerebellar vermis agenesis/hypoplasia, arachnoid cyst, and complete or partial agenesis of the corpus callosum [
Individuals who do not have MOPDI can still have one or more of the abovementioned brain anomalies, including partial agenesis of the corpus callosum and bilateral hypoplastic and malrotated hippocampi [
Individuals with the mildest cognitive impairment do not always demonstrate brain abnormalities on MRI.
Immunodeficiency. Findings include recurrent sinopulmonary infections, severe bacterial infections, hypogammaglobulinemia, and impaired antibody responses.
Ophthalmologic findings
Findings of retinal dystrophy consistent with cone-rod dystrophy include decreased central visual acuity, constricted visual fields, defective dark adaptation (evident when moving from a well-lit environment to a poorly-lit environment), pale optic discs, narrowing of retinal vasculature, and variable retinal pigmentary changes; presence of nystagmus is variable [
Other findings include strabismus [
The diagnosis of RNU4atac-opathy
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
When the phenotypic and imaging findings suggest the diagnosis of RNU4atac-opathy, molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in RNU4atac-opathy
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 larger deletions or duplications.
A tandem duplication of
• Pre- and postnatal growth restriction
• Microcephaly. In the most severely affected individuals (clinically designated as MOPDI), the skull is microcephalic and dolichocephalic with prominent occiput and sloping forehead. Ridged metopic suture may be present.
• Skeletal dysplasia (see
• Developmental delay / cognitive impairment (mild, moderate, or profound)
• Facial features (see
• Brain anomalies
• Individuals at the most severe end of the spectrum (MOPDI) characteristically have significant brain abnormalities.
• Brain imaging findings include lissencephaly, abnormal cortical gyral pattern, hypoplastic frontal lobes, intracranial (interhemispheric) cyst, colpocephaly, cerebellar vermis agenesis/hypoplasia, arachnoid cyst, and complete or partial agenesis of the corpus callosum [
• Individuals who do not have MOPDI can still have one or more of the abovementioned brain anomalies, including partial agenesis of the corpus callosum and bilateral hypoplastic and malrotated hippocampi [
• Individuals with the mildest cognitive impairment do not always demonstrate brain abnormalities on MRI.
• Individuals at the most severe end of the spectrum (MOPDI) characteristically have significant brain abnormalities.
• Brain imaging findings include lissencephaly, abnormal cortical gyral pattern, hypoplastic frontal lobes, intracranial (interhemispheric) cyst, colpocephaly, cerebellar vermis agenesis/hypoplasia, arachnoid cyst, and complete or partial agenesis of the corpus callosum [
• Individuals who do not have MOPDI can still have one or more of the abovementioned brain anomalies, including partial agenesis of the corpus callosum and bilateral hypoplastic and malrotated hippocampi [
• Individuals with the mildest cognitive impairment do not always demonstrate brain abnormalities on MRI.
• Immunodeficiency. Findings include recurrent sinopulmonary infections, severe bacterial infections, hypogammaglobulinemia, and impaired antibody responses.
• Ophthalmologic findings
• Findings of retinal dystrophy consistent with cone-rod dystrophy include decreased central visual acuity, constricted visual fields, defective dark adaptation (evident when moving from a well-lit environment to a poorly-lit environment), pale optic discs, narrowing of retinal vasculature, and variable retinal pigmentary changes; presence of nystagmus is variable [
• Other findings include strabismus [
• Findings of retinal dystrophy consistent with cone-rod dystrophy include decreased central visual acuity, constricted visual fields, defective dark adaptation (evident when moving from a well-lit environment to a poorly-lit environment), pale optic discs, narrowing of retinal vasculature, and variable retinal pigmentary changes; presence of nystagmus is variable [
• Other findings include strabismus [
• Individuals at the most severe end of the spectrum (MOPDI) characteristically have significant brain abnormalities.
• Brain imaging findings include lissencephaly, abnormal cortical gyral pattern, hypoplastic frontal lobes, intracranial (interhemispheric) cyst, colpocephaly, cerebellar vermis agenesis/hypoplasia, arachnoid cyst, and complete or partial agenesis of the corpus callosum [
• Individuals who do not have MOPDI can still have one or more of the abovementioned brain anomalies, including partial agenesis of the corpus callosum and bilateral hypoplastic and malrotated hippocampi [
• Individuals with the mildest cognitive impairment do not always demonstrate brain abnormalities on MRI.
• Findings of retinal dystrophy consistent with cone-rod dystrophy include decreased central visual acuity, constricted visual fields, defective dark adaptation (evident when moving from a well-lit environment to a poorly-lit environment), pale optic discs, narrowing of retinal vasculature, and variable retinal pigmentary changes; presence of nystagmus is variable [
• Other findings include strabismus [
• For an introduction to multigene panels click
## Suggestive Findings
RNU4atac-opathy
Pre- and postnatal growth restriction
Microcephaly. In the most severely affected individuals (clinically designated as MOPDI), the skull is microcephalic and dolichocephalic with prominent occiput and sloping forehead. Ridged metopic suture may be present.
Skeletal dysplasia (see
Developmental delay / cognitive impairment (mild, moderate, or profound)
Facial features (see
Brain anomalies
Individuals at the most severe end of the spectrum (MOPDI) characteristically have significant brain abnormalities.
Brain imaging findings include lissencephaly, abnormal cortical gyral pattern, hypoplastic frontal lobes, intracranial (interhemispheric) cyst, colpocephaly, cerebellar vermis agenesis/hypoplasia, arachnoid cyst, and complete or partial agenesis of the corpus callosum [
Individuals who do not have MOPDI can still have one or more of the abovementioned brain anomalies, including partial agenesis of the corpus callosum and bilateral hypoplastic and malrotated hippocampi [
Individuals with the mildest cognitive impairment do not always demonstrate brain abnormalities on MRI.
Immunodeficiency. Findings include recurrent sinopulmonary infections, severe bacterial infections, hypogammaglobulinemia, and impaired antibody responses.
Ophthalmologic findings
Findings of retinal dystrophy consistent with cone-rod dystrophy include decreased central visual acuity, constricted visual fields, defective dark adaptation (evident when moving from a well-lit environment to a poorly-lit environment), pale optic discs, narrowing of retinal vasculature, and variable retinal pigmentary changes; presence of nystagmus is variable [
Other findings include strabismus [
• Pre- and postnatal growth restriction
• Microcephaly. In the most severely affected individuals (clinically designated as MOPDI), the skull is microcephalic and dolichocephalic with prominent occiput and sloping forehead. Ridged metopic suture may be present.
• Skeletal dysplasia (see
• Developmental delay / cognitive impairment (mild, moderate, or profound)
• Facial features (see
• Brain anomalies
• Individuals at the most severe end of the spectrum (MOPDI) characteristically have significant brain abnormalities.
• Brain imaging findings include lissencephaly, abnormal cortical gyral pattern, hypoplastic frontal lobes, intracranial (interhemispheric) cyst, colpocephaly, cerebellar vermis agenesis/hypoplasia, arachnoid cyst, and complete or partial agenesis of the corpus callosum [
• Individuals who do not have MOPDI can still have one or more of the abovementioned brain anomalies, including partial agenesis of the corpus callosum and bilateral hypoplastic and malrotated hippocampi [
• Individuals with the mildest cognitive impairment do not always demonstrate brain abnormalities on MRI.
• Individuals at the most severe end of the spectrum (MOPDI) characteristically have significant brain abnormalities.
• Brain imaging findings include lissencephaly, abnormal cortical gyral pattern, hypoplastic frontal lobes, intracranial (interhemispheric) cyst, colpocephaly, cerebellar vermis agenesis/hypoplasia, arachnoid cyst, and complete or partial agenesis of the corpus callosum [
• Individuals who do not have MOPDI can still have one or more of the abovementioned brain anomalies, including partial agenesis of the corpus callosum and bilateral hypoplastic and malrotated hippocampi [
• Individuals with the mildest cognitive impairment do not always demonstrate brain abnormalities on MRI.
• Immunodeficiency. Findings include recurrent sinopulmonary infections, severe bacterial infections, hypogammaglobulinemia, and impaired antibody responses.
• Ophthalmologic findings
• Findings of retinal dystrophy consistent with cone-rod dystrophy include decreased central visual acuity, constricted visual fields, defective dark adaptation (evident when moving from a well-lit environment to a poorly-lit environment), pale optic discs, narrowing of retinal vasculature, and variable retinal pigmentary changes; presence of nystagmus is variable [
• Other findings include strabismus [
• Findings of retinal dystrophy consistent with cone-rod dystrophy include decreased central visual acuity, constricted visual fields, defective dark adaptation (evident when moving from a well-lit environment to a poorly-lit environment), pale optic discs, narrowing of retinal vasculature, and variable retinal pigmentary changes; presence of nystagmus is variable [
• Other findings include strabismus [
• Individuals at the most severe end of the spectrum (MOPDI) characteristically have significant brain abnormalities.
• Brain imaging findings include lissencephaly, abnormal cortical gyral pattern, hypoplastic frontal lobes, intracranial (interhemispheric) cyst, colpocephaly, cerebellar vermis agenesis/hypoplasia, arachnoid cyst, and complete or partial agenesis of the corpus callosum [
• Individuals who do not have MOPDI can still have one or more of the abovementioned brain anomalies, including partial agenesis of the corpus callosum and bilateral hypoplastic and malrotated hippocampi [
• Individuals with the mildest cognitive impairment do not always demonstrate brain abnormalities on MRI.
• Findings of retinal dystrophy consistent with cone-rod dystrophy include decreased central visual acuity, constricted visual fields, defective dark adaptation (evident when moving from a well-lit environment to a poorly-lit environment), pale optic discs, narrowing of retinal vasculature, and variable retinal pigmentary changes; presence of nystagmus is variable [
• Other findings include strabismus [
## Establishing the Diagnosis
The diagnosis of RNU4atac-opathy
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
When the phenotypic and imaging findings suggest the diagnosis of RNU4atac-opathy, molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in RNU4atac-opathy
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 larger deletions or duplications.
A tandem duplication of
• For an introduction to multigene panels click
## Option 1
When the phenotypic and imaging findings suggest the diagnosis of RNU4atac-opathy, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in RNU4atac-opathy
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 larger deletions or duplications.
A tandem duplication of
## Clinical Characteristics
To date, fewer than 100 individuals have been identified with
In this
RNU4atac-opathy: Comparison of Phenotypes by Select Features
+ = reported / variably described; ++ = common; +++ = present in nearly all affected individuals; U = unknown / not reported
MED = multiple epiphyseal dysplasia; MOPDI = microcephalic osteodysplastic primordial dwarfism type I/III (MOPDI); SED = spondyloepiphyseal dysplasia; SEMD = spondyloepimetaphyseal dysplasia
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Pre- and postnatal growth restriction is typical in RNU4atac-opathy, with one published exception [
RNU4atac-opathy: Growth Restriction and Microcephaly
SD = standard deviation(s)
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Primordial Dwarfism Registry
MB and AD, personal observation
While all individuals with RNU4atac-opathy have epiphyseal involvement, the extent of skeletal involvement varies across the phenotypic spectrum (see
RNU4atac-opathy: Skeletal Dysplasia
+ = reported / variably described; ++ = common; +++ = present in nearly all affected individuals; U = unknown / not reported
MED = multiple epiphyseal dysplasia; SED = spondyloepiphyseal dysplasia; SEMD = spondyloepimetaphyseal dysplasia
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
It is important to note that the degree of cognitive impairment does not correlate with the degree of microcephaly. See
RNU4atac-opathy: Developmental Delay / Cognitive Impairment
DD = developmental delay; ID = intellectual disability
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
In MOPDI, some individuals have required shunting for hydrocephalus and/or cyst drainage.
In MOPDI, seizures are common [
During two separate episodes of physiologic stress, one individual with MOPDI experienced atypical hemorrhagic hypoxic events (that did not follow a vascular pattern and that included the cortex and brain stem) each of which resulted in a dramatic neurologic decline.
In another child, symptoms resulting from an acute ischemic event in the left frontal region (with no areas of significant stenosis noted on MRA) resolved within a few months.
Context of acute events has repeatedly been in times of stress, with significant illness and/or anesthesia, so minimizing unnecessary anesthesia is preferred.
In many of these individuals, infection frequency and severity improved with immunoglobulin replacement therapy (see Management,
In MOPDI, severe infection has been reported as a cause of early death [
Some individuals have fair skin/hair; one has also had features of ectodermal dysplasia with minimal sweating. Chilblain-like lesions have also been observed [
In MOPDI, skin can be hyperkeratotic. Scant scalp hair and eyebrows are common, as are small nails and dental findings including enamel hypoplasia [
In Roifman syndrome, electrolyte derangements suggestive of renal tubular dysfunction have been described in late childhood [
In MOPDI, persistent neonatal hyperbilirubinemia (not requiring additional intervention) with or without hepatosplenomegaly has been frequently reported [
In Roifman syndrome, neonatal cholestasis and hepatosplenomegaly have been reported [
In Roifman syndrome, hypogonadotropic hypogonadism has been described for at least one individual [
In Lowry-Wood syndrome, normal pubertal development was noted for at least one male and one female [
In MOPDI, although children have historically died in infancy or early childhood, they can also live for years. Death has often followed a severe infection with fever [
Genotype-phenotype correlations have been described, but due to the small number of individuals with RNU4atac-opathy, caution should be exercised in prospective prediction of phenotype severity. Intrafamilial variability has been reported [
The term "RNU4atac-opathy" refers to the entire phenotypic spectrum that can be associated with biallelic
MOPDI, Roifman syndrome, and Lowry-Wood syndrome are listed in the "primordial dwarfism and slender bones" group of the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
To date, fewer than 100 individuals have been reported worldwide with biallelic
The
## Clinical Description
To date, fewer than 100 individuals have been identified with
In this
RNU4atac-opathy: Comparison of Phenotypes by Select Features
+ = reported / variably described; ++ = common; +++ = present in nearly all affected individuals; U = unknown / not reported
MED = multiple epiphyseal dysplasia; MOPDI = microcephalic osteodysplastic primordial dwarfism type I/III (MOPDI); SED = spondyloepiphyseal dysplasia; SEMD = spondyloepimetaphyseal dysplasia
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Pre- and postnatal growth restriction is typical in RNU4atac-opathy, with one published exception [
RNU4atac-opathy: Growth Restriction and Microcephaly
SD = standard deviation(s)
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Primordial Dwarfism Registry
MB and AD, personal observation
While all individuals with RNU4atac-opathy have epiphyseal involvement, the extent of skeletal involvement varies across the phenotypic spectrum (see
RNU4atac-opathy: Skeletal Dysplasia
+ = reported / variably described; ++ = common; +++ = present in nearly all affected individuals; U = unknown / not reported
MED = multiple epiphyseal dysplasia; SED = spondyloepiphyseal dysplasia; SEMD = spondyloepimetaphyseal dysplasia
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
It is important to note that the degree of cognitive impairment does not correlate with the degree of microcephaly. See
RNU4atac-opathy: Developmental Delay / Cognitive Impairment
DD = developmental delay; ID = intellectual disability
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
In MOPDI, some individuals have required shunting for hydrocephalus and/or cyst drainage.
In MOPDI, seizures are common [
During two separate episodes of physiologic stress, one individual with MOPDI experienced atypical hemorrhagic hypoxic events (that did not follow a vascular pattern and that included the cortex and brain stem) each of which resulted in a dramatic neurologic decline.
In another child, symptoms resulting from an acute ischemic event in the left frontal region (with no areas of significant stenosis noted on MRA) resolved within a few months.
Context of acute events has repeatedly been in times of stress, with significant illness and/or anesthesia, so minimizing unnecessary anesthesia is preferred.
In many of these individuals, infection frequency and severity improved with immunoglobulin replacement therapy (see Management,
In MOPDI, severe infection has been reported as a cause of early death [
Some individuals have fair skin/hair; one has also had features of ectodermal dysplasia with minimal sweating. Chilblain-like lesions have also been observed [
In MOPDI, skin can be hyperkeratotic. Scant scalp hair and eyebrows are common, as are small nails and dental findings including enamel hypoplasia [
In Roifman syndrome, electrolyte derangements suggestive of renal tubular dysfunction have been described in late childhood [
In MOPDI, persistent neonatal hyperbilirubinemia (not requiring additional intervention) with or without hepatosplenomegaly has been frequently reported [
In Roifman syndrome, neonatal cholestasis and hepatosplenomegaly have been reported [
In Roifman syndrome, hypogonadotropic hypogonadism has been described for at least one individual [
In Lowry-Wood syndrome, normal pubertal development was noted for at least one male and one female [
In MOPDI, although children have historically died in infancy or early childhood, they can also live for years. Death has often followed a severe infection with fever [
## Growth Restriction and Microcephaly
Pre- and postnatal growth restriction is typical in RNU4atac-opathy, with one published exception [
RNU4atac-opathy: Growth Restriction and Microcephaly
SD = standard deviation(s)
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Primordial Dwarfism Registry
MB and AD, personal observation
## Skeletal Dysplasia
While all individuals with RNU4atac-opathy have epiphyseal involvement, the extent of skeletal involvement varies across the phenotypic spectrum (see
RNU4atac-opathy: Skeletal Dysplasia
+ = reported / variably described; ++ = common; +++ = present in nearly all affected individuals; U = unknown / not reported
MED = multiple epiphyseal dysplasia; SED = spondyloepiphyseal dysplasia; SEMD = spondyloepimetaphyseal dysplasia
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
## Developmental Delay / Cognitive Impairment
It is important to note that the degree of cognitive impairment does not correlate with the degree of microcephaly. See
RNU4atac-opathy: Developmental Delay / Cognitive Impairment
DD = developmental delay; ID = intellectual disability
Phenotype clinically designated in the "primordial dwarfism and slender bones" group the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
Phenotypes not clinically designated in the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
## Other Manifestations
In MOPDI, some individuals have required shunting for hydrocephalus and/or cyst drainage.
In MOPDI, seizures are common [
During two separate episodes of physiologic stress, one individual with MOPDI experienced atypical hemorrhagic hypoxic events (that did not follow a vascular pattern and that included the cortex and brain stem) each of which resulted in a dramatic neurologic decline.
In another child, symptoms resulting from an acute ischemic event in the left frontal region (with no areas of significant stenosis noted on MRA) resolved within a few months.
Context of acute events has repeatedly been in times of stress, with significant illness and/or anesthesia, so minimizing unnecessary anesthesia is preferred.
In many of these individuals, infection frequency and severity improved with immunoglobulin replacement therapy (see Management,
In MOPDI, severe infection has been reported as a cause of early death [
Some individuals have fair skin/hair; one has also had features of ectodermal dysplasia with minimal sweating. Chilblain-like lesions have also been observed [
In MOPDI, skin can be hyperkeratotic. Scant scalp hair and eyebrows are common, as are small nails and dental findings including enamel hypoplasia [
In Roifman syndrome, electrolyte derangements suggestive of renal tubular dysfunction have been described in late childhood [
In MOPDI, persistent neonatal hyperbilirubinemia (not requiring additional intervention) with or without hepatosplenomegaly has been frequently reported [
In Roifman syndrome, neonatal cholestasis and hepatosplenomegaly have been reported [
In Roifman syndrome, hypogonadotropic hypogonadism has been described for at least one individual [
In Lowry-Wood syndrome, normal pubertal development was noted for at least one male and one female [
In MOPDI, although children have historically died in infancy or early childhood, they can also live for years. Death has often followed a severe infection with fever [
## Genotype-Phenotype Correlations
Genotype-phenotype correlations have been described, but due to the small number of individuals with RNU4atac-opathy, caution should be exercised in prospective prediction of phenotype severity. Intrafamilial variability has been reported [
## Nomenclature
The term "RNU4atac-opathy" refers to the entire phenotypic spectrum that can be associated with biallelic
MOPDI, Roifman syndrome, and Lowry-Wood syndrome are listed in the "primordial dwarfism and slender bones" group of the 2019 revision of the "Nosology and Classification of Genetic Skeletal Disorders" [
## Prevalence
To date, fewer than 100 individuals have been reported worldwide with biallelic
The
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The differential diagnosis of RNU4atac-opathy depends on presenting features and the severity of the findings on the phenotype spectrum. While the differential diagnosis can be narrowed for individuals with a severe phenotype, the differential diagnosis for individuals with milder growth restriction and skeletal dysplasia is extensive; thus, all genes known to be associated with the primary clinical finding (e.g., microcephaly / skeletal dysplasia / retinal dystrophy / immunodeficiency) should be considered.
When growth restriction is extreme (occipitofrontal circumference and height >4 SD below the mean), the differential diagnosis is the same as for other forms of microcephalic dwarfism (see Microcephalic Osteodysplastic Primordial Dwarfism Type II,
Milder growth restriction has a wider differential, in which either skeletal dysplasia, retinal dystrophy, and/or immunodeficiency may provide diagnostic prompts.
Epiphyseal dysplasia (with or without spondylo/metaphyseal involvement) alongside microcephaly should be strongly discriminant for RNU4atac-opathy with a limited differential diagnosis, particularly if immunodeficiency and/or retinal dystrophy is also present (see
Individuals with RNU4atac-opathy do not always have microcephaly; therefore, absence of this clinical feature does not exclude the diagnosis.
Skeletal Dysplasias Associated with Microcephaly in the Differential Diagnosis of RNU4atac-opathy
AD = autosomal dominant; AR = autosomal recessive; CVID = combined variable immunodeficiency; IUGR = intrauterine growth restriction; MOI = mode of inheritance; SCID = severe combined immunodeficiency; SD = standard deviation(s)
Meier-Gorlin syndrome is inherited in an autosomal recessive manner with the exception of
The genes listed below are those in which pathogenic variants were identified in at least two persons in a cohort of individuals with microcephalic dwarfism (defined as height and head circumference both greater than 4 SD below the mean at the time of exam) [AJ, personal communication]. Other genes are also associated with extreme microcephalic dwarfism in some persons.
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## Growth Restriction
When growth restriction is extreme (occipitofrontal circumference and height >4 SD below the mean), the differential diagnosis is the same as for other forms of microcephalic dwarfism (see Microcephalic Osteodysplastic Primordial Dwarfism Type II,
Milder growth restriction has a wider differential, in which either skeletal dysplasia, retinal dystrophy, and/or immunodeficiency may provide diagnostic prompts.
## Skeletal Dysplasia
Epiphyseal dysplasia (with or without spondylo/metaphyseal involvement) alongside microcephaly should be strongly discriminant for RNU4atac-opathy with a limited differential diagnosis, particularly if immunodeficiency and/or retinal dystrophy is also present (see
Individuals with RNU4atac-opathy do not always have microcephaly; therefore, absence of this clinical feature does not exclude the diagnosis.
Skeletal Dysplasias Associated with Microcephaly in the Differential Diagnosis of RNU4atac-opathy
AD = autosomal dominant; AR = autosomal recessive; CVID = combined variable immunodeficiency; IUGR = intrauterine growth restriction; MOI = mode of inheritance; SCID = severe combined immunodeficiency; SD = standard deviation(s)
Meier-Gorlin syndrome is inherited in an autosomal recessive manner with the exception of
## Other Genes Identified in Individuals with Growth Deficiency and Microcephaly
The genes listed below are those in which pathogenic variants were identified in at least two persons in a cohort of individuals with microcephalic dwarfism (defined as height and head circumference both greater than 4 SD below the mean at the time of exam) [AJ, personal communication]. Other genes are also associated with extreme microcephalic dwarfism in some persons.
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## Management
No clinical practice guidelines for RNU4atac-opathy have been published. The recommendations in this section are based on the authors' experience in caring for 20 individuals over almost 20 years.
To establish the extent of disease and needs in an individual diagnosed with RNU4atac-opathy, the evaluations summarized in
RNU4atac-opathy: Recommended Evaluations Following Initial Diagnosis
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Baseline brain MRI if not previously performed
Consider EEG if seizures are a concern.
Referral to neurologist as indicated
Immunoglobulins (IgG, IgA, IgM)
Tetanus & pneumococcal antibody titers
Complete blood count w/differential
Lymphocyte subsets
B cell phenotyping
T lymphocyte proliferation assay
Evidence of renal tubular acidosis;
Renal ultrasound for CAKUT incl cystic or dysplastic kidneys.
Community or
Social work involvement for parental support;
Home nursing referral.
AP = anteroposterior; CAKUT = congenital anomalies of the kidney and urinary tract; MOI = mode of inheritance; MOPDI = microcephalic osteodysplastic primordial dwarfism type I/III
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
RNU4atac-opathy: Treatment of Manifestations
Standard treatments as indicated by orthopedics
If possible, referral to skeletal dysplasia center for care
Shunting may be required for interhemispheric cyst or hydrocephalus.
MOPDI: Minimize medically stressful situations as much as possible, incl stress during anesthesia, due to energy-related strokes.
Prompt identification & treatment of infections requiring antibiotics
Antimicrobial prophylaxis may be indicated for some persons.
Standard treatment of CAKUT by urologist
Standard treatment of renal functional impairment by nephrologist
MOPDI = microcephalic osteodysplastic primordial dwarfism type I/III
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.
Physical accommodations for short stature should be a part of the IEP.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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, enlarged text, and modified classroom equipment/furniture for short stature.
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.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations listed in
RNU4atac-opathy: Recommended Surveillance
In children w/MOPDI, be aware that stroke can occur & that brain MRI could be warranted if deterioration is apparent.
Low threshold for EEG, as seizures can be associated
Annually; more often as clinically indicated
Repeat immune eval as performed on initial diagnosis (see
MOPDI = microcephalic osteodysplastic primordial dwarfism type I/III
As prenatal and postnatal strokes have not followed a vascular distribution and were associated with normal vascular anatomy, a screening brain MRA/I (as recommended with
For those with microcephalic osteodysplastic primordial dwarfism type I/III (MOPDI), minimize medically stressful situations as much as possible, including stress during anesthesia, due to energy-related strokes previously described in MOPDI.
Perform immunologic evaluation prior to administration of live vaccines.
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Baseline brain MRI if not previously performed
• Consider EEG if seizures are a concern.
• Referral to neurologist as indicated
• Immunoglobulins (IgG, IgA, IgM)
• Tetanus & pneumococcal antibody titers
• Complete blood count w/differential
• Lymphocyte subsets
• B cell phenotyping
• T lymphocyte proliferation assay
• Evidence of renal tubular acidosis;
• Renal ultrasound for CAKUT incl cystic or dysplastic kidneys.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Standard treatments as indicated by orthopedics
• If possible, referral to skeletal dysplasia center for care
• Shunting may be required for interhemispheric cyst or hydrocephalus.
• MOPDI: Minimize medically stressful situations as much as possible, incl stress during anesthesia, due to energy-related strokes.
• Prompt identification & treatment of infections requiring antibiotics
• Antimicrobial prophylaxis may be indicated for some persons.
• Standard treatment of CAKUT by urologist
• Standard treatment of renal functional impairment by nephrologist
• 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.
• Physical accommodations for short stature should be a part of the IEP.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical accommodations for short stature should be a part of the IEP.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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, enlarged text, and modified classroom equipment/furniture for short stature.
• 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.
• Physical accommodations for short stature should be a part of the IEP.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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 children w/MOPDI, be aware that stroke can occur & that brain MRI could be warranted if deterioration is apparent.
• Low threshold for EEG, as seizures can be associated
• Annually; more often as clinically indicated
• Repeat immune eval as performed on initial diagnosis (see
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with RNU4atac-opathy, the evaluations summarized in
RNU4atac-opathy: Recommended Evaluations Following Initial Diagnosis
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Baseline brain MRI if not previously performed
Consider EEG if seizures are a concern.
Referral to neurologist as indicated
Immunoglobulins (IgG, IgA, IgM)
Tetanus & pneumococcal antibody titers
Complete blood count w/differential
Lymphocyte subsets
B cell phenotyping
T lymphocyte proliferation assay
Evidence of renal tubular acidosis;
Renal ultrasound for CAKUT incl cystic or dysplastic kidneys.
Community or
Social work involvement for parental support;
Home nursing referral.
AP = anteroposterior; CAKUT = congenital anomalies of the kidney and urinary tract; MOI = mode of inheritance; MOPDI = microcephalic osteodysplastic primordial dwarfism type I/III
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Baseline brain MRI if not previously performed
• Consider EEG if seizures are a concern.
• Referral to neurologist as indicated
• Immunoglobulins (IgG, IgA, IgM)
• Tetanus & pneumococcal antibody titers
• Complete blood count w/differential
• Lymphocyte subsets
• B cell phenotyping
• T lymphocyte proliferation assay
• Evidence of renal tubular acidosis;
• Renal ultrasound for CAKUT incl cystic or dysplastic kidneys.
• 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
RNU4atac-opathy: Treatment of Manifestations
Standard treatments as indicated by orthopedics
If possible, referral to skeletal dysplasia center for care
Shunting may be required for interhemispheric cyst or hydrocephalus.
MOPDI: Minimize medically stressful situations as much as possible, incl stress during anesthesia, due to energy-related strokes.
Prompt identification & treatment of infections requiring antibiotics
Antimicrobial prophylaxis may be indicated for some persons.
Standard treatment of CAKUT by urologist
Standard treatment of renal functional impairment by nephrologist
MOPDI = microcephalic osteodysplastic primordial dwarfism type I/III
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.
Physical accommodations for short stature should be a part of the IEP.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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, enlarged text, and modified classroom equipment/furniture for short stature.
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.
• Standard treatments as indicated by orthopedics
• If possible, referral to skeletal dysplasia center for care
• Shunting may be required for interhemispheric cyst or hydrocephalus.
• MOPDI: Minimize medically stressful situations as much as possible, incl stress during anesthesia, due to energy-related strokes.
• Prompt identification & treatment of infections requiring antibiotics
• Antimicrobial prophylaxis may be indicated for some persons.
• Standard treatment of CAKUT by urologist
• Standard treatment of renal functional impairment by nephrologist
• 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.
• Physical accommodations for short stature should be a part of the IEP.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical accommodations for short stature should be a part of the IEP.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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, enlarged text, and modified classroom equipment/furniture for short stature.
• 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.
• Physical accommodations for short stature should be a part of the IEP.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
Physical accommodations for short stature should be a part of the IEP.
PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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, enlarged text, and modified classroom equipment/furniture for short stature.
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.
• Physical accommodations for short stature should be a part of the IEP.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical accommodations for short stature should be a part of the IEP.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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, enlarged text, and modified classroom equipment/furniture for short stature.
• 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.
• Physical accommodations for short stature should be a part of the IEP.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations listed in
RNU4atac-opathy: Recommended Surveillance
In children w/MOPDI, be aware that stroke can occur & that brain MRI could be warranted if deterioration is apparent.
Low threshold for EEG, as seizures can be associated
Annually; more often as clinically indicated
Repeat immune eval as performed on initial diagnosis (see
MOPDI = microcephalic osteodysplastic primordial dwarfism type I/III
As prenatal and postnatal strokes have not followed a vascular distribution and were associated with normal vascular anatomy, a screening brain MRA/I (as recommended with
• In children w/MOPDI, be aware that stroke can occur & that brain MRI could be warranted if deterioration is apparent.
• Low threshold for EEG, as seizures can be associated
• Annually; more often as clinically indicated
• Repeat immune eval as performed on initial diagnosis (see
## Agents/Circumstances to Avoid
For those with microcephalic osteodysplastic primordial dwarfism type I/III (MOPDI), minimize medically stressful situations as much as possible, including stress during anesthesia, due to energy-related strokes previously described in MOPDI.
Perform immunologic evaluation prior to administration of live vaccines.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
RNU4atac-opathy 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
Intrafamilial clinical variability has been reported between sibs who inherit the same 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
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 the reproductive partners of known carriers and for the reproductive partners of individuals affected with RNU4atac-opathy can be considered. 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 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
• Intrafamilial clinical variability has been reported between sibs who inherit the same 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 the reproductive partners of known carriers and for the reproductive partners of individuals affected with RNU4atac-opathy can be considered. An
## Mode of Inheritance
RNU4atac-opathy 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
Intrafamilial clinical variability has been reported between sibs who inherit the same 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
• Intrafamilial clinical variability has been reported between sibs who inherit the same 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
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 the reproductive partners of known carriers and for the reproductive partners of individuals affected with RNU4atac-opathy can be considered. 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 for the reproductive partners of known carriers and for the reproductive partners of individuals affected with RNU4atac-opathy can be considered. 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 use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
## Resources
United Kingdom
United Kingdom
Nemours Children’s Health
1600 Rockland Road
Wilmington DE 19803
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• United Kingdom
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• United Kingdom
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• Nemours Children’s Health
• 1600 Rockland Road
• Wilmington DE 19803
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•
•
## Molecular Genetics
RNU4atac-opathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for RNU4atac-opathy (
The 5' stem II region. Interacts with U6atac (n.1-19)
The 5' stem loop structure. Interacts with RNA binding proteins during minor spliceosome assembly (n.26-57)
The Sm protein binding region at the 3' end of the molecule. Sm proteins are required for small nuclear RNA maturation (n.83-115).
Mapping novel variants to the
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• The 5' stem II region. Interacts with U6atac (n.1-19)
• The 5' stem loop structure. Interacts with RNA binding proteins during minor spliceosome assembly (n.26-57)
• The Sm protein binding region at the 3' end of the molecule. Sm proteins are required for small nuclear RNA maturation (n.83-115).
## Molecular Pathogenesis
The 5' stem II region. Interacts with U6atac (n.1-19)
The 5' stem loop structure. Interacts with RNA binding proteins during minor spliceosome assembly (n.26-57)
The Sm protein binding region at the 3' end of the molecule. Sm proteins are required for small nuclear RNA maturation (n.83-115).
Mapping novel variants to the
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
• The 5' stem II region. Interacts with U6atac (n.1-19)
• The 5' stem loop structure. Interacts with RNA binding proteins during minor spliceosome assembly (n.26-57)
• The Sm protein binding region at the 3' end of the molecule. Sm proteins are required for small nuclear RNA maturation (n.83-115).
## Chapter Notes
Angela Duker and Michael B Bober are actively involved in clinical research regarding individuals with RNU4atac-opathy. They would be happy to communicate with persons who have any questions regarding this diagnosis or other considerations.
Andrew Jackson is interested in hearing from clinicians treating families affected by microcephalic dwarfism or findings suggestive of an RNU4atac-opathy in whom no causative variant has been identified through molecular genetic testing.
The authors wish to sincerely thank the Potentials Foundation and the Walking With Giants Foundation for their support of families worldwide with primordial dwarfism, as well as for their support of research on this condition. Work in the Jackson lab has been supported by the European Union's Horizon 2020 research and innovation program ERC Advanced Grant (788093) and by a UK Medical Research Council (MRC) Human Genetics Unit core grant (MRC, U127580972).
16 February 2023 (bp) Review posted live
24 May 2022 (mb) Original submission
• 16 February 2023 (bp) Review posted live
• 24 May 2022 (mb) Original submission
## Author Notes
Angela Duker and Michael B Bober are actively involved in clinical research regarding individuals with RNU4atac-opathy. They would be happy to communicate with persons who have any questions regarding this diagnosis or other considerations.
Andrew Jackson is interested in hearing from clinicians treating families affected by microcephalic dwarfism or findings suggestive of an RNU4atac-opathy in whom no causative variant has been identified through molecular genetic testing.
## Acknowledgments
The authors wish to sincerely thank the Potentials Foundation and the Walking With Giants Foundation for their support of families worldwide with primordial dwarfism, as well as for their support of research on this condition. Work in the Jackson lab has been supported by the European Union's Horizon 2020 research and innovation program ERC Advanced Grant (788093) and by a UK Medical Research Council (MRC) Human Genetics Unit core grant (MRC, U127580972).
## Revision History
16 February 2023 (bp) Review posted live
24 May 2022 (mb) Original submission
• 16 February 2023 (bp) Review posted live
• 24 May 2022 (mb) Original submission
## References
## Literature Cited
Radiographic features of RNU4atac-opathy
Panels A/B: Anteroposterior (AP) and lateral thoracolumbar spine images of a nine-month-old female with microcephalic osteodysplastic primordial dwarfism type I/III (MOPDI). The chest is broad and scoliosis is present. Note a thoracolumbar kyphosis with end plate irregularities of the vertebral bodies.
Panels C/D: AP images of the lower extremities of a different female with MOPDI at ages ten months and three years, eight months, respectively. Note flattening of the acetabular roofs and femoral bowing in both images. Metaphyseal changes are present. Note that the femoral shafts appear thinner and more gracile over time, and capital femoral epiphyseal ossification is delayed (Panel D).
Panel E: AP radiograph of the hand of a nine-month-old female with MOPDI. Note delayed carpal ossification, tapered phalanges, and dysplastic radial metaphysis.
Panels F/G: AP radiographs of the hips and knees of a female age three years, eight months with a more moderate RNU4atac-opathy phenotype. The capital femoral, distal femoral, and proximal tibial epiphyses are small and dysplastic.
Panel H: Standing AP radiograph of the lower extremities of the female in Panels F/G at age five years, six months. Note mesomelic proportions with genu valgum, significant and predominant epiphyseal dysplasia throughout, as well as minor metaphyseal changes.
Facial phenotype of RNU4atac-opathy
Craniofacial features vary, with a more consistent and notable gestalt associated with the more severe end of the RNU4atac-opathy spectrum, whereas features seen in the mild/moderate range of the spectrum are more variable. In addition to microcephaly and dolicocephaly, individuals with microcephalic osteodysplastic primordial dwarfism type I/III (MOPDI) have a sloping forehead and ridged metopic suture at birth. The eyes are prominent and appear large; the nasal root is high and the nasal bridge is broad. Lips tend to be full and chin is micrognathic. Ears tend to be small, low set, and posteriorly rotated [
In contrast, the midfacial phenotype in individuals with the historical diagnosis of Roifman syndrome have been variably reported to show thin vermilion of the upper lip, long philtrum, and narrow nasal tip in childhood [
Panels A/B: Female at ages 15 months and 11 years, respectively, diagnosed with MOPDI. Note sloping forehead, prominent eyes, and high and broad nasal bridge with bulbous nasal tip (which is more apparent with age), as well as full lips and micrognathia.
Panels C/D: Male in infancy and at age 20 months, respectively, diagnosed with moderate RNU4atac-opathy.
Panels E/F: Female in infancy and at age eight years, respectively, diagnosed with moderate RNU4atac-opathy. In Panels C/D and E/F, note that eyes appear large and prominent, with broad and high nasal bridge and broad nasal tip, with full lips and micrognathia.
Panels G/H: Male in infancy and at age 7.5 years, respectively, diagnosed with Roifman syndrome. Note long philtrum and thin upper lip with narrow nasal tip. Eyes are prominent in infancy.
Panels I/J: Female in infancy and at age 13 years, respectively, diagnosed with Lowry-Wood syndrome. Note broad and high nasal bridge with long philtrum and micrognathia.
Reported pathogenic variants in RNU4atac-opathy
In addition to the single nucleotide variants shown, a disease-associated tandem 85-bp duplication (nt. 16_100) has been reported [
LWS = Lowry-Wood syndrome; MOPDI = microcephalic osteodysplastic primordial dwarfism type I/III; Roifman = Roifman syndrome
Adapted from
|
[] |
16/2/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
rob-ad
|
rob-ad
|
[
"Fetal Face Syndrome",
"Fetal Face Syndrome",
"Protein Wnt-5a",
"Segment polarity protein dishevelled homolog DVL-1",
"Segment polarity protein dishevelled homolog DVL-3",
"DVL1",
"DVL3",
"WNT5A",
"Autosomal Dominant Robinow Syndrome"
] |
Autosomal Dominant Robinow Syndrome
|
Maian Roifman, Han Brunner, Jamie Lohr, Juliana Mazzeu, David Chitayat
|
Summary Autosomal dominant Robinow syndrome (ADRS) is characterized by skeletal findings (short stature, mesomelic limb shortening predominantly of the upper limbs, and brachydactyly), genital abnormalities (in males: micropenis / webbed penis, hypoplastic scrotum, cryptorchidism; in females: hypoplastic clitoris and labia majora), dysmorphic facial features (widely spaced and prominent eyes, frontal bossing, anteverted nares, midface retrusion), dental abnormalities (including malocclusion, crowding, hypodontia, late eruption of permanent teeth), bilobed tongue, and occasional prenatal macrocephaly that persists postnatally. Less common findings include renal anomalies, radial head dislocation, vertebral abnormalities such as hemivertebrae and scoliosis, nail dysplasia, cardiac defects, cleft lip/palate, and (rarely) cognitive delay. When present, cardiac defects are a major cause of morbidity and mortality. A variant of Robinow syndrome, associated with osteosclerosis and caused by a heterozygous pathogenic variant in The diagnosis of autosomal dominant Robinow syndrome is established in a proband with typical suggestive findings and/or by the identification of a heterozygous pathogenic variant in ADRS is inherited in an autosomal dominant manner. A proband may have the disorder as a result of either an inherited or
|
## Diagnosis
Autosomal dominant Robinow syndrome (ADRS)
Short stature
Mesomelic limb shortening predominantly affecting the upper limbs
Brachydactyly
In males: micropenis / webbed penis, hypoplastic scrotum, and cryptorchidism
In females: hypoplastic clitoris and labia majora
Dysmorphic facial features resembling a fetal face: widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears (See
Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar ridge, alveolar ridge deformation, and bilobed tongue
Family history is consistent with autosomal dominant inheritance. Note: Absence of a known family history of autosomal dominant Robinow syndrome does not preclude the diagnosis.
The diagnosis of autosomal dominant Robinow syndrome
Note: (1) If a heterozygous pathogenic variant is not identified in
Molecular genetic testing approaches can include a combination of
Perform sequence analysis of
Note: All reported disease-associated variants in
For an introduction to multigene panels click
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Autosomal Dominant Robinow 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 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
Since ADRS occurs through a gain-of-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant.
All pathogenic variants identified to date are frameshift variants.
Pathogenic variants in
Omodysplasia type 2, caused by pathogenic variants in
• Short stature
• Mesomelic limb shortening predominantly affecting the upper limbs
• Brachydactyly
• In males: micropenis / webbed penis, hypoplastic scrotum, and cryptorchidism
• In females: hypoplastic clitoris and labia majora
• Dysmorphic facial features resembling a fetal face: widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears (See
• Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar ridge, alveolar ridge deformation, and bilobed tongue
• Perform sequence analysis of
• Note: All reported disease-associated variants in
• For an introduction to multigene panels click
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Autosomal dominant Robinow syndrome (ADRS)
Short stature
Mesomelic limb shortening predominantly affecting the upper limbs
Brachydactyly
In males: micropenis / webbed penis, hypoplastic scrotum, and cryptorchidism
In females: hypoplastic clitoris and labia majora
Dysmorphic facial features resembling a fetal face: widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears (See
Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar ridge, alveolar ridge deformation, and bilobed tongue
Family history is consistent with autosomal dominant inheritance. Note: Absence of a known family history of autosomal dominant Robinow syndrome does not preclude the diagnosis.
• Short stature
• Mesomelic limb shortening predominantly affecting the upper limbs
• Brachydactyly
• In males: micropenis / webbed penis, hypoplastic scrotum, and cryptorchidism
• In females: hypoplastic clitoris and labia majora
• Dysmorphic facial features resembling a fetal face: widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears (See
• Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar ridge, alveolar ridge deformation, and bilobed tongue
## Clinical Findings
Short stature
Mesomelic limb shortening predominantly affecting the upper limbs
Brachydactyly
In males: micropenis / webbed penis, hypoplastic scrotum, and cryptorchidism
In females: hypoplastic clitoris and labia majora
Dysmorphic facial features resembling a fetal face: widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears (See
Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar ridge, alveolar ridge deformation, and bilobed tongue
• Short stature
• Mesomelic limb shortening predominantly affecting the upper limbs
• Brachydactyly
• In males: micropenis / webbed penis, hypoplastic scrotum, and cryptorchidism
• In females: hypoplastic clitoris and labia majora
• Dysmorphic facial features resembling a fetal face: widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, and low-set ears (See
• Dental malocclusion, dental crowding and hypodontia, late eruption of permanent teeth, wide retromolar ridge, alveolar ridge deformation, and bilobed tongue
## Family History
Family history is consistent with autosomal dominant inheritance. Note: Absence of a known family history of autosomal dominant Robinow syndrome does not preclude the diagnosis.
## Establishing the Diagnosis
The diagnosis of autosomal dominant Robinow syndrome
Note: (1) If a heterozygous pathogenic variant is not identified in
Molecular genetic testing approaches can include a combination of
Perform sequence analysis of
Note: All reported disease-associated variants in
For an introduction to multigene panels click
More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Autosomal Dominant Robinow 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 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
Since ADRS occurs through a gain-of-function mechanism and large intragenic deletion or duplication has not been reported, testing for intragenic deletions or duplications is unlikely to identify a disease-causing variant.
All pathogenic variants identified to date are frameshift variants.
Pathogenic variants in
Omodysplasia type 2, caused by pathogenic variants in
• Perform sequence analysis of
• Note: All reported disease-associated variants in
• For an introduction to multigene panels click
• More comprehensive genomic testing (when available) including exome sequencing and genome sequencing may be considered. Such testing may provide or suggest a diagnosis not previously considered (e.g., mutation of a different gene or genes that results in a similar clinical presentation).
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Autosomal dominant Robinow syndrome (ADRS) is a skeletal dysplasia in which affected individuals typically have short stature, mesomelic limb shortening (predominantly of the upper limbs), and brachydactyly. A variety of other (variably present) anomalies may also suggest the diagnosis.
In addition to macrocephaly, prominent facial features in adulthood include widely spaced eyes, wide nasal bridge, and broad nasal tip.
Dental malocclusion becomes apparent in early childhood and persists into adulthood, affecting the permanent dentition as well. One case of persistent primary dentition requiring extraction at age 18 years has been reported [
Short stature persists into adulthood but is typically not severe, with a final adult height either at or just below -2SD in most cases [
Some individuals with
Micropenis may be present. However, in some cases, the penis may measure normally but appear small because it is webbed / embedded in the scrotal tissue or because of the abnormal insertion of penile crura inferiorly and posteriorly onto the medial aspect of the ischial tuberosity [
Micropenis appears to be common in ADRS (and is a constant feature of
The frequency of penoscrotal transposition in ADRS is unclear at this time.
Cardiac defects reported in Robinow syndrome (in both dominant and recessive types) include pulmonary valve stenosis/atresia, atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia [
When present, cardiac defects are a major cause of morbidity and mortality.
Renal anomalies (usually hydronephrosis)
Radial head dislocation
Vertebral abnormalities and scoliosis
Persistent primary teeth requiring extraction
Nail dysplasia
Cleft lip/palate
No clear genotype-phenotype correlation is known.
ADRS is very rare. The exact prevalence of the disorder is unknown. Fewer than 80 families with ADRS have been described in the literature.
• In addition to macrocephaly, prominent facial features in adulthood include widely spaced eyes, wide nasal bridge, and broad nasal tip.
• Dental malocclusion becomes apparent in early childhood and persists into adulthood, affecting the permanent dentition as well. One case of persistent primary dentition requiring extraction at age 18 years has been reported [
• Short stature persists into adulthood but is typically not severe, with a final adult height either at or just below -2SD in most cases [
• Some individuals with
• Micropenis may be present. However, in some cases, the penis may measure normally but appear small because it is webbed / embedded in the scrotal tissue or because of the abnormal insertion of penile crura inferiorly and posteriorly onto the medial aspect of the ischial tuberosity [
• Micropenis appears to be common in ADRS (and is a constant feature of
• The frequency of penoscrotal transposition in ADRS is unclear at this time.
• Cardiac defects reported in Robinow syndrome (in both dominant and recessive types) include pulmonary valve stenosis/atresia, atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia [
• When present, cardiac defects are a major cause of morbidity and mortality.
• Renal anomalies (usually hydronephrosis)
• Radial head dislocation
• Vertebral abnormalities and scoliosis
• Persistent primary teeth requiring extraction
• Nail dysplasia
• Cleft lip/palate
## Clinical Description
Autosomal dominant Robinow syndrome (ADRS) is a skeletal dysplasia in which affected individuals typically have short stature, mesomelic limb shortening (predominantly of the upper limbs), and brachydactyly. A variety of other (variably present) anomalies may also suggest the diagnosis.
In addition to macrocephaly, prominent facial features in adulthood include widely spaced eyes, wide nasal bridge, and broad nasal tip.
Dental malocclusion becomes apparent in early childhood and persists into adulthood, affecting the permanent dentition as well. One case of persistent primary dentition requiring extraction at age 18 years has been reported [
Short stature persists into adulthood but is typically not severe, with a final adult height either at or just below -2SD in most cases [
Some individuals with
Micropenis may be present. However, in some cases, the penis may measure normally but appear small because it is webbed / embedded in the scrotal tissue or because of the abnormal insertion of penile crura inferiorly and posteriorly onto the medial aspect of the ischial tuberosity [
Micropenis appears to be common in ADRS (and is a constant feature of
The frequency of penoscrotal transposition in ADRS is unclear at this time.
Cardiac defects reported in Robinow syndrome (in both dominant and recessive types) include pulmonary valve stenosis/atresia, atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia [
When present, cardiac defects are a major cause of morbidity and mortality.
Renal anomalies (usually hydronephrosis)
Radial head dislocation
Vertebral abnormalities and scoliosis
Persistent primary teeth requiring extraction
Nail dysplasia
Cleft lip/palate
• In addition to macrocephaly, prominent facial features in adulthood include widely spaced eyes, wide nasal bridge, and broad nasal tip.
• Dental malocclusion becomes apparent in early childhood and persists into adulthood, affecting the permanent dentition as well. One case of persistent primary dentition requiring extraction at age 18 years has been reported [
• Short stature persists into adulthood but is typically not severe, with a final adult height either at or just below -2SD in most cases [
• Some individuals with
• Micropenis may be present. However, in some cases, the penis may measure normally but appear small because it is webbed / embedded in the scrotal tissue or because of the abnormal insertion of penile crura inferiorly and posteriorly onto the medial aspect of the ischial tuberosity [
• Micropenis appears to be common in ADRS (and is a constant feature of
• The frequency of penoscrotal transposition in ADRS is unclear at this time.
• Cardiac defects reported in Robinow syndrome (in both dominant and recessive types) include pulmonary valve stenosis/atresia, atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia [
• When present, cardiac defects are a major cause of morbidity and mortality.
• Renal anomalies (usually hydronephrosis)
• Radial head dislocation
• Vertebral abnormalities and scoliosis
• Persistent primary teeth requiring extraction
• Nail dysplasia
• Cleft lip/palate
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
No clear genotype-phenotype correlation is known.
## Prevalence
ADRS is very rare. The exact prevalence of the disorder is unknown. Fewer than 80 families with ADRS have been described in the literature.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Note: The NXN protein is a relevant partner in the WNT5A signaling pathway that is intimately involved in Robinow syndrome causation. ROR2 binds to WNT5A and interacts with FZD2. The effect of this interaction is routed to disheveled proteins (DVL1, DVL3) that are further stabilized by NXN. This complex activates JNK signaling responsible for cytoskeletal reorganization and cell polarity.
## Management
To establish the extent of disease and needs in an individual diagnosed with autosomal dominant Robinow syndrome (ADRS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Autosomal Dominant Robinow Syndrome
Treatment of Manifestations in Individuals with Autosomal Dominant Robinow Syndrome
Injection of human chorionic gonadotropin and testosterone improved penile length and testicular volume in three boys with severe micropenis [
Recommended Surveillance for Individuals with Autosomal Dominant Robinow Syndrome
It is appropriate to evaluate the sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and surveillance. If the
See
Pregnancy in affected women appears to be generally uncomplicated. For an affected fetus, cesarean section may be required for abnormal presentation and/or cephalopelvic disproportion. Breech presentation requiring cesarean section has been reported in one case of ADRS [
Search
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with autosomal dominant Robinow syndrome (ADRS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Autosomal Dominant Robinow Syndrome
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Autosomal Dominant Robinow Syndrome
Injection of human chorionic gonadotropin and testosterone improved penile length and testicular volume in three boys with severe micropenis [
## Surveillance
Recommended Surveillance for Individuals with Autosomal Dominant Robinow Syndrome
## Evaluation of Relatives at Risk
It is appropriate to evaluate the sibs of a proband in order to identify as early as possible those who would benefit from institution of treatment and surveillance. If the
See
## Pregnancy Management
Pregnancy in affected women appears to be generally uncomplicated. For an affected fetus, cesarean section may be required for abnormal presentation and/or cephalopelvic disproportion. Breech presentation requiring cesarean section has been reported in one case of ADRS [
## Therapies Under Investigation
Search
## Genetic Counseling
Robinow syndrome caused by pathogenic variants in
Some individuals diagnosed with autosomal dominant Robinow syndrome (ADRS) have an affected parent.
A proband with ADRS may have the disorder as a result of a
Recommendations for the evaluation of parents of a proband with an apparent
If the
Evaluation of the parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. 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 variant and may be mildly/minimally affected [
If a parent of the proband is affected, the risk to the sibs is 50%. However, the severity of the clinical manifestations cannot be predicted from the results of molecular genetic testing.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
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.
• Some individuals diagnosed with autosomal dominant Robinow syndrome (ADRS) have an affected parent.
• A proband with ADRS may have the disorder as a result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• If the
• Evaluation of the parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. 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 variant and may be mildly/minimally affected [
• If a parent of the proband is affected, the risk to the sibs is 50%. However, the severity of the clinical manifestations cannot be predicted from the results of molecular genetic testing.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• 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.
## Mode of Inheritance
Robinow syndrome caused by pathogenic variants in
## Risk to Family Members
Some individuals diagnosed with autosomal dominant Robinow syndrome (ADRS) have an affected parent.
A proband with ADRS may have the disorder as a result of a
Recommendations for the evaluation of parents of a proband with an apparent
If the
Evaluation of the parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. 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 variant and may be mildly/minimally affected [
If a parent of the proband is affected, the risk to the sibs is 50%. However, the severity of the clinical manifestations cannot be predicted from the results of molecular genetic testing.
When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
If the
• Some individuals diagnosed with autosomal dominant Robinow syndrome (ADRS) have an affected parent.
• A proband with ADRS may have the disorder as a result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• If the
• Evaluation of the parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. 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 variant and may be mildly/minimally affected [
• If a parent of the proband is affected, the risk to the sibs is 50%. However, the severity of the clinical manifestations cannot be predicted from the results of molecular genetic testing.
• When the parents are clinically unaffected, the risk to the sibs of a proband appears to be low.
• 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
## Resources
United Kingdom
•
•
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
Autosomal Dominant Robinow Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Autosomal Dominant Robinow Syndrome (
The Wnt family of proteins regulates critical morphogenic events, including embryonic patterning, and cell differentiation, growth, and migration. Wnt signaling pathways fall into two categories: canonic, which involve β-catenin, and non-canonic, which are independent of β-catenin.
WNT5A, which functions in the both the canonic and non-canonic pathways, is a Wnt family member critical for developmental processes requiring cell migration (reviewed in
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Two families had this variant.
The
## Molecular Pathogenesis
The Wnt family of proteins regulates critical morphogenic events, including embryonic patterning, and cell differentiation, growth, and migration. Wnt signaling pathways fall into two categories: canonic, which involve β-catenin, and non-canonic, which are independent of β-catenin.
WNT5A, which functions in the both the canonic and non-canonic pathways, is a Wnt family member critical for developmental processes requiring cell migration (reviewed in
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Two families had this variant.
The
##
Variants listed in the table have been provided by the authors.
Variants listed in the table have been provided by the authors.
##
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Two families had this variant.
The
## Chapter Notes
3 October 2019 (aa) Revision:
9 August 2018 (ma) Comprehensive update posted live
30 July 2015 (aa) Revision:
8 January 2015 (me) Review posted live
18 June 2014 (mr) Original submission
• 3 October 2019 (aa) Revision:
• 9 August 2018 (ma) Comprehensive update posted live
• 30 July 2015 (aa) Revision:
• 8 January 2015 (me) Review posted live
• 18 June 2014 (mr) Original submission
## Revision History
3 October 2019 (aa) Revision:
9 August 2018 (ma) Comprehensive update posted live
30 July 2015 (aa) Revision:
8 January 2015 (me) Review posted live
18 June 2014 (mr) Original submission
• 3 October 2019 (aa) Revision:
• 9 August 2018 (ma) Comprehensive update posted live
• 30 July 2015 (aa) Revision:
• 8 January 2015 (me) Review posted live
• 18 June 2014 (mr) Original submission
## References
## Literature Cited
A mother and son, both affected with
A. Affected mother in infancy
B, C. Affected son at birth
D. Mother (age 39 years) and son (age 2 years)
E. Son at age three years
Note the widely spaced and prominent eyes, high anterior hairline, frontal bossing, depressed nasal bridge, short nose with anteverted nares, wide nasal bridge with a broad nasal tip, long philtrum, midface retrusion, low-set ears, and limb shortening predominantly affecting the upper limbs.
A boy with
|
[
"J Al-Ata, M Paquet, AS Teebi. Congenital heart disease in Robinow syndrome.. Am J Med Genet. 1998;77:332-3",
"S Beiraghi, V Leon-Salazar, BE Larson, MT John, ML Cunningham, A Petryk, JL Lohr. Craniofacial and intraoral phenotype of Robinow syndrome forms.. Clin Genet. 2011;80:15-24",
"KJ Bunn, P Daniel, HS Rosken, AC O'Neill, SR Cameron-Christie, T Morgan, HG Brunner, A Lai, HPM Kunst, DM Markie, SP Robertson. Mutations in DVL1 cause an osteosclerotic form of Robinow syndrome.. Am J Hum Genet. 2015;96:623-30",
"S Castro, E Peraza, A Barraza, M. Zapata. Prenatal diagnosis of Robinow syndrome: a case report.. J Clin Ultrasound. 2014;42:297-300",
"M Danyel, F Kortüm, K Dathe, K Kutsche, D. Horn. Autosomal dominant Robinow syndrome associated with a novel DVL3 splice mutation.. Am J Med Genet A. 2018;176:992-6",
"B Gao, H Song, K Bishop, G Elliot, L Garrett, MA English, P Andre, J Robinson, R Sood, Y Minami, AN Economides, Y Yang. Wnt signaling gradients establish planar cell polarity by inducing Vangl2 phosphorylation through Ror2.. Dev Cell. 2011;20:163-76",
"JF Mazzeu, E Pardono, AM Vianna-Morgante, A Richieri-Costa, C Ae Kim, D Brunoni, L Martelli, CE de Andrade, G Colin, PA Otto. Clinical characterization of autosomal dominant and recessive variants of Robinow syndrome.. Am J Med Genet A. 2007;143:320-5",
"AJ Mikels, R Nusse. Purified Wnt5a protein activates or inhibits beta-catenin-TCF signaling depending on receptor context.. PLoS Biol. 2006;4",
"M Nishita, M Enomoto, K Yamagata, Y. Minami. Cell/tissue-tropic functions of Wnt5a signaling in normal and cancer cells.. Trends Cell Biol. 2010;20:346-54",
"I Oishi, H Suzuki, N Onishi, R Takada, S Kani, B Ohkawara, I Koshida, K Suzuki, G Yamada, GC Schwabe, S Mundlos, H Shibuya, S Takada, Y Minami. The receptor tyrosine kinase Ror2 is involved in non-canonical Wnt5a/JNK signalling pathway.. Genes Cells. 2003;8:645-54",
"AD Person, S Beiraghi, CM Sieben, S Hermanson, AN Neumann, ME Robu, JR Schleiffarth, CJ Billington, H van Bokhoven, JM Hoogeboom, JF Mazzeu, A Petryk, LA Schimmenti, HG Brunner, SC Ekker, JL Lohr. WNT5A mutations in patients with autosomal dominant Robinow syndrome.. Dev Dyn. 2010;239:327-37",
"M Roifman, CL Marcelis, T Paton, C Marshall, R Silver, JL Lohr, HG Yntema, H Venselaar, H Kayserili, B van Bon, G Seaward, HG Brunner, D Chitayat. De novo WNT5A-associated autosomal dominant Robinow syndrome suggests specificity of genotype and phenotype.. Clin Genet. 2015;87:34-41",
"A Schambony, D. Wedlich. Wnt-5A/Ror2 regulate expression of XPAPC through an alternative noncanonical signaling pathway.. Dev Cell. 2007;12:779-92",
"AT Soliman, A Rajab, I Alsalmi, SM Bedair. Recessive Robinow syndrome: with emphasis on endocrine functions.. Metabolism. 1998;47:1337-43",
"SG Tevosian. Gone without the WNT: a requirement for WNT5A in germ cell migration and testis development.. Biol Reprod. 2012;86:1-2",
"SA Webber, DS Wargowski, D Chitayat, GG Sandor. Congenital heart disease and Robinow syndrome: coincidence or an additional component of the syndrome?. Am J Med Genet. 1990;37:519-21",
"J White, JF Mazzeu, A Hoischen, SN Jhangiani, T Gambin, M Calijorne Alcino, S Penney, JM Saraiva, H Hove, F Skovby, H Kayserili, E Estrella, A Vulto-van Silfhout, M Steehouwer, DM Muzny, VR Sutton, RA Gibbs, JR Lupski, HG Brunner, BWM van Bon, CMB Carvalho. CVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome.. Am J Hum Genet. 2015;96:612-22",
"JJ White, JF Mazzeu, Z Coban-Akdemir, Y Bayram, V Bahrambeigi, A Hoischen, BWM van Bon, A Gezdirici, EY Gulec, F Ramond, R Touraine, J Thevenon, M Shinawi, E Beaver, J Heeley, J Hoover-Fong, CD Durmaz, HG Karabulut, E Marzioglu-Ozdemir, A Cayir, MB Duz, M Seven, S Price, BM Ferreira, AM Vianna-Morgante, S Ellard, A Parrish, K Stals, J Flores-Daboub, SN Jhangiani, RA Gibbs, HG Brunner, VR Sutton, JR Lupski, CMB Carvalho. WNT signaling perturbations underlie the genetic heterogeneity of Robinow syndrome.. Am J Hum Genet. 2018;102:27-43",
"JJ White, JF Mazzeu, A Hoischen, Y Bayram, M Withers, A Gezdirici, V Kimonis, M Steehouwer, SN Jhangiani, DM Muzny, RA Gibbs, BWM van Bon, VR Sutton, JR Lupski, HG Brunner, CMB Carvalho. DVL3 alleles resulting in a -1 frameshift of the last exon mediate autosomal-dominant Robinow syndrome.. Am J Hum Genet. 2016;98:553-61",
"DT Wilcox, FM Quinn, CS Ng, C Dicks-Mireaux, PD Mouriquand. Redefining the genital abnormality in the Robinow syndrome.. J Urol. 1997;157:2312-4",
"S Xiong, D Chitayat, X Wei, J Zhu, W Lu, LM Sun, M Chopra. A novel de-novo WNT5A mutation in a Chinese patient with Robinow syndrome.. Clin Dysmorphol. 2016;25:186-9"
] |
8/1/2015
|
9/8/2018
|
3/10/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
rob
|
rob
|
[
"Fetal Face Syndrome",
"Fetal Face Syndrome",
"Tyrosine-protein kinase transmembrane receptor ROR2",
"ROR2",
"ROR2-Related Robinow Syndrome"
] |
Carlos A Bacino
|
Summary The diagnosis of
|
## Diagnosis
Macrocephaly
Dysmorphic facial features including: broad prominent forehead, marked ocular hypertelorism, prominent eyes with apparent exophthalmos resulting from deficiency of the lower eyelid (giving the eyes a more prominent appearance), midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth (usually with tethering of the upper lip in the center so it appears like an inverted V and exposes the incisors and upper gum), micrognathia, and simple, low-set ears (which can be posteriorly rotated)
Cleft lip and/or cleft palate
Crowded and misaligned teeth, gum hypertrophy, and ankyloglossia (with bifid tongue in severe cases)
Short stature. Birth length is reduced; height was consistently ≥2 SD below the mean in one series [
Mesomelic or acromesomelic limb shortening, mostly in the forearms
Brachydactyly with shortening of the distal phalanx, especially the second and fifth digit; clefting of the distal phalanx of the thumb and occasionally other distal phalanges; variable soft-tissue syndactyly involving two or more digits
Hemivertebrae with fusion of thoracic vertebrae; ribs usually fused or absent [
In males, micropenis with normal scrotum and testes, or cryptorchidism
In females, reduced clitoral size and hypoplasia of the labia majora
Family history is consistent with autosomal recessive inheritance. To date
The diagnosis of
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 findings and family history 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
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 frequency of exon or whole-gene deletions and duplications in this disorder is not known; however, exon deletions have been reported [
• Macrocephaly
• Dysmorphic facial features including: broad prominent forehead, marked ocular hypertelorism, prominent eyes with apparent exophthalmos resulting from deficiency of the lower eyelid (giving the eyes a more prominent appearance), midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth (usually with tethering of the upper lip in the center so it appears like an inverted V and exposes the incisors and upper gum), micrognathia, and simple, low-set ears (which can be posteriorly rotated)
• Cleft lip and/or cleft palate
• Crowded and misaligned teeth, gum hypertrophy, and ankyloglossia (with bifid tongue in severe cases)
• Short stature. Birth length is reduced; height was consistently ≥2 SD below the mean in one series [
• Mesomelic or acromesomelic limb shortening, mostly in the forearms
• Brachydactyly with shortening of the distal phalanx, especially the second and fifth digit; clefting of the distal phalanx of the thumb and occasionally other distal phalanges; variable soft-tissue syndactyly involving two or more digits
• Hemivertebrae with fusion of thoracic vertebrae; ribs usually fused or absent [
• In males, micropenis with normal scrotum and testes, or cryptorchidism
• In females, reduced clitoral size and hypoplasia of the labia majora
• For an introduction to multigene panels click
## Suggestive Findings
Macrocephaly
Dysmorphic facial features including: broad prominent forehead, marked ocular hypertelorism, prominent eyes with apparent exophthalmos resulting from deficiency of the lower eyelid (giving the eyes a more prominent appearance), midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth (usually with tethering of the upper lip in the center so it appears like an inverted V and exposes the incisors and upper gum), micrognathia, and simple, low-set ears (which can be posteriorly rotated)
Cleft lip and/or cleft palate
Crowded and misaligned teeth, gum hypertrophy, and ankyloglossia (with bifid tongue in severe cases)
Short stature. Birth length is reduced; height was consistently ≥2 SD below the mean in one series [
Mesomelic or acromesomelic limb shortening, mostly in the forearms
Brachydactyly with shortening of the distal phalanx, especially the second and fifth digit; clefting of the distal phalanx of the thumb and occasionally other distal phalanges; variable soft-tissue syndactyly involving two or more digits
Hemivertebrae with fusion of thoracic vertebrae; ribs usually fused or absent [
In males, micropenis with normal scrotum and testes, or cryptorchidism
In females, reduced clitoral size and hypoplasia of the labia majora
Family history is consistent with autosomal recessive inheritance. To date
• Macrocephaly
• Dysmorphic facial features including: broad prominent forehead, marked ocular hypertelorism, prominent eyes with apparent exophthalmos resulting from deficiency of the lower eyelid (giving the eyes a more prominent appearance), midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth (usually with tethering of the upper lip in the center so it appears like an inverted V and exposes the incisors and upper gum), micrognathia, and simple, low-set ears (which can be posteriorly rotated)
• Cleft lip and/or cleft palate
• Crowded and misaligned teeth, gum hypertrophy, and ankyloglossia (with bifid tongue in severe cases)
• Short stature. Birth length is reduced; height was consistently ≥2 SD below the mean in one series [
• Mesomelic or acromesomelic limb shortening, mostly in the forearms
• Brachydactyly with shortening of the distal phalanx, especially the second and fifth digit; clefting of the distal phalanx of the thumb and occasionally other distal phalanges; variable soft-tissue syndactyly involving two or more digits
• Hemivertebrae with fusion of thoracic vertebrae; ribs usually fused or absent [
• In males, micropenis with normal scrotum and testes, or cryptorchidism
• In females, reduced clitoral size and hypoplasia of the labia majora
## Clinical Findings
Macrocephaly
Dysmorphic facial features including: broad prominent forehead, marked ocular hypertelorism, prominent eyes with apparent exophthalmos resulting from deficiency of the lower eyelid (giving the eyes a more prominent appearance), midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth (usually with tethering of the upper lip in the center so it appears like an inverted V and exposes the incisors and upper gum), micrognathia, and simple, low-set ears (which can be posteriorly rotated)
Cleft lip and/or cleft palate
Crowded and misaligned teeth, gum hypertrophy, and ankyloglossia (with bifid tongue in severe cases)
Short stature. Birth length is reduced; height was consistently ≥2 SD below the mean in one series [
Mesomelic or acromesomelic limb shortening, mostly in the forearms
Brachydactyly with shortening of the distal phalanx, especially the second and fifth digit; clefting of the distal phalanx of the thumb and occasionally other distal phalanges; variable soft-tissue syndactyly involving two or more digits
Hemivertebrae with fusion of thoracic vertebrae; ribs usually fused or absent [
In males, micropenis with normal scrotum and testes, or cryptorchidism
In females, reduced clitoral size and hypoplasia of the labia majora
• Macrocephaly
• Dysmorphic facial features including: broad prominent forehead, marked ocular hypertelorism, prominent eyes with apparent exophthalmos resulting from deficiency of the lower eyelid (giving the eyes a more prominent appearance), midface hypoplasia, short upturned nose with depressed nasal bridge and flared nostrils, large and triangular mouth (usually with tethering of the upper lip in the center so it appears like an inverted V and exposes the incisors and upper gum), micrognathia, and simple, low-set ears (which can be posteriorly rotated)
• Cleft lip and/or cleft palate
• Crowded and misaligned teeth, gum hypertrophy, and ankyloglossia (with bifid tongue in severe cases)
• Short stature. Birth length is reduced; height was consistently ≥2 SD below the mean in one series [
• Mesomelic or acromesomelic limb shortening, mostly in the forearms
• Brachydactyly with shortening of the distal phalanx, especially the second and fifth digit; clefting of the distal phalanx of the thumb and occasionally other distal phalanges; variable soft-tissue syndactyly involving two or more digits
• Hemivertebrae with fusion of thoracic vertebrae; ribs usually fused or absent [
• In males, micropenis with normal scrotum and testes, or cryptorchidism
• In females, reduced clitoral size and hypoplasia of the labia majora
## Family History
Family history is consistent with autosomal recessive inheritance. To date
## Establishing the Diagnosis
The diagnosis of
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 findings and family history 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
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 frequency of exon or whole-gene deletions and duplications in this disorder is not known; however, exon deletions have been reported [
• For an introduction to multigene panels click
## Option 1
When the phenotypic findings and family history 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
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 frequency of exon or whole-gene deletions and duplications in this disorder is not known; however, exon deletions have been reported [
## Clinical Characteristics
Midline cleft lip and palate has been reported but is not a common finding. A rather unusual form of clefting involving the lower lip has been described in some individuals.
Dental problems, including wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding, and hypodontia, are also common in Robinow syndrome.
Hyperplastic gingival tissues may also interfere with dental eruption and orthodontic treatments [
The forearms are more noticeably affected by mesomelic or acromesomelic shortening than the lower limbs, often with radioulnar dislocation.
The phalanges and carpal bones may be fused. Partial cutaneous syndactyly or ectrodactyly (i.e., split hand) may be seen. Hand function is not severely affected.
Kyphoscoliosis is often severe. The chest may be deformed and ribs are often fused, as in spondylocostal dysostosis; some ribs may even be absent. Primary lung function is normal, but changes in the chest wall and thoracic vertebrae may reduce cough effort and predispose to respiratory infections [
Endocrine investigations are usually normal; however,
Renal abnormalities may be associated with the genital abnormalities. Hydronephrosis is common and cystic dysplasia of the kidney has been reported.
Congenital heart defects are seen in 15%. In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia [
Nail hypoplasia or dystrophy may be present.
Intellect is usually within the normal range; however, developmental delay has been reported.
No genotype-phenotype correlations are known.
Other names by which Robinow syndrome has been known in the past:
Costovertebral segmentation defect with mesomelia (COVESDEM): this name is no longer used because it causes confusion with similar vertebral defect syndromes, and in
Robinow-Silverman syndrome
• Congenital heart defects are seen in 15%. In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia [
• Nail hypoplasia or dystrophy may be present.
• Intellect is usually within the normal range; however, developmental delay has been reported.
• Costovertebral segmentation defect with mesomelia (COVESDEM): this name is no longer used because it causes confusion with similar vertebral defect syndromes, and in
• Robinow-Silverman syndrome
## Clinical Description
Midline cleft lip and palate has been reported but is not a common finding. A rather unusual form of clefting involving the lower lip has been described in some individuals.
Dental problems, including wide retromolar ridge, alveolar ridge deformation, malocclusion, dental crowding, and hypodontia, are also common in Robinow syndrome.
Hyperplastic gingival tissues may also interfere with dental eruption and orthodontic treatments [
The forearms are more noticeably affected by mesomelic or acromesomelic shortening than the lower limbs, often with radioulnar dislocation.
The phalanges and carpal bones may be fused. Partial cutaneous syndactyly or ectrodactyly (i.e., split hand) may be seen. Hand function is not severely affected.
Kyphoscoliosis is often severe. The chest may be deformed and ribs are often fused, as in spondylocostal dysostosis; some ribs may even be absent. Primary lung function is normal, but changes in the chest wall and thoracic vertebrae may reduce cough effort and predispose to respiratory infections [
Endocrine investigations are usually normal; however,
Renal abnormalities may be associated with the genital abnormalities. Hydronephrosis is common and cystic dysplasia of the kidney has been reported.
Congenital heart defects are seen in 15%. In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia [
Nail hypoplasia or dystrophy may be present.
Intellect is usually within the normal range; however, developmental delay has been reported.
• Congenital heart defects are seen in 15%. In addition to pulmonary valve stenosis or atresia, cardiac defects include atrial septal defect, ventricular septal defect, coarctation of the aorta, tetralogy of Fallot, and tricuspid atresia [
• Nail hypoplasia or dystrophy may be present.
• Intellect is usually within the normal range; however, developmental delay has been reported.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
## Nomenclature
Other names by which Robinow syndrome has been known in the past:
Costovertebral segmentation defect with mesomelia (COVESDEM): this name is no longer used because it causes confusion with similar vertebral defect syndromes, and in
Robinow-Silverman syndrome
• Costovertebral segmentation defect with mesomelia (COVESDEM): this name is no longer used because it causes confusion with similar vertebral defect syndromes, and in
• Robinow-Silverman syndrome
## Prevalence
## Genetically Related (Allelic) Disorders
BDB1 affects the fourth and fifth digits with shortening of the middle phalanges and absence of the terminal phalanges. Affected individuals may show mildly abnormal facial features including wide-spaced eyes, downslanting palpebral fissures, short philtrum, and prominent nose. Inheritance is autosomal dominant.
## Differential Diagnosis
Note: The NXN protein is a relevant partner in the WNT5A signaling pathway that is intimately involved in Robinow syndrome causation. ROR2 binds to WNT5A and interacts with FZD2. The effect of this interaction is routed to disheveled proteins (DVL1, DVL3) that are further stabilized by NXN. This complex activates JNK signaling responsible for cytoskeletal reorganization and cell polarity.
Vertebral anomalies and radial head dislocation are rare [
Vertebral anomalies and scoliosis are seen in far fewer of those with AD Robinow syndrome (75%) [
Height is usually nearer the normal range in AD Robinow syndrome.
Autosomal dominant Robinow syndrome is rarer than autosomal recessive Robinow syndrome.
The diagnosis of autosomal dominant Robinow syndrome is established in a proband with typical suggestive findings and/or by the identification of a heterozygous pathogenic variant in
• Vertebral anomalies and radial head dislocation are rare [
• Vertebral anomalies and scoliosis are seen in far fewer of those with AD Robinow syndrome (75%) [
• Height is usually nearer the normal range in AD Robinow syndrome.
## Management
To establish the extent of disease and needs in an individual diagnosed with
Clinical assessment for presence of cleft lip/palate and the need for surgical repair
Orthodontics consultation as needed for misaligned, crowded teeth
Clinical and radiographic evaluation of the spine and rib cage to assess the severity of kyphoscoliosis and vertebral and rib anomalies, as these can lead to postural and respiratory complications [
Radiographic documentation of radioulnar synostosis, forearm shortening, and brachydactyly
Urology consultation in males with cryptorchidism and abnormal penile insertion / penoscrotal transposition for consideration of reconstructive surgery
Endocrine consultation to assess the possibility of hormone therapy for males with micropenis
Renal ultrasound examination
Echocardiogram to evaluate for structural heart defects
Consultation with a clinical geneticist and/or genetic counselor
Corrective surgeries may be required for the following:
Syndactyly
Severe scoliosis secondary to hemivertebrae and rib abnormalities
Cleft lip/palate
Abnormal penile insertion / penoscrotal transposition. Although it was not possible to detach the abnormal insertion of the penile crura, which can cause a normal-sized penis to be buried in the scrotum and thus appear small,
Injection of human chorionic gonadotropin and testosterone therapy improved penile length and testicular volume in three boys with severe micropenis [
Orthodontic treatment is usually required.
Preoperative radiologic assessment of the vertebrae and ribs because of the risk for respiratory complications
Preoperative cardiac evaluation for the presence of congenital heart defects
Awareness that endotracheal intubation may be difficult as a result of midface hypoplasia
The following are appropriate:
Surveillance for evidence of scoliosis until growth is completed
Dental evaluation every six months to one year or as recommended by the dental professional on initial assessment
Regular cardiac and renal assessment by respective specialists as needed if abnormalities are identified
See
Search
• Clinical assessment for presence of cleft lip/palate and the need for surgical repair
• Orthodontics consultation as needed for misaligned, crowded teeth
• Clinical and radiographic evaluation of the spine and rib cage to assess the severity of kyphoscoliosis and vertebral and rib anomalies, as these can lead to postural and respiratory complications [
• Radiographic documentation of radioulnar synostosis, forearm shortening, and brachydactyly
• Urology consultation in males with cryptorchidism and abnormal penile insertion / penoscrotal transposition for consideration of reconstructive surgery
• Endocrine consultation to assess the possibility of hormone therapy for males with micropenis
• Renal ultrasound examination
• Echocardiogram to evaluate for structural heart defects
• Consultation with a clinical geneticist and/or genetic counselor
• Syndactyly
• Severe scoliosis secondary to hemivertebrae and rib abnormalities
• Cleft lip/palate
• Abnormal penile insertion / penoscrotal transposition. Although it was not possible to detach the abnormal insertion of the penile crura, which can cause a normal-sized penis to be buried in the scrotum and thus appear small,
• Preoperative radiologic assessment of the vertebrae and ribs because of the risk for respiratory complications
• Preoperative cardiac evaluation for the presence of congenital heart defects
• Awareness that endotracheal intubation may be difficult as a result of midface hypoplasia
• Surveillance for evidence of scoliosis until growth is completed
• Dental evaluation every six months to one year or as recommended by the dental professional on initial assessment
• Regular cardiac and renal assessment by respective specialists as needed if abnormalities are identified
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Clinical assessment for presence of cleft lip/palate and the need for surgical repair
Orthodontics consultation as needed for misaligned, crowded teeth
Clinical and radiographic evaluation of the spine and rib cage to assess the severity of kyphoscoliosis and vertebral and rib anomalies, as these can lead to postural and respiratory complications [
Radiographic documentation of radioulnar synostosis, forearm shortening, and brachydactyly
Urology consultation in males with cryptorchidism and abnormal penile insertion / penoscrotal transposition for consideration of reconstructive surgery
Endocrine consultation to assess the possibility of hormone therapy for males with micropenis
Renal ultrasound examination
Echocardiogram to evaluate for structural heart defects
Consultation with a clinical geneticist and/or genetic counselor
• Clinical assessment for presence of cleft lip/palate and the need for surgical repair
• Orthodontics consultation as needed for misaligned, crowded teeth
• Clinical and radiographic evaluation of the spine and rib cage to assess the severity of kyphoscoliosis and vertebral and rib anomalies, as these can lead to postural and respiratory complications [
• Radiographic documentation of radioulnar synostosis, forearm shortening, and brachydactyly
• Urology consultation in males with cryptorchidism and abnormal penile insertion / penoscrotal transposition for consideration of reconstructive surgery
• Endocrine consultation to assess the possibility of hormone therapy for males with micropenis
• Renal ultrasound examination
• Echocardiogram to evaluate for structural heart defects
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Corrective surgeries may be required for the following:
Syndactyly
Severe scoliosis secondary to hemivertebrae and rib abnormalities
Cleft lip/palate
Abnormal penile insertion / penoscrotal transposition. Although it was not possible to detach the abnormal insertion of the penile crura, which can cause a normal-sized penis to be buried in the scrotum and thus appear small,
Injection of human chorionic gonadotropin and testosterone therapy improved penile length and testicular volume in three boys with severe micropenis [
Orthodontic treatment is usually required.
Preoperative radiologic assessment of the vertebrae and ribs because of the risk for respiratory complications
Preoperative cardiac evaluation for the presence of congenital heart defects
Awareness that endotracheal intubation may be difficult as a result of midface hypoplasia
• Syndactyly
• Severe scoliosis secondary to hemivertebrae and rib abnormalities
• Cleft lip/palate
• Abnormal penile insertion / penoscrotal transposition. Although it was not possible to detach the abnormal insertion of the penile crura, which can cause a normal-sized penis to be buried in the scrotum and thus appear small,
• Preoperative radiologic assessment of the vertebrae and ribs because of the risk for respiratory complications
• Preoperative cardiac evaluation for the presence of congenital heart defects
• Awareness that endotracheal intubation may be difficult as a result of midface hypoplasia
## Surveillance
The following are appropriate:
Surveillance for evidence of scoliosis until growth is completed
Dental evaluation every six months to one year or as recommended by the dental professional on initial assessment
Regular cardiac and renal assessment by respective specialists as needed if abnormalities are identified
• Surveillance for evidence of scoliosis until growth is completed
• Dental evaluation every six months to one year or as recommended by the dental professional on initial assessment
• Regular cardiac and renal assessment by respective specialists as needed if abnormalities are identified
## 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 may display findings consistent with brachydactyly type B1 [
Molecular genetic testing of parents could be considered for confirmation studies and for future prenatal testing purposes.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a heterozygote and usually asymptomatic, and a 25% chance of being unaffected and not a carrier.
Heterozygotes may display findings consistent with brachydactyly type B1.
The offspring of an individual with Robinow syndrome are obligate heterozygotes for an
The risk that the offspring of a proband will be affected is small unless the reproductive partner is related to the proband or has a family history of
Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and may display findings consistent with brachydactyly type B1.
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 child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes may display findings consistent with brachydactyly type B1 [
• Molecular genetic testing of parents could be considered for confirmation studies and for future prenatal testing purposes.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a heterozygote and usually asymptomatic, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes may display findings consistent with brachydactyly type B1.
• The offspring of an individual with Robinow syndrome are obligate heterozygotes for an
• The risk that the offspring of a proband will be affected is small unless the reproductive partner is related to the proband or has a family history 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
## Risk to Family Members
The parents of an affected child are obligate heterozygotes (i.e., carriers of one
Heterozygotes may display findings consistent with brachydactyly type B1 [
Molecular genetic testing of parents could be considered for confirmation studies and for future prenatal testing purposes.
At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a heterozygote and usually asymptomatic, and a 25% chance of being unaffected and not a carrier.
Heterozygotes may display findings consistent with brachydactyly type B1.
The offspring of an individual with Robinow syndrome are obligate heterozygotes for an
The risk that the offspring of a proband will be affected is small unless the reproductive partner is related to the proband or has a family history of
• The parents of an affected child are obligate heterozygotes (i.e., carriers of one
• Heterozygotes may display findings consistent with brachydactyly type B1 [
• Molecular genetic testing of parents could be considered for confirmation studies and for future prenatal testing purposes.
• At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being a heterozygote and usually asymptomatic, and a 25% chance of being unaffected and not a carrier.
• Heterozygotes may display findings consistent with brachydactyly type B1.
• The offspring of an individual with Robinow syndrome are obligate heterozygotes for an
• The risk that the offspring of a proband will be affected is small unless the reproductive partner is related to the proband or has a family history of
## Heterozygote Detection
Carrier testing for at-risk family members is possible if the pathogenic variants have been identified in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and may display findings consistent with brachydactyly type B1.
## 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
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
•
•
•
•
•
•
•
•
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• United Kingdom
•
## Molecular Genetics
ROR2-Related Robinow Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for ROR2-Related Robinow Syndrome (
Homozygous deletions involving exons 6 and 7 have also been reported in Robinow syndrome [
ROR2 is essential for normal bone growth. Murine
Studies by
## Molecular Pathogenesis
Homozygous deletions involving exons 6 and 7 have also been reported in Robinow syndrome [
ROR2 is essential for normal bone growth. Murine
Studies by
## Chapter Notes
Ali R Afzal, MD, MSc, PhD; St George's Hospital Medical School (2004-2011)Carlos A Bacino, MD (2011-present)Rohan Taylor, SRCS, MRCPath; St George's Healthcare NHS Trust (2004-2011)
12 September 2019 (aa) Revision:
26 July 2018 (bp) Comprehensive update posted live
25 August 2011 (me) Comprehensive update posted live
28 July 2005 (me) Review posted live
8 November 2004 (aa) Original submission
• 12 September 2019 (aa) Revision:
• 26 July 2018 (bp) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 28 July 2005 (me) Review posted live
• 8 November 2004 (aa) Original submission
## Author History
Ali R Afzal, MD, MSc, PhD; St George's Hospital Medical School (2004-2011)Carlos A Bacino, MD (2011-present)Rohan Taylor, SRCS, MRCPath; St George's Healthcare NHS Trust (2004-2011)
## Revision History
12 September 2019 (aa) Revision:
26 July 2018 (bp) Comprehensive update posted live
25 August 2011 (me) Comprehensive update posted live
28 July 2005 (me) Review posted live
8 November 2004 (aa) Original submission
• 12 September 2019 (aa) Revision:
• 26 July 2018 (bp) Comprehensive update posted live
• 25 August 2011 (me) Comprehensive update posted live
• 28 July 2005 (me) Review posted live
• 8 November 2004 (aa) Original submission
## References
## Literature Cited
|
[
"AR Afzal, S Jeffery. One gene, two phenotypes: ROR2 mutations in autosomal recessive Robinow syndrome and autosomal dominant brachydactyly type B.. Hum Mutat. 2003;22:1-11",
"AR Afzal, A Rajab, CD Fenske, M Oldridge, N Elanko, E Ternes-Pereira, B Tuysuz, VA Murday, MA Patton, AO Wilkie, S Jeffery. Recessive Robinow syndrome, allelic to dominant brachydactyly type B, is caused by mutation of ROR2.. Nat Genet 2000;25:419-22",
"M Aglan, K Amr, S Ismail, A Ashour, GA Otaify, MA Mehrez, EH Aboul-Ezz, M El-Ruby, I Mazen, MS Abdel-Hamid, SA Temtamy. Clinical and molecular characterization of seven Egyptian families with autosomal recessive robinow syndrome: Identification of four novel ROR2 gene mutations.. Am J Med Genet A. 2015;167A:3054-61",
"J Al-Ata, M Paquet, AS Teebi. Congenital heart disease in Robinow syndrome.. Am J Med Genet 1998;77:332-3",
"MD Bain, RM Winter, J Burn. Robinow syndrome without mesomelic 'brachymelia': a report of five cases.. J Med Genet 1986;23:350-4",
"S Beiraghi, V Leon-Salazar, BE Larson, MT John, ML Cunningham, A Petryk, JL Lohr. Craniofacial and intraoral phenotype of Robinow syndrome forms.. Clin Genet. 2011;80:15-24",
"N Brunetti-Pierri, D Del Gaudio, H Peters, H Justino, CE Ott, S Mundlos, CA Bacino. Robinow syndrome: phenotypic variability in a family with a novel intragenic ROR2 mutation.. Am J Med Genet A. 2008;146A:2804-9",
"R Grothe, C Anderson-Cermin, S Beiraghi. Autosomal recessive Robinow syndrome: a case report.. J Dent Child (Chic) 2008;75:48-54",
"MA Guven, C Batukan, S Ceylaner, M Uzel, A Ozbek, G Demirpolat. Prenatal and postnatal findings in a case with the autosomal recessive type of Robinow syndrome.. Fetal Diagn Ther 2006;21:386-9",
"P Lirk, J Rieder, A Schuerholz, C Keller. Anaesthetic implications of Robinow syndrome.. Paediatr Anaesth 2003;13:725-7",
"I Macdonald, OR Dearlove. Anaesthesia and Robinow syndrome.. Anaesthesia. 1995;50:1097",
"P Masiakowski, RD Carroll. A novel family of cell surface receptors with tyrosine kinase-like domain.. J Biol Chem 1992;267:26181-90",
"T Matsuda, M Nomi, M Ikeya, S Kani, I Oishi, T Terashima, S Takada, Y Minami. Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development.. Mech Dev 2001;105:153-6",
"JF Mazzeu, E Pardono, AM Vianna-Morgante, A Richieri-Costa, C Ae Kim, D Brunoni, L Martelli, CE de Andrade, G Colin, PA Otto. Clinical characterization of autosomal dominant and recessive variants of Robinow syndrome.. Am J Med Genet A. 2007;143:320-5",
"M Oldridge, AM Fortuna, M Maringa, P Propping, S Mansour, C Pollitt, TM DeChiara, RB Kimble, DM Valenzuela, GD Yancopoulos, AO Wilkie. Dominant mutations in ROR2, encoding an orphan receptor tyrosine kinase, cause brachydactyly type B.. Nat Genet 2000;24:275-8",
"MA Patton, AR Afzal. Robinow syndrome.. J Med Genet. 2002;39:305-10",
"EF Percin, T Guvenal, A Cetin, S Percin, F Goze, S Arici. First-trimester diagnosis of Robinow syndrome.. Fetal Diagn Ther 2001;16:308-11",
"M Robinow, FN Silverman, HD Smith. A newly recognized dwarfing syndrome.. Am J Dis Child 1969;117:645-51",
"GC Schwabe, S Tinschert, C Buschow, P Meinecke, G Wolff, G Gillessen-Kaesbach, M Oldridge, AO Wilkie, R Komec, S Mundlos. Distinct mutations in the receptor tyrosine kinase gene ROR2 cause brachydactyly type B.. Am J Hum Genet 2000;67:822-31",
"W Schwarzer, F Witte, A Rajab, S Mundlos, S Stricker. A gradient of ROR2 protein stability and membrane localization confers brachydactyly type B or Robinow syndrome phenotypes.. Hum Mol Genet. 2009;18:4013-21",
"JB Sleesman, JD Tobias. Anaesthetic implications of the child with Robinow syndrome.. Paediatr Anaesth. 2003;13:629-32",
"AT Soliman, A Rajab, I Alsalmi, SM Bedair. Recessive Robinow syndrome: with emphasis on endocrine functions.. Metabolism 1998;47:1337-43",
"S Stricker, V Rauschenberger, A. Schambony. ROR-family receptor tyrosine kinases.. Curr Top Dev Biol. 2017;123:105-42",
"F Tufan, K Cefle, S Türkmen, A Türkmen, U Zorba, M Dursun, S Oztürk, S Palandüz, T Ecder, S Mundlos, D Horn. Clinical and molecular characterization of two adults with autosomal recessive Robinow syndrome.. Am J Med Genet A. 2005;136:185-9",
"H van Bokhoven, J Celli, H Kayserili, E van Beusekom, S Balci, W Brussel, F Skovby, B Kerr, EF Percin, N Akarsu, HG Brunner. Mutation of the gene encoding the ROR2 tyrosine kinase causes autosomal recessive Robinow syndrome.. Nat Genet 2000;25:423-6",
"CP Venditti, J Farmer, KL Russell, CA Friedrich, C Alter, D Canning, L Whitaker, MT Mennuti, DA Driscoll, EH Zackai. Omodysplasia: an affected mother and son.. Am J Med Genet 2002;111:169-77",
"JJ White, JF Mazzeu, Z Coban-Akdemir, Y Bayram, V Bahrambeigi, A Hoischen, BWM van Bon, A Gezdirici, EY Gulec, F Ramond, R Touraine, J Thevenon, M Shinawi, E Beaver, J Heeley, J Hoover-Fong, CD Durmaz, HG Karabulut, E Marzioglu-Ozdemir, A Cayir, MB Duz, M Seven, S Price, BM Ferreira, AM Vianna-Morgante, S Ellard, A Parrish, K Stals, J Flores-Daboub, SN Jhangiani, RA Gibbs, HG Brunner, VR Sutton, JR Lupski, CMB Carvalho. WNT signaling perturbations underlie the genetic heterogeneity of Robinow syndrome.. Am J Hum Genet. 2018;102:27-43",
"DT Wilcox, FMJ Quinn, CS Ng, C Mireaux-Dicks, PDE Mouriquand. Redefining the genital abnormality in the Robinow syndrome.. J Urol 1997;157:2312-4"
] |
28/7/2005
|
26/7/2018
|
12/9/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
rotor
|
rotor
|
[
"Rotor-Type Hyperbilirubinemia",
"Rotor-Type Hyperbilirubinemia",
"Solute carrier organic anion transporter family member 1B1",
"Solute carrier organic anion transporter family member 1B3",
"SLCO1B1",
"SLCO1B3",
"Rotor Syndrome"
] |
Rotor Syndrome
|
Milan Jirsa, AS Knisely, Alfred Schinkel, Stanislav Kmoch
|
Summary Rotor syndrome is characterized by mild conjugated and unconjugated hyperbilirubinemia that usually begins shortly after birth or in childhood. Jaundice may be intermittent. Conjunctival icterus may be the only clinical manifestation. The diagnosis of Rotor syndrome is established in a proband with isolated, predominantly conjugated hyperbilirubinemia without cholestatic liver injury and typical findings on cholescintigraphy. Identification of biallelic pathogenic variants in Rotor syndrome is inherited in an autosomal recessive digenic manner that clinically resembles monogenic autosomal recessive inheritance. (Although Rotor syndrome is a digenic disorder, pathogenic variants in
|
## Diagnosis
Rotor syndrome
Mild jaundice (may be intermittent)
Conjunctival icterus (in some affected individuals)
Otherwise normal physical examination
Conjugated hyperbilirubinemia with serum total bilirubin concentration usually between 2 and 5 mg/dL but possibly higher. Conjugated bilirubin usually exceeds 50% of total bilirubin.
Presence of bilirubin in the urine
Absence of hemolysis*
Normal serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) activity*
Total urinary porphyrins: elevated coproporphyrin
* Tests for hemolysis and measurements of ALT, AST, ALP, and GGT activity are needed to evaluate for hemolytic anemia and hepatobiliary diseases that are considered in the
Laboratory Findings in Rotor Syndrome
Rarely, levels exceeding 20 mg/dL are possible [
For total and direct bilirubin in persons older than age one year. Note: Although normal levels of total and direct bilirubin may be higher in the neonatal period and infancy, Rotor syndrome is not usually diagnosed in this age group.
Coproporphyrinuria is frequently observed in those with parenchymal liver diseases. It is not specific to Rotor syndrome.
The clinical diagnosis of Rotor syndrome can be
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 can include a combination of
For an introduction to multigene panels click
Molecular Genetic Testing Used in Rotor 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; exon or whole-gene deletions/duplications are frequent. 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, 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.
The Rotor syndrome locus comprises both
A splice site variant, a 7.2-kb deletion removing exon 13, a 6.1-kb LINE-1 (L1) insertion in intron 5, and a complex rearrangement in which insertion of L1 in intron 3 is directly followed by a 1185-bp inversion encompassing exon 4, were found in
Of the seven individuals reported by
• Mild jaundice (may be intermittent)
• Conjunctival icterus (in some affected individuals)
• Otherwise normal physical examination
• Conjugated hyperbilirubinemia with serum total bilirubin concentration usually between 2 and 5 mg/dL but possibly higher. Conjugated bilirubin usually exceeds 50% of total bilirubin.
• Presence of bilirubin in the urine
• Absence of hemolysis*
• Normal serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) activity*
• Total urinary porphyrins: elevated coproporphyrin
• For an introduction to multigene panels click
## Suggestive Findings
Rotor syndrome
Mild jaundice (may be intermittent)
Conjunctival icterus (in some affected individuals)
Otherwise normal physical examination
Conjugated hyperbilirubinemia with serum total bilirubin concentration usually between 2 and 5 mg/dL but possibly higher. Conjugated bilirubin usually exceeds 50% of total bilirubin.
Presence of bilirubin in the urine
Absence of hemolysis*
Normal serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) activity*
Total urinary porphyrins: elevated coproporphyrin
* Tests for hemolysis and measurements of ALT, AST, ALP, and GGT activity are needed to evaluate for hemolytic anemia and hepatobiliary diseases that are considered in the
Laboratory Findings in Rotor Syndrome
Rarely, levels exceeding 20 mg/dL are possible [
For total and direct bilirubin in persons older than age one year. Note: Although normal levels of total and direct bilirubin may be higher in the neonatal period and infancy, Rotor syndrome is not usually diagnosed in this age group.
Coproporphyrinuria is frequently observed in those with parenchymal liver diseases. It is not specific to Rotor syndrome.
• Mild jaundice (may be intermittent)
• Conjunctival icterus (in some affected individuals)
• Otherwise normal physical examination
• Conjugated hyperbilirubinemia with serum total bilirubin concentration usually between 2 and 5 mg/dL but possibly higher. Conjugated bilirubin usually exceeds 50% of total bilirubin.
• Presence of bilirubin in the urine
• Absence of hemolysis*
• Normal serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) activity*
• Total urinary porphyrins: elevated coproporphyrin
## Establishing the Diagnosis
The clinical diagnosis of Rotor syndrome can be
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 can include a combination of
For an introduction to multigene panels click
Molecular Genetic Testing Used in Rotor 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; exon or whole-gene deletions/duplications are frequent. 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, 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.
The Rotor syndrome locus comprises both
A splice site variant, a 7.2-kb deletion removing exon 13, a 6.1-kb LINE-1 (L1) insertion in intron 5, and a complex rearrangement in which insertion of L1 in intron 3 is directly followed by a 1185-bp inversion encompassing exon 4, were found in
Of the seven individuals reported by
• For an introduction to multigene panels click
## Clinical Diagnosis
The clinical diagnosis of Rotor syndrome can be
## Molecular Diagnosis
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 can include a combination of
For an introduction to multigene panels click
Molecular Genetic Testing Used in Rotor 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; exon or whole-gene deletions/duplications are frequent. 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, 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.
The Rotor syndrome locus comprises both
A splice site variant, a 7.2-kb deletion removing exon 13, a 6.1-kb LINE-1 (L1) insertion in intron 5, and a complex rearrangement in which insertion of L1 in intron 3 is directly followed by a 1185-bp inversion encompassing exon 4, were found in
Of the seven individuals reported by
• For an introduction to multigene panels click
## Other Testing
## Clinical Characteristics
The only clinical feature of Rotor syndrome is mild jaundice due to conjugated and unconjugated hyperbilirubinemia that usually begins shortly after birth or in childhood.
Jaundice may be intermittent. Conjunctival icterus may be the only clinical manifestation.
Hyperbilirubinemia develops only in persons with biallelic inactivating pathogenic variants in both
A combination of a variant that results in reduced activity in one allele of either
The prevalence of Rotor syndrome is unknown but is very low (<1:1,000,000).
A high carrier frequency of an insertion of a ~6.1-kb L1 retrotransposon in intron 5 of
## Clinical Description
The only clinical feature of Rotor syndrome is mild jaundice due to conjugated and unconjugated hyperbilirubinemia that usually begins shortly after birth or in childhood.
Jaundice may be intermittent. Conjunctival icterus may be the only clinical manifestation.
## Genotype-Phenotype Correlations
Hyperbilirubinemia develops only in persons with biallelic inactivating pathogenic variants in both
A combination of a variant that results in reduced activity in one allele of either
## Prevalence
The prevalence of Rotor syndrome is unknown but is very low (<1:1,000,000).
A high carrier frequency of an insertion of a ~6.1-kb L1 retrotransposon in intron 5 of
## Genetically Related (Allelic) Disorders
Sequence variants that predict an amino acid change in
## Differential Diagnosis
Inherited disorders of bilirubin clearance can present with either conjugated or unconjugated hyperbilirubinemia. Dubin-Johnson syndrome, a benign conjugated hyperbilirubinemia similar to Rotor syndrome, is caused by decreased secretion of conjugated bilirubin into bile. Defects in bilirubin conjugation resulting in increased levels of unconjugated bilirubin are represented by Gilbert syndrome, Crigler-Najjar syndrome type II, and Crigler-Najjar syndrome type I (a rare, severe, life-threatening disease associated with kernicterus typically manifesting within the first days after birth). Since Rotor syndrome is usually diagnosed after the neonatal period, only benign forms of genetic jaundice are included in the differential diagnosis (see
Benign Forms of Genetic Jaundice in the Differential Diagnosis of Rotor Syndrome
Benign
Hyperbilirubinemia (<6 mg/dL) is predominantly unconjugated, w/conjugated bilirubin <20% of total serum bilirubin.
Most frequently occurring form of hereditary jaundice, affecting ~5%-10% of all Europeans
Benign
Hyperbilirubinemia is predominantly unconjugated (range: 6-20 mg/dL).
More common than Rotor syndrome
In addition to jaundice, abdominal pain & hepatomegaly may be present in some persons w/DJS, although DJS is typically benign.
Caused by pathogenic variants in
Caused by pathogenic variants in the coding region of
Disorder of secretion of conjugated bilirubin into bile.
Comparison of Findings in Dubin-Johnson Syndrome and Rotor Syndrome
Rarely, levels exceeding 20 mg/dL are possible [
For total and direct bilirubin in persons older than age one year. Note: Although normal levels of total and direct bilirubin may be higher in the neonatal period and infancy, Rotor syndrome is not usually diagnosed in this age group.
Serum alanine transaminase (ALT), aspartate transaminase (AST), alkaline phosphatase (ALP), and gamma-glutamyl transferase (GGT) activity
Red blood count and reticulocyte count
Total urinary porphyrin output is normal; however, predominance of coproporphyrin isomer I among urinary porphyrin species is observed on chromatography.
Total urinary porphyrin output
Includes bromosulfophthalein (BSP), indocyanine green, and cholescintigraphy radiotracers (
• Benign
• Hyperbilirubinemia (<6 mg/dL) is predominantly unconjugated, w/conjugated bilirubin <20% of total serum bilirubin.
• Most frequently occurring form of hereditary jaundice, affecting ~5%-10% of all Europeans
• Benign
• Hyperbilirubinemia is predominantly unconjugated (range: 6-20 mg/dL).
• More common than Rotor syndrome
• In addition to jaundice, abdominal pain & hepatomegaly may be present in some persons w/DJS, although DJS is typically benign.
## Management
No clinical practice guidelines for Rotor syndrome have been published as no treatment or surveillance is recommended.
In most instances an individual diagnosed with Rotor syndrome is the child of a consanguineous couple. In some centers, identification of consanguinity may be an indication for consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant).
No treatment is required.
No adverse drug effects have been documented in Rotor syndrome; however, the absence of the hepatic proteins SLCO1B1 and SLCO1B3 may have serious consequences for liver uptake and toxicity of numerous commonly used drugs and/or their metabolites, which enter the liver via either of the two OATP1B transporters.
A list of drugs that enter the liver mainly via SLCO1B1 and whose pharmacokinetics are known to be influenced by genetic variability in
Statins – simvastatin, atorvastatin, pravastatin, pitavastatin, rosuvastatin
Ezetimibe
Anticancer drugs – methotrexate and irinotecan, cabazitaxel, some tyrosine kinase inhibitors (e.g., sunitinib)
Sartans – olmesartan and valsartan
Rifampicin
Mycophenolic acid
Torsemide
Thiazolidine diones – pioglitazone and rosiglitazone
Glinides – nateglinide and repaglinide
Lopinavir
Fexofenadine
Cyclosporin A
See
No special pregnancy management issues from the perspective of either an affected mother or an affected fetus are known.
Of note, during pregnancy the hyperbilirubinemia of Rotor syndrome may complicate the diagnosis and management of liver disease related to pregnancy (e.g., intrahepatic cholestasis of pregnancy) and liver disease not related to pregnancy.
Search
• Statins – simvastatin, atorvastatin, pravastatin, pitavastatin, rosuvastatin
• Ezetimibe
• Anticancer drugs – methotrexate and irinotecan, cabazitaxel, some tyrosine kinase inhibitors (e.g., sunitinib)
• Sartans – olmesartan and valsartan
• Rifampicin
• Mycophenolic acid
• Torsemide
• Thiazolidine diones – pioglitazone and rosiglitazone
• Glinides – nateglinide and repaglinide
• Lopinavir
• Fexofenadine
• Cyclosporin A
## Evaluations Following Initial Diagnosis
In most instances an individual diagnosed with Rotor syndrome is the child of a consanguineous couple. In some centers, identification of consanguinity may be an indication for consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant).
## Treatment of Manifestations
No treatment is required.
## Agents/Circumstances to Avoid
No adverse drug effects have been documented in Rotor syndrome; however, the absence of the hepatic proteins SLCO1B1 and SLCO1B3 may have serious consequences for liver uptake and toxicity of numerous commonly used drugs and/or their metabolites, which enter the liver via either of the two OATP1B transporters.
A list of drugs that enter the liver mainly via SLCO1B1 and whose pharmacokinetics are known to be influenced by genetic variability in
Statins – simvastatin, atorvastatin, pravastatin, pitavastatin, rosuvastatin
Ezetimibe
Anticancer drugs – methotrexate and irinotecan, cabazitaxel, some tyrosine kinase inhibitors (e.g., sunitinib)
Sartans – olmesartan and valsartan
Rifampicin
Mycophenolic acid
Torsemide
Thiazolidine diones – pioglitazone and rosiglitazone
Glinides – nateglinide and repaglinide
Lopinavir
Fexofenadine
Cyclosporin A
• Statins – simvastatin, atorvastatin, pravastatin, pitavastatin, rosuvastatin
• Ezetimibe
• Anticancer drugs – methotrexate and irinotecan, cabazitaxel, some tyrosine kinase inhibitors (e.g., sunitinib)
• Sartans – olmesartan and valsartan
• Rifampicin
• Mycophenolic acid
• Torsemide
• Thiazolidine diones – pioglitazone and rosiglitazone
• Glinides – nateglinide and repaglinide
• Lopinavir
• Fexofenadine
• Cyclosporin A
## Evaluation of Relatives at Risk
See
## Pregnancy Management
No special pregnancy management issues from the perspective of either an affected mother or an affected fetus are known.
Of note, during pregnancy the hyperbilirubinemia of Rotor syndrome may complicate the diagnosis and management of liver disease related to pregnancy (e.g., intrahepatic cholestasis of pregnancy) and liver disease not related to pregnancy.
## Therapies Under Investigation
Search
## Genetic Counseling
Rotor syndrome is inherited in an autosomal recessive digenic manner. It is caused by biallelic pathogenic variants in both
Note: Although Rotor syndrome is a digenic disorder, pathogenic variants in
The parents of an affected child are presumed to be heterozygous for pathogenic variants in both
If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents of the proband can confirm their genetic status and allow reliable recurrence risk assessment.
Individuals with heterozygous
If both parents are known to be heterozygous for
Carriers (i.e., individuals with one, two, or three pathogenic variants) are asymptomatic and are not at risk of developing Rotor syndrome.
Carrier testing for at-risk relatives requires prior identification of the
Because most individuals with Rotor syndrome are born to consanguineous couples, the diagnosis of Rotor syndrome may coincidentally identify such consanguinity. In some centers, this may be an indication for clinical genetics consultation and/or genetic counseling.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 Rotor syndrome-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Requests for prenatal testing for benign, clinically unimportant conditions such as Rotor syndrome are not expected to be common. 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 pathogenic variants in both
• If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents of the proband can confirm their genetic status and allow reliable recurrence risk assessment.
• Individuals with heterozygous
• If both parents are known to be heterozygous for
• Carriers (i.e., individuals with one, two, or three pathogenic variants) are asymptomatic and are not at risk of developing Rotor 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, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Rotor syndrome is inherited in an autosomal recessive digenic manner. It is caused by biallelic pathogenic variants in both
Note: Although Rotor syndrome is a digenic disorder, pathogenic variants in
## Risk to Family Members
The parents of an affected child are presumed to be heterozygous for pathogenic variants in both
If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents of the proband can confirm their genetic status and allow reliable recurrence risk assessment.
Individuals with heterozygous
If both parents are known to be heterozygous for
Carriers (i.e., individuals with one, two, or three pathogenic variants) are asymptomatic and are not at risk of developing Rotor syndrome.
• The parents of an affected child are presumed to be heterozygous for pathogenic variants in both
• If a molecular diagnosis has been established in the proband, molecular genetic testing of the parents of the proband can confirm their genetic status and allow reliable recurrence risk assessment.
• Individuals with heterozygous
• If both parents are known to be heterozygous for
• Carriers (i.e., individuals with one, two, or three pathogenic variants) are asymptomatic and are not at risk of developing Rotor syndrome.
## Carrier Detection
Carrier testing for at-risk relatives requires prior identification of the
## Related Genetic Counseling Issues
Because most individuals with Rotor syndrome are born to consanguineous couples, the diagnosis of Rotor syndrome may coincidentally identify such consanguinity. In some centers, this may be an indication for clinical genetics consultation and/or genetic counseling.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 Rotor syndrome-causing pathogenic variants have been identified in an affected family member, prenatal and preimplantation genetic testing are possible.
Requests for prenatal testing for benign, clinically unimportant conditions such as Rotor syndrome are not expected to be common. 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
Rotor Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Rotor Syndrome (
In individuals with Rotor syndrome, liver histologic findings are normal; however, expression of SLCO1B1 (solute carrier organic anion transporter family member 1B1, encoded by
Deficiency of SLCO1B1 and SLCO1B3 also explains the poor uptake by the liver of unconjugated bilirubin and anionic dyes such as bromosulfophthalein, indocyanine green, and cholescintigraphy radiotracers (
Reduced hepatic (re)uptake of coproporphyrin isomers probably underlies the increased urinary excretion of coproporphyrins.
Gene-Specific Laboratory Considerations
## Molecular Pathogenesis
In individuals with Rotor syndrome, liver histologic findings are normal; however, expression of SLCO1B1 (solute carrier organic anion transporter family member 1B1, encoded by
Deficiency of SLCO1B1 and SLCO1B3 also explains the poor uptake by the liver of unconjugated bilirubin and anionic dyes such as bromosulfophthalein, indocyanine green, and cholescintigraphy radiotracers (
Reduced hepatic (re)uptake of coproporphyrin isomers probably underlies the increased urinary excretion of coproporphyrins.
Gene-Specific Laboratory Considerations
## Chapter Notes
Milan Jirsa (
Dr Jirsa is also interested in hearing from clinicians treating families affected by Rotor syndrome 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 Dr Jirsa to inquire about review of
Milan Jirsa has been supported by DRO IKEM IN 00023001.
27 February 2025 (sw) Comprehensive update posted live
11 July 2019 (sw) Comprehensive update posted live
13 December 2012 (bp) Review posted live
6 September 2012 (mj) Original submission
• 27 February 2025 (sw) Comprehensive update posted live
• 11 July 2019 (sw) Comprehensive update posted live
• 13 December 2012 (bp) Review posted live
• 6 September 2012 (mj) Original submission
## Author Notes
Milan Jirsa (
Dr Jirsa is also interested in hearing from clinicians treating families affected by Rotor syndrome 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 Dr Jirsa to inquire about review of
## Acknowledgments
Milan Jirsa has been supported by DRO IKEM IN 00023001.
## Revision History
27 February 2025 (sw) Comprehensive update posted live
11 July 2019 (sw) Comprehensive update posted live
13 December 2012 (bp) Review posted live
6 September 2012 (mj) Original submission
• 27 February 2025 (sw) Comprehensive update posted live
• 11 July 2019 (sw) Comprehensive update posted live
• 13 December 2012 (bp) Review posted live
• 6 September 2012 (mj) Original submission
## References
## Literature Cited
|
[] |
13/12/2012
|
27/2/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
rp-overview
|
rp-overview
|
[
"Adhesion G protein-coupled receptor A3",
"ADP-ribosylation factor-like protein 2-binding protein",
"ADP-ribosylation factor-like protein 3",
"ADP-ribosylation factor-like protein 6",
"BBSome complex member BBS1",
"BBSome complex member BBS2",
"Bestrophin-1",
"Carbonic anhydrase 4",
"CCA tRNA nucleotidyltransferase 1, mitochondrial",
"Centriole and centriolar satellite protein OFD1",
"Centrosomal protein kizuna",
"Ceramide kinase-like protein",
"Cilia- and flagella-associated protein 418",
"Clarin-1",
"Cone-rod homeobox protein",
"Cyclic nucleotide-gated channel alpha-1",
"Cyclic nucleotide-gated channel beta-1",
"Cytochrome P450 4V2",
"Cytosolic carboxypeptidase-like protein 5",
"Dehydrodolichyl diphosphate synthase complex subunit DHDDS",
"E3 ubiquitin-protein ligase Topors",
"ER membrane protein complex subunit 1",
"Fascin-2",
"Guanylyl cyclase-activating protein 2",
"Heparan-alpha-glucosaminide N-acetyltransferase",
"Hexokinase-1",
"Inosine-5'-monophosphate dehydrogenase 1",
"Interphotoreceptor matrix proteoglycan 2",
"Intraflagellar transport protein 140 homolog",
"Intraflagellar transport protein 172 homolog",
"Isocitrate dehydrogenase [NAD] subunit beta, mitochondrial",
"Kelch-like protein 7",
"Lecithin retinol acyltransferase",
"Mevalonate kinase",
"Neural retina-specific leucine zipper protein",
"Neurogenic differentiation factor 1",
"Oxygen-regulated protein 1",
"Peripherin-2",
"Photoreceptor cilium actin regulator",
"Photoreceptor disk component PRCD",
"Photoreceptor-specific nuclear receptor",
"Pre-mRNA-processing factor 6",
"Pre-mRNA-processing-splicing factor 8",
"Pre-mRNA-splicing factor ATP-dependent RNA helicase PRP16",
"Prominin-1",
"Protein crumbs homolog 1",
"Protein eyes shut homolog",
"Protein FAM161A",
"Protein O-linked-mannose beta-1,2-N-acetylglucosaminyltransferase 1",
"Protein XRP2",
"Retinal rod rhodopsin-sensitive cGMP 3',5'-cyclic phosphodiesterase subunit gamma",
"Retinaldehyde-binding protein 1",
"Retinal-specific phospholipid-transporting ATPase ABCA4",
"Retinitis pigmentosa 9 protein",
"Retinoid isomerohydrolase",
"Retinol dehydrogenase 12",
"Retinol-binding protein 3",
"Rhodopsin",
"Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit alpha",
"Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta",
"Rod outer segment membrane protein 1",
"RPE-retinal G protein-coupled receptor",
"S-arrestin",
"Secreted phosphoprotein 24",
"Semaphorin-4A",
"Serine/threonine-protein kinase MAK",
"Serine/threonine-protein kinase Nek2",
"Solute carrier family 7 member 14",
"Spermatogenesis-associated protein 7",
"Tetratricopeptide repeat protein 8",
"Tubby-related protein 1",
"Tyrosine-protein kinase Mer",
"U4/U6 small nuclear ribonucleoprotein Prp3",
"U4/U6 small nuclear ribonucleoprotein Prp31",
"U5 small nuclear ribonucleoprotein 200 kDa helicase",
"UPF0606 protein KIAA1549",
"Usherin",
"X-linked retinitis pigmentosa GTPase regulator",
"Zinc finger protein 408",
"Zinc finger protein 513",
"ABCA4",
"ADGRA3",
"AGBL5",
"ARL2BP",
"ARL3",
"ARL6",
"BBS1",
"BBS2",
"BEST1",
"CA4",
"CERKL",
"CFAP418",
"CLRN1",
"CNGA1",
"CNGB1",
"CRB1",
"CRX",
"CYP4V2",
"DHDDS",
"DHX38",
"EMC1",
"EYS",
"FAM161A",
"FSCN2",
"GUCA1B",
"HGSNAT",
"HK1",
"IDH3B",
"IFT140",
"IFT172",
"IMPDH1",
"IMPG2",
"KIAA1549",
"KIZ",
"KLHL7",
"LRAT",
"MAK",
"MERTK",
"MVK",
"NEK2",
"NEUROD1",
"NR2E3",
"NRL",
"OFD1",
"PCARE",
"PDE6A",
"PDE6B",
"PDE6G",
"POMGNT1",
"PRCD",
"PROM1",
"PRPF3",
"PRPF31",
"PRPF6",
"PRPF8",
"PRPH2",
"RBP3",
"RDH12",
"RGR",
"RHO",
"RLBP1",
"ROM1",
"RP1",
"RP2",
"RP9",
"RPE65",
"RPGR",
"SAG",
"SEMA4A",
"SLC7A14",
"SNRNP200",
"SPATA7",
"SPP2",
"TOPORS",
"TRNT1",
"TTC8",
"TULP1",
"USH2A",
"ZNF408",
"ZNF513",
"Nonsyndromic Retinitis Pigmentosa",
"Overview"
] |
Nonsyndromic Retinitis Pigmentosa Overview
|
Abigail T Fahim, Stephen P Daiger, Richard G Weleber
|
Summary The purpose of this overview is to: Describe the Review the Provide an Provide a brief summary of Inform
|
## Clinical Characteristics of Nonsyndromic Retinitis Pigmentosa
Retinitis pigmentosa (RP) refers to a group of inherited disorders in which abnormalities of the photoreceptors (rods and cones) of the retina lead to progressive visual loss. RP is classified as nonsyndromic, or "simple" (not affecting other organs or tissues); syndromic (affecting other neurosensory systems such as hearing); or systemic (affecting multiple tissues). This overview focuses on nonsyndromic forms of RP.
Some investigators have found a general correlation between age-related visual acuity and mode of inheritance.
The earliest observed changes in the fundus are arteriolar narrowing, fine dust-like intraretinal pigmentation, and loss of pigment from the pigment epithelium. As photoreceptor deterioration progresses, there is increasing loss of pigment from the pigment epithelium with intraretinal clumping of melanin, appearing most often as coarse clumps in a "bone spicule" configuration.
Moderate to severe retinal vessel attenuation and waxy pallor of the optic nerve become apparent in individuals with advanced RP. The cause of the retinal vessel attenuation is unknown, but it appears to be a secondary change and not the primary cause of disease.
Sectoral changes have been observed in autosomal dominant RP (e.g., in people with the common
The low incidence of sector RP may indicate its rarity, or may reflect the fact that the mildness of symptoms results in infrequent diagnosis.
Physiologic changes during pregnancy, such as increased thickness and curvature of the cornea and changes in the accommodative power of the lens, can alter a woman's refractive state.
Pregnant women are at increased risk for central serous retinopathy, progression of preexisting diabetic retinopathy, and other conditions that can affect vision.
Some woman with poor nutritional intake may be at increased risk for vitamin A deficiency and nyctalopia during pregnancy (for review see
A consensus conference [
Rod dysfunction as measured by one of the following:
Dark adaptation (elevated rod final threshold)
Electroretinogram (ERG) (nondetectable or severely reduced rod responses, with prolonged implicit time, often with lesser reduction and prolongation of cone-mediated responses)
Progressive loss in photoreceptor function
Loss of peripheral vision that often is greater superiorly but can involve other regions as well
Bilateral involvement that has a high degree of symmetry, with respect to both the severity and the pattern of visual field loss and retinal changes
The American Academy of Ophthalmology (AAO) Recommendations on Clinical Assessment of Patients with Inherited Retinal Degenerations [
Ocular and medical history
Pedigree detailing the family history of eye disease
Clinical eye examination
Best corrected visual acuity (BCVA)
Slit lamp biomicroscopy
Intraocular pressure
Indirect ophthalmoscopy
Imaging
Color fundus photos
Fundus autofluorescence (reduced illumination when possible)
Spectral domain optical coherence tomography (sdOCT)
Visual fields
Full-field electroretinography (ffERG)
Molecular genetic testing (See
Recent advances in
The full-field ERG (ffERG) stimulates and records responses from the entire retina and has traditionally been used to follow disease progression in people with retinitis pigmentosa.
The multifocal ERG (mfERG) stimulates the central retina only and, thus, can record local responses across the macula. The mfERG can detect residual macular function in individuals with advanced disease from RP and – in conjunction with the ffERG – distinguish cone-rod degeneration from rod-cone degeneration. Therefore, it is useful in long-term follow up as well as monitoring of visual function in clinical trials involving advanced RP [
It should be noted that individuals who present with initial symptoms of photopsia (sensation of lights flashing), abnormal central vision, abnormal color vision, or marked asymmetry in ocular involvement may not have RP, but another retinal degeneration or retinal disease.
Some disorders to consider in the differential diagnosis of typical retinitis pigmentosa (RP) are listed below. In many instances, they are caused by pathogenic variants in the same genes implicated in RP.
Usher syndrome type III. Bilateral variable sensorineural hearing loss, vestibular dysfunction, and RP – all of which are slowly progressive
It is important to note the three inherited disorders with retinal degeneration and systemic manifestations for which treatment exists.
Many non-inherited causes of retinal inflammation can present with fundus findings similar to retinitis pigmentosa, including trauma, infection, autoimmune retinopathy, and drug toxicity [
The prevalence of RP is 1:3,000 to 1:7,000 persons, or 14 to 33 per 100,000 [
RP shows no ethnic predilection; however, the spectrum of pathogenic variants within a given RP-associated gene may vary between populations. This is especially true for certain isolated populations or those with a high rate of consanguinity. Furthermore, the frequency of a specific dominant or recessive pathogenic variant may be common in a particular population as a result of a founder effect or may change due to genetic drift. For example, the
• Rod dysfunction as measured by one of the following:
• Dark adaptation (elevated rod final threshold)
• Electroretinogram (ERG) (nondetectable or severely reduced rod responses, with prolonged implicit time, often with lesser reduction and prolongation of cone-mediated responses)
• Dark adaptation (elevated rod final threshold)
• Electroretinogram (ERG) (nondetectable or severely reduced rod responses, with prolonged implicit time, often with lesser reduction and prolongation of cone-mediated responses)
• Progressive loss in photoreceptor function
• Loss of peripheral vision that often is greater superiorly but can involve other regions as well
• Bilateral involvement that has a high degree of symmetry, with respect to both the severity and the pattern of visual field loss and retinal changes
• Dark adaptation (elevated rod final threshold)
• Electroretinogram (ERG) (nondetectable or severely reduced rod responses, with prolonged implicit time, often with lesser reduction and prolongation of cone-mediated responses)
• Ocular and medical history
• Pedigree detailing the family history of eye disease
• Clinical eye examination
• Best corrected visual acuity (BCVA)
• Slit lamp biomicroscopy
• Intraocular pressure
• Indirect ophthalmoscopy
• Best corrected visual acuity (BCVA)
• Slit lamp biomicroscopy
• Intraocular pressure
• Indirect ophthalmoscopy
• Imaging
• Color fundus photos
• Fundus autofluorescence (reduced illumination when possible)
• Spectral domain optical coherence tomography (sdOCT)
• Color fundus photos
• Fundus autofluorescence (reduced illumination when possible)
• Spectral domain optical coherence tomography (sdOCT)
• Visual fields
• Full-field electroretinography (ffERG)
• Molecular genetic testing (See
• Best corrected visual acuity (BCVA)
• Slit lamp biomicroscopy
• Intraocular pressure
• Indirect ophthalmoscopy
• Color fundus photos
• Fundus autofluorescence (reduced illumination when possible)
• Spectral domain optical coherence tomography (sdOCT)
• Usher syndrome type III. Bilateral variable sensorineural hearing loss, vestibular dysfunction, and RP – all of which are slowly progressive
## Clinical Manifestations of Retinitis Pigmentosa
Some investigators have found a general correlation between age-related visual acuity and mode of inheritance.
The earliest observed changes in the fundus are arteriolar narrowing, fine dust-like intraretinal pigmentation, and loss of pigment from the pigment epithelium. As photoreceptor deterioration progresses, there is increasing loss of pigment from the pigment epithelium with intraretinal clumping of melanin, appearing most often as coarse clumps in a "bone spicule" configuration.
Moderate to severe retinal vessel attenuation and waxy pallor of the optic nerve become apparent in individuals with advanced RP. The cause of the retinal vessel attenuation is unknown, but it appears to be a secondary change and not the primary cause of disease.
Sectoral changes have been observed in autosomal dominant RP (e.g., in people with the common
The low incidence of sector RP may indicate its rarity, or may reflect the fact that the mildness of symptoms results in infrequent diagnosis.
Physiologic changes during pregnancy, such as increased thickness and curvature of the cornea and changes in the accommodative power of the lens, can alter a woman's refractive state.
Pregnant women are at increased risk for central serous retinopathy, progression of preexisting diabetic retinopathy, and other conditions that can affect vision.
Some woman with poor nutritional intake may be at increased risk for vitamin A deficiency and nyctalopia during pregnancy (for review see
## Establishing the Clinical Diagnosis of Retinitis Pigmentosa
A consensus conference [
Rod dysfunction as measured by one of the following:
Dark adaptation (elevated rod final threshold)
Electroretinogram (ERG) (nondetectable or severely reduced rod responses, with prolonged implicit time, often with lesser reduction and prolongation of cone-mediated responses)
Progressive loss in photoreceptor function
Loss of peripheral vision that often is greater superiorly but can involve other regions as well
Bilateral involvement that has a high degree of symmetry, with respect to both the severity and the pattern of visual field loss and retinal changes
The American Academy of Ophthalmology (AAO) Recommendations on Clinical Assessment of Patients with Inherited Retinal Degenerations [
Ocular and medical history
Pedigree detailing the family history of eye disease
Clinical eye examination
Best corrected visual acuity (BCVA)
Slit lamp biomicroscopy
Intraocular pressure
Indirect ophthalmoscopy
Imaging
Color fundus photos
Fundus autofluorescence (reduced illumination when possible)
Spectral domain optical coherence tomography (sdOCT)
Visual fields
Full-field electroretinography (ffERG)
Molecular genetic testing (See
Recent advances in
The full-field ERG (ffERG) stimulates and records responses from the entire retina and has traditionally been used to follow disease progression in people with retinitis pigmentosa.
The multifocal ERG (mfERG) stimulates the central retina only and, thus, can record local responses across the macula. The mfERG can detect residual macular function in individuals with advanced disease from RP and – in conjunction with the ffERG – distinguish cone-rod degeneration from rod-cone degeneration. Therefore, it is useful in long-term follow up as well as monitoring of visual function in clinical trials involving advanced RP [
• Rod dysfunction as measured by one of the following:
• Dark adaptation (elevated rod final threshold)
• Electroretinogram (ERG) (nondetectable or severely reduced rod responses, with prolonged implicit time, often with lesser reduction and prolongation of cone-mediated responses)
• Dark adaptation (elevated rod final threshold)
• Electroretinogram (ERG) (nondetectable or severely reduced rod responses, with prolonged implicit time, often with lesser reduction and prolongation of cone-mediated responses)
• Progressive loss in photoreceptor function
• Loss of peripheral vision that often is greater superiorly but can involve other regions as well
• Bilateral involvement that has a high degree of symmetry, with respect to both the severity and the pattern of visual field loss and retinal changes
• Dark adaptation (elevated rod final threshold)
• Electroretinogram (ERG) (nondetectable or severely reduced rod responses, with prolonged implicit time, often with lesser reduction and prolongation of cone-mediated responses)
• Ocular and medical history
• Pedigree detailing the family history of eye disease
• Clinical eye examination
• Best corrected visual acuity (BCVA)
• Slit lamp biomicroscopy
• Intraocular pressure
• Indirect ophthalmoscopy
• Best corrected visual acuity (BCVA)
• Slit lamp biomicroscopy
• Intraocular pressure
• Indirect ophthalmoscopy
• Imaging
• Color fundus photos
• Fundus autofluorescence (reduced illumination when possible)
• Spectral domain optical coherence tomography (sdOCT)
• Color fundus photos
• Fundus autofluorescence (reduced illumination when possible)
• Spectral domain optical coherence tomography (sdOCT)
• Visual fields
• Full-field electroretinography (ffERG)
• Molecular genetic testing (See
• Best corrected visual acuity (BCVA)
• Slit lamp biomicroscopy
• Intraocular pressure
• Indirect ophthalmoscopy
• Color fundus photos
• Fundus autofluorescence (reduced illumination when possible)
• Spectral domain optical coherence tomography (sdOCT)
## Differential Diagnosis of Nonsyndromic Retinitis Pigmentosa
It should be noted that individuals who present with initial symptoms of photopsia (sensation of lights flashing), abnormal central vision, abnormal color vision, or marked asymmetry in ocular involvement may not have RP, but another retinal degeneration or retinal disease.
Some disorders to consider in the differential diagnosis of typical retinitis pigmentosa (RP) are listed below. In many instances, they are caused by pathogenic variants in the same genes implicated in RP.
Usher syndrome type III. Bilateral variable sensorineural hearing loss, vestibular dysfunction, and RP – all of which are slowly progressive
It is important to note the three inherited disorders with retinal degeneration and systemic manifestations for which treatment exists.
Many non-inherited causes of retinal inflammation can present with fundus findings similar to retinitis pigmentosa, including trauma, infection, autoimmune retinopathy, and drug toxicity [
• Usher syndrome type III. Bilateral variable sensorineural hearing loss, vestibular dysfunction, and RP – all of which are slowly progressive
## Treatable Disorders
It is important to note the three inherited disorders with retinal degeneration and systemic manifestations for which treatment exists.
## Non-Inherited Retinopathies
Many non-inherited causes of retinal inflammation can present with fundus findings similar to retinitis pigmentosa, including trauma, infection, autoimmune retinopathy, and drug toxicity [
## Prevalence of Retinitis Pigmentosa
The prevalence of RP is 1:3,000 to 1:7,000 persons, or 14 to 33 per 100,000 [
RP shows no ethnic predilection; however, the spectrum of pathogenic variants within a given RP-associated gene may vary between populations. This is especially true for certain isolated populations or those with a high rate of consanguinity. Furthermore, the frequency of a specific dominant or recessive pathogenic variant may be common in a particular population as a result of a founder effect or may change due to genetic drift. For example, the
## Causes of Nonsyndromic Retinitis Pigmentosa
Gene mapping and gene discovery have revealed unusually complicated molecular genetic causes of RP [
The complexity of RP is evident:
Nonsyndromic RP can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner. Rare digenic forms also occur. Digenic RP occurs in individuals who are heterozygous for both a
The likelihood of finding the underlying pathogenic variant(s) in an individual with RP depends on the type of disease, mode of inheritance, and testing methods used. In general, reported success rates using multigene panels, next-generation sequencing, or exome sequencing range from 50% to 80% [
Causes of Nonsyndromic Retinitis Pigmentosa by Mode of Inheritance
Simplex refers to a single reported occurrence of RP in a family.
Genes Associated with Nonsyndromic Autosomal Dominant Retinitis Pigmentosa (adRP)
Information is presented alphabetically by gene.
Data are compiled from the following standard references: gene from
See
OMIM gene description is provided if an OMIM retinitis pigmentosa phenotype description is not available.
For additional information including allelic disorders (i.e., other phenotypes associated with a pathogenic variant in a given gene) see
Noncoding variants have been identified that would not be detected by exome sequencing [
Genes Associated with Nonsyndromic Autosomal Recessive Retinitis Pigmentosa (arRP)
Information is presented alphabetically by gene.
Data are compiled from the following standard references: gene from
See
OMIM gene description is provided if an OMIM retinitis pigmentosa phenotype description is not available.
For additional information including allelic disorders (i.e., other phenotypes associated with a pathogenic variant in a given gene) see
Noncoding variants have been identified that would not be detected by exome sequencing [
The symptoms of nonsyndromic autosomal recessive RP may overlap with other autosomal recessive retinopathies, in particular, autosomal recessive early-onset RP and
Genes Associated with Nonsyndromic X-Linked RP (xlRP)
Information is presented alphabetically by gene.
Data are compiled from the following standard references: gene from
See
OMIM gene description is provided if an OMIM retinitis pigmentosa phenotype description is not available.
For additional information including allelic disorders (i.e., other phenotypes associated with mutation in a given gene) see
Pathogenic variants in
Of note, 15% of males with RP who are simplex cases (i.e., a single occurrence of RP in a family) have an
Retinal disease in females with xlRP is typically less severe than that seen in males; in contrast, in adRP males and females are, on average, equally affected. Because females heterozygous for a pathogenic variant in an X-linked RP-related gene may be unaffected or express mild to severe retinal degeneration [
Digenic RP is caused by the simultaneous presence of a pathogenic variant in
## Nonsyndromic Autosomal Dominant RP
Genes Associated with Nonsyndromic Autosomal Dominant Retinitis Pigmentosa (adRP)
Information is presented alphabetically by gene.
Data are compiled from the following standard references: gene from
See
OMIM gene description is provided if an OMIM retinitis pigmentosa phenotype description is not available.
For additional information including allelic disorders (i.e., other phenotypes associated with a pathogenic variant in a given gene) see
Noncoding variants have been identified that would not be detected by exome sequencing [
## Nonsyndromic Autosomal Recessive RP
Genes Associated with Nonsyndromic Autosomal Recessive Retinitis Pigmentosa (arRP)
Information is presented alphabetically by gene.
Data are compiled from the following standard references: gene from
See
OMIM gene description is provided if an OMIM retinitis pigmentosa phenotype description is not available.
For additional information including allelic disorders (i.e., other phenotypes associated with a pathogenic variant in a given gene) see
Noncoding variants have been identified that would not be detected by exome sequencing [
The symptoms of nonsyndromic autosomal recessive RP may overlap with other autosomal recessive retinopathies, in particular, autosomal recessive early-onset RP and
## Nonsyndromic X-Linked RP
Genes Associated with Nonsyndromic X-Linked RP (xlRP)
Information is presented alphabetically by gene.
Data are compiled from the following standard references: gene from
See
OMIM gene description is provided if an OMIM retinitis pigmentosa phenotype description is not available.
For additional information including allelic disorders (i.e., other phenotypes associated with mutation in a given gene) see
Pathogenic variants in
Of note, 15% of males with RP who are simplex cases (i.e., a single occurrence of RP in a family) have an
Retinal disease in females with xlRP is typically less severe than that seen in males; in contrast, in adRP males and females are, on average, equally affected. Because females heterozygous for a pathogenic variant in an X-linked RP-related gene may be unaffected or express mild to severe retinal degeneration [
## Digenic RP
Digenic RP is caused by the simultaneous presence of a pathogenic variant in
## Evaluation Strategy to Identify the Genetic Cause of Nonsyndromic Retinitis Pigmentosa in a Proband
The diagnosis of nonsyndromic retinitis pigmentosa
The recommendations of the American Academy of Ophthalmology (AAO) task force on genetic testing of inherited eye diseases:
Offer genetic testing to individuals with clinical findings suggestive of a Mendelian disorder the genetic cause(s) of which have been identified;
Use a Clinical Laboratories Improvement Amendments (CLIA)-certified lab;
Provide a copy of the genetic test report to the individual and avoid direct-to-consumer genetic testing [
Molecular genetic testing approaches can include a combination of
Targeted-gene testing requires the clinician to determine which gene(s) are likely involved, whereas genomic testing may not. Because the causes of nonsyndromic RP cannot in general be distinguished by clinical findings or family history, most individuals with nonsyndromic RP are diagnosed by use of the
For an introduction to multigene panels click
In any family with a
Note: Unlike exome sequencing, genome sequencing can identify noncoding variants. Although most confirmed pathogenic variants identified by genome sequencing are within exons [
For an introduction to comprehensive genomic testing click
• Offer genetic testing to individuals with clinical findings suggestive of a Mendelian disorder the genetic cause(s) of which have been identified;
• Use a Clinical Laboratories Improvement Amendments (CLIA)-certified lab;
• Provide a copy of the genetic test report to the individual and avoid direct-to-consumer genetic testing [
• In any family with a
## Recommended Testing
For an introduction to multigene panels click
In any family with a
• In any family with a
## Testing to Consider
Note: Unlike exome sequencing, genome sequencing can identify noncoding variants. Although most confirmed pathogenic variants identified by genome sequencing are within exons [
For an introduction to comprehensive genomic testing click
## Management of Nonsyndromic Retinitis Pigmentosa
The timing of lens extraction may change as an individual ages and the visual field becomes more constricted: most individuals with RP with a visual field greater than 10 degrees are not greatly incapacitated by mild to modest posterior subcapsular cataracts, whereas those with a visual field of less than 10 degrees usually report significantly improved vision following lens extraction [
Individuals with retinitis pigmentosa are at a greater-than-average risk for postoperative inflammation and induced CME. Thus, it is important at the time of lens extraction to avoid unnecessary manipulation of the iris; following surgery it is important to administer anti-inflammatory agents longer than would be indicated for individuals who do not have RP.
Various optical aids have been proposed for individuals with peripheral visual loss and preserved central vision, although all have drawbacks.
Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields.
Wide-field, high-intensity flashlights produce a bright wide beam of light and improve the nighttime mobility of individuals with RP. They are inexpensive and allow binocular viewing, but are large, heavy, and conspicuous.
Google Glass
Generally Goldmann visual field perimetry (GVF) or full-field static perimetry [
Modeling of full-field static perimetry with generation of volumetric indices that reflect both the magnitude and extent of visual field sensitivity are used: for monitoring for rate of progression; as endpoints for clinical trials [
Vitamin E may adversely affect the course of RP; thus, it is recommended that individuals with RP avoid high-dose supplements (e.g., 400 IU/d) [
Increased exposure to light has been demonstrated to accelerate progression in animal models of retinitis pigmentosa, particularly those with pathogenic variants in the gene encoding rhodopsin [
Smoking has been demonstrated as a strong risk factor for age-related macular degeneration [
Women of childbearing age need to be cautioned about potential teratogenic effects of high-dose vitamin A palmitate (see
Several trials of nutritional supplements to treat retinitis pigmentosa have been conducted with varying success; the results are often controversial [
Therapy with 15,000 IU per day of vitamin A palmitate has been reported to possibly slow changes in retinal function as detected by ERG [
High-dose vitamin A should not be used for individuals with ABCA4-deficient Stargardt disease or ABCA4-deficient autosomal recessive RP because it increases the accumulation of the toxic byproduct A2E [
Vitamin A palmitate therapy is not recommended for those under age 18 years.
Although liver toxicity with long-term use of vitamin A at 15,000 IU per day has not been noted [
Women of childbearing age need to be cautioned about potential teratogenic effects of high-dose vitamin A palmitate.
Because long-term high intake of vitamin A daily has been reported to increase several-fold the risk of osteoporosis, bone density should be monitored with such supplementation [
DHA therapy (1,200 mg/day) showed no effect on disease course in individuals receiving vitamin A palmitate [
DHA 400 mg/day showed no effect on visual acuity or visual field in males with xlRP, although RBC concentration of DHA correlated with preservation of cone ERG function [
A systematic literature review reported some improvement in outcomes with omega-3 fatty acid supplementation, but meta-analysis was not possible and additional studies are required [
A later study using a food questionnaire to estimate DHA intake in individuals with RP taking vitamin A palmitate demonstrated a slower decline in visual acuity in those with high DHA intake [
One study of oral supplementation with 20 mg/d lutein for six months demonstrated increased macular pigment in approximately 50% of individuals with RP or Usher syndrome but no change in central vision [
A Phase I/II clinical study showed that lutein supplementation had a significant effect on visual field, but no effect on visual acuity or contrast sensitivity [
A more recent clinical trial of lutein supplementation over four years in individuals also receiving vitamin A palmitate demonstrated no toxic effects from lutein and a slower loss of mid-peripheral visual field than in untreated individuals [
Gene therapy is being actively pursued for a number of retinal degenerations; published clinical trials have demonstrated limited success in individuals with
An ongoing trial is evaluating gene therapy for autosomal recessive
Multiple studies have investigated embryonic stem cells and induced pluripotent stem cells, which can be differentiated in vitro into retinal cell types and transplanted into animal retinas (for review, see
A Phase I/II clinical trial reported no safety concerns of transplanting stem cell-derived retinal pigment epithelial (RPE) cells in a small group of individuals with Stargardt disease, an inherited macular dystrophy, and age-related macular degeneration; however, to date no similar clinical trials have been performed for RP [
Search
• Therapy with 15,000 IU per day of vitamin A palmitate has been reported to possibly slow changes in retinal function as detected by ERG [
• High-dose vitamin A should not be used for individuals with ABCA4-deficient Stargardt disease or ABCA4-deficient autosomal recessive RP because it increases the accumulation of the toxic byproduct A2E [
• Vitamin A palmitate therapy is not recommended for those under age 18 years.
• Although liver toxicity with long-term use of vitamin A at 15,000 IU per day has not been noted [
• Women of childbearing age need to be cautioned about potential teratogenic effects of high-dose vitamin A palmitate.
• Because long-term high intake of vitamin A daily has been reported to increase several-fold the risk of osteoporosis, bone density should be monitored with such supplementation [
• DHA therapy (1,200 mg/day) showed no effect on disease course in individuals receiving vitamin A palmitate [
• DHA 400 mg/day showed no effect on visual acuity or visual field in males with xlRP, although RBC concentration of DHA correlated with preservation of cone ERG function [
• A systematic literature review reported some improvement in outcomes with omega-3 fatty acid supplementation, but meta-analysis was not possible and additional studies are required [
• A later study using a food questionnaire to estimate DHA intake in individuals with RP taking vitamin A palmitate demonstrated a slower decline in visual acuity in those with high DHA intake [
• One study of oral supplementation with 20 mg/d lutein for six months demonstrated increased macular pigment in approximately 50% of individuals with RP or Usher syndrome but no change in central vision [
• A Phase I/II clinical study showed that lutein supplementation had a significant effect on visual field, but no effect on visual acuity or contrast sensitivity [
• A more recent clinical trial of lutein supplementation over four years in individuals also receiving vitamin A palmitate demonstrated no toxic effects from lutein and a slower loss of mid-peripheral visual field than in untreated individuals [
## Treatment of Manifestations
The timing of lens extraction may change as an individual ages and the visual field becomes more constricted: most individuals with RP with a visual field greater than 10 degrees are not greatly incapacitated by mild to modest posterior subcapsular cataracts, whereas those with a visual field of less than 10 degrees usually report significantly improved vision following lens extraction [
Individuals with retinitis pigmentosa are at a greater-than-average risk for postoperative inflammation and induced CME. Thus, it is important at the time of lens extraction to avoid unnecessary manipulation of the iris; following surgery it is important to administer anti-inflammatory agents longer than would be indicated for individuals who do not have RP.
Various optical aids have been proposed for individuals with peripheral visual loss and preserved central vision, although all have drawbacks.
Low vision aids such as magnifiers and closed circuit television may provide useful reading vision for individuals with reduced central acuity and constricted visual fields.
Wide-field, high-intensity flashlights produce a bright wide beam of light and improve the nighttime mobility of individuals with RP. They are inexpensive and allow binocular viewing, but are large, heavy, and conspicuous.
Google Glass
## Surveillance
Generally Goldmann visual field perimetry (GVF) or full-field static perimetry [
Modeling of full-field static perimetry with generation of volumetric indices that reflect both the magnitude and extent of visual field sensitivity are used: for monitoring for rate of progression; as endpoints for clinical trials [
## Agents/Circumstances to Avoid
Vitamin E may adversely affect the course of RP; thus, it is recommended that individuals with RP avoid high-dose supplements (e.g., 400 IU/d) [
Increased exposure to light has been demonstrated to accelerate progression in animal models of retinitis pigmentosa, particularly those with pathogenic variants in the gene encoding rhodopsin [
Smoking has been demonstrated as a strong risk factor for age-related macular degeneration [
## Pregnancy Management
Women of childbearing age need to be cautioned about potential teratogenic effects of high-dose vitamin A palmitate (see
## Therapies Under Investigation
Several trials of nutritional supplements to treat retinitis pigmentosa have been conducted with varying success; the results are often controversial [
Therapy with 15,000 IU per day of vitamin A palmitate has been reported to possibly slow changes in retinal function as detected by ERG [
High-dose vitamin A should not be used for individuals with ABCA4-deficient Stargardt disease or ABCA4-deficient autosomal recessive RP because it increases the accumulation of the toxic byproduct A2E [
Vitamin A palmitate therapy is not recommended for those under age 18 years.
Although liver toxicity with long-term use of vitamin A at 15,000 IU per day has not been noted [
Women of childbearing age need to be cautioned about potential teratogenic effects of high-dose vitamin A palmitate.
Because long-term high intake of vitamin A daily has been reported to increase several-fold the risk of osteoporosis, bone density should be monitored with such supplementation [
DHA therapy (1,200 mg/day) showed no effect on disease course in individuals receiving vitamin A palmitate [
DHA 400 mg/day showed no effect on visual acuity or visual field in males with xlRP, although RBC concentration of DHA correlated with preservation of cone ERG function [
A systematic literature review reported some improvement in outcomes with omega-3 fatty acid supplementation, but meta-analysis was not possible and additional studies are required [
A later study using a food questionnaire to estimate DHA intake in individuals with RP taking vitamin A palmitate demonstrated a slower decline in visual acuity in those with high DHA intake [
One study of oral supplementation with 20 mg/d lutein for six months demonstrated increased macular pigment in approximately 50% of individuals with RP or Usher syndrome but no change in central vision [
A Phase I/II clinical study showed that lutein supplementation had a significant effect on visual field, but no effect on visual acuity or contrast sensitivity [
A more recent clinical trial of lutein supplementation over four years in individuals also receiving vitamin A palmitate demonstrated no toxic effects from lutein and a slower loss of mid-peripheral visual field than in untreated individuals [
Gene therapy is being actively pursued for a number of retinal degenerations; published clinical trials have demonstrated limited success in individuals with
An ongoing trial is evaluating gene therapy for autosomal recessive
Multiple studies have investigated embryonic stem cells and induced pluripotent stem cells, which can be differentiated in vitro into retinal cell types and transplanted into animal retinas (for review, see
A Phase I/II clinical trial reported no safety concerns of transplanting stem cell-derived retinal pigment epithelial (RPE) cells in a small group of individuals with Stargardt disease, an inherited macular dystrophy, and age-related macular degeneration; however, to date no similar clinical trials have been performed for RP [
Search
• Therapy with 15,000 IU per day of vitamin A palmitate has been reported to possibly slow changes in retinal function as detected by ERG [
• High-dose vitamin A should not be used for individuals with ABCA4-deficient Stargardt disease or ABCA4-deficient autosomal recessive RP because it increases the accumulation of the toxic byproduct A2E [
• Vitamin A palmitate therapy is not recommended for those under age 18 years.
• Although liver toxicity with long-term use of vitamin A at 15,000 IU per day has not been noted [
• Women of childbearing age need to be cautioned about potential teratogenic effects of high-dose vitamin A palmitate.
• Because long-term high intake of vitamin A daily has been reported to increase several-fold the risk of osteoporosis, bone density should be monitored with such supplementation [
• DHA therapy (1,200 mg/day) showed no effect on disease course in individuals receiving vitamin A palmitate [
• DHA 400 mg/day showed no effect on visual acuity or visual field in males with xlRP, although RBC concentration of DHA correlated with preservation of cone ERG function [
• A systematic literature review reported some improvement in outcomes with omega-3 fatty acid supplementation, but meta-analysis was not possible and additional studies are required [
• A later study using a food questionnaire to estimate DHA intake in individuals with RP taking vitamin A palmitate demonstrated a slower decline in visual acuity in those with high DHA intake [
• One study of oral supplementation with 20 mg/d lutein for six months demonstrated increased macular pigment in approximately 50% of individuals with RP or Usher syndrome but no change in central vision [
• A Phase I/II clinical study showed that lutein supplementation had a significant effect on visual field, but no effect on visual acuity or contrast sensitivity [
• A more recent clinical trial of lutein supplementation over four years in individuals also receiving vitamin A palmitate demonstrated no toxic effects from lutein and a slower loss of mid-peripheral visual field than in untreated individuals [
## Supplementation
Several trials of nutritional supplements to treat retinitis pigmentosa have been conducted with varying success; the results are often controversial [
Therapy with 15,000 IU per day of vitamin A palmitate has been reported to possibly slow changes in retinal function as detected by ERG [
High-dose vitamin A should not be used for individuals with ABCA4-deficient Stargardt disease or ABCA4-deficient autosomal recessive RP because it increases the accumulation of the toxic byproduct A2E [
Vitamin A palmitate therapy is not recommended for those under age 18 years.
Although liver toxicity with long-term use of vitamin A at 15,000 IU per day has not been noted [
Women of childbearing age need to be cautioned about potential teratogenic effects of high-dose vitamin A palmitate.
Because long-term high intake of vitamin A daily has been reported to increase several-fold the risk of osteoporosis, bone density should be monitored with such supplementation [
DHA therapy (1,200 mg/day) showed no effect on disease course in individuals receiving vitamin A palmitate [
DHA 400 mg/day showed no effect on visual acuity or visual field in males with xlRP, although RBC concentration of DHA correlated with preservation of cone ERG function [
A systematic literature review reported some improvement in outcomes with omega-3 fatty acid supplementation, but meta-analysis was not possible and additional studies are required [
A later study using a food questionnaire to estimate DHA intake in individuals with RP taking vitamin A palmitate demonstrated a slower decline in visual acuity in those with high DHA intake [
One study of oral supplementation with 20 mg/d lutein for six months demonstrated increased macular pigment in approximately 50% of individuals with RP or Usher syndrome but no change in central vision [
A Phase I/II clinical study showed that lutein supplementation had a significant effect on visual field, but no effect on visual acuity or contrast sensitivity [
A more recent clinical trial of lutein supplementation over four years in individuals also receiving vitamin A palmitate demonstrated no toxic effects from lutein and a slower loss of mid-peripheral visual field than in untreated individuals [
• Therapy with 15,000 IU per day of vitamin A palmitate has been reported to possibly slow changes in retinal function as detected by ERG [
• High-dose vitamin A should not be used for individuals with ABCA4-deficient Stargardt disease or ABCA4-deficient autosomal recessive RP because it increases the accumulation of the toxic byproduct A2E [
• Vitamin A palmitate therapy is not recommended for those under age 18 years.
• Although liver toxicity with long-term use of vitamin A at 15,000 IU per day has not been noted [
• Women of childbearing age need to be cautioned about potential teratogenic effects of high-dose vitamin A palmitate.
• Because long-term high intake of vitamin A daily has been reported to increase several-fold the risk of osteoporosis, bone density should be monitored with such supplementation [
• DHA therapy (1,200 mg/day) showed no effect on disease course in individuals receiving vitamin A palmitate [
• DHA 400 mg/day showed no effect on visual acuity or visual field in males with xlRP, although RBC concentration of DHA correlated with preservation of cone ERG function [
• A systematic literature review reported some improvement in outcomes with omega-3 fatty acid supplementation, but meta-analysis was not possible and additional studies are required [
• A later study using a food questionnaire to estimate DHA intake in individuals with RP taking vitamin A palmitate demonstrated a slower decline in visual acuity in those with high DHA intake [
• One study of oral supplementation with 20 mg/d lutein for six months demonstrated increased macular pigment in approximately 50% of individuals with RP or Usher syndrome but no change in central vision [
• A Phase I/II clinical study showed that lutein supplementation had a significant effect on visual field, but no effect on visual acuity or contrast sensitivity [
• A more recent clinical trial of lutein supplementation over four years in individuals also receiving vitamin A palmitate demonstrated no toxic effects from lutein and a slower loss of mid-peripheral visual field than in untreated individuals [
## Gene Therapy
Gene therapy is being actively pursued for a number of retinal degenerations; published clinical trials have demonstrated limited success in individuals with
An ongoing trial is evaluating gene therapy for autosomal recessive
## Stem Cells
Multiple studies have investigated embryonic stem cells and induced pluripotent stem cells, which can be differentiated in vitro into retinal cell types and transplanted into animal retinas (for review, see
A Phase I/II clinical trial reported no safety concerns of transplanting stem cell-derived retinal pigment epithelial (RPE) cells in a small group of individuals with Stargardt disease, an inherited macular dystrophy, and age-related macular degeneration; however, to date no similar clinical trials have been performed for RP [
## Other
Search
## Genetic Risk Assessment
Nonsyndromic forms of retinitis pigmentosa (RP) can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner depending on the gene involved. Rare digenic forms also occur (see
Note: Pedigree analysis may not be reliable in determining mode of inheritance, as both xlRP and arRP pedigrees can be consistent with autosomal dominant inheritance (see
If a parent is affected, the risk to the sibs is 50%.
If the RP-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one RP-related pathogenic variant).
Heterozygotes for a pathogenic variant causing arRP are asymptomatic in most cases.
At conception, each sib 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 for a pathogenic variant causing arRP are asymptomatic in most cases.
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 pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
If the mother of the proband has an pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not have symptoms [
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.
All of their daughters, who will be heterozygotes and may or may not have symptoms;
None of their sons.
Autosomal recessive inheritance with no affected sibs
Autosomal dominant or X-linked inheritance with reduced penetrance in prior generations
Reduced or inaccurate reporting of family history
Once the RP-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for RP are possible. However, clinical severity (which can range from mild to severe) and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression cannot be predicted based on the results of molecular 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.
• If a parent is affected, the risk to the sibs is 50%.
• If the RP-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one RP-related pathogenic variant).
• Heterozygotes for a pathogenic variant causing arRP are asymptomatic in most cases.
• At conception, each sib 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 for a pathogenic variant causing arRP are asymptomatic in most cases.
• 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 pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
• If the mother of the proband has an pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not have symptoms [
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.
• All of their daughters, who will be heterozygotes and may or may not have symptoms;
• None of their sons.
• Autosomal recessive inheritance with no affected sibs
• Autosomal dominant or X-linked inheritance with reduced penetrance in prior generations
• Reduced or inaccurate reporting of family history
## Mode of Inheritance
Nonsyndromic forms of retinitis pigmentosa (RP) can be inherited in an autosomal dominant, autosomal recessive, or X-linked manner depending on the gene involved. Rare digenic forms also occur (see
Note: Pedigree analysis may not be reliable in determining mode of inheritance, as both xlRP and arRP pedigrees can be consistent with autosomal dominant inheritance (see
## Autosomal Dominant RP (adRP) – Risk to Family Members
If a parent is affected, the risk to the sibs is 50%.
If the RP-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.
• If a parent is affected, the risk to the sibs is 50%.
• If the RP-related pathogenic variant found in the proband cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of parental germline mosaicism.
## Autosomal Recessive RP (arRP) – Risk to Family Members
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one RP-related pathogenic variant).
Heterozygotes for a pathogenic variant causing arRP are asymptomatic in most cases.
At conception, each sib 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 for a pathogenic variant causing arRP are asymptomatic in most cases.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one RP-related pathogenic variant).
• Heterozygotes for a pathogenic variant causing arRP are asymptomatic in most cases.
• At conception, each sib 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 for a pathogenic variant causing arRP are asymptomatic in most cases.
## X-Linked RP (xlRP) – 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 pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
If the mother of the proband has an pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not have symptoms [
If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.
All of their daughters, who will be heterozygotes and may or may not have symptoms;
None of their sons.
• 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 pathogenic variant cannot be detected in her leukocyte DNA, she has germline mosaicism.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a heterozygote or the affected male may have a
• If the mother of the proband has an pathogenic variant, the chance of transmitting it in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and may or may not have symptoms [
• If the proband represents a simplex case (i.e., a single occurrence in a family) and if the pathogenic variant cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population (though still <1%) because of the possibility of maternal germline mosaicism.
• All of their daughters, who will be heterozygotes and may or may not have symptoms;
• None of their sons.
## Related Genetic Counseling Issues
Autosomal recessive inheritance with no affected sibs
Autosomal dominant or X-linked inheritance with reduced penetrance in prior generations
Reduced or inaccurate reporting of family history
• Autosomal recessive inheritance with no affected sibs
• Autosomal dominant or X-linked inheritance with reduced penetrance in prior generations
• Reduced or inaccurate reporting of family history
## Determining Mode of Inheritance
Autosomal recessive inheritance with no affected sibs
Autosomal dominant or X-linked inheritance with reduced penetrance in prior generations
Reduced or inaccurate reporting of family history
• Autosomal recessive inheritance with no affected sibs
• Autosomal dominant or X-linked inheritance with reduced penetrance in prior generations
• Reduced or inaccurate reporting of family history
## Prenatal Testing and Preimplantation Genetic Testing
Once the RP-related pathogenic variant(s) have been identified in an affected family member, prenatal and preimplantation genetic testing for RP are possible. However, clinical severity (which can range from mild to severe) and disease phenotype often differ among individuals with the same pathogenic variant; thus, age of onset and/or disease progression cannot be predicted based on the results of molecular 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
Ireland
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•
•
•
•
•
•
• Ireland
•
## Chapter Notes
Stephen P Daiger, PhD (2000-present)Abigail Fahim, MD, PhD (2013-present)Roberta A Pagon, MD; University of Washington (2000-2013)Richard G Weleber, MD, DABMG, FACMG (2013-present)
6 April 2023 (gm) Revision: information about likely pathogenic variants in noncoding regions detected by genome sequencing added to
19 January 2017 (bp) Comprehensive update posted live
21 March 2013 (me) Comprehensive update posted live
16 September 2005 (me) Comprehensive update posted live
23 June 2003 (me) Comprehensive update posted live
4 August 2000 (bp, me) Overview posted live
November 1997 (bp, sd) Original submission
• 6 April 2023 (gm) Revision: information about likely pathogenic variants in noncoding regions detected by genome sequencing added to
• 19 January 2017 (bp) Comprehensive update posted live
• 21 March 2013 (me) Comprehensive update posted live
• 16 September 2005 (me) Comprehensive update posted live
• 23 June 2003 (me) Comprehensive update posted live
• 4 August 2000 (bp, me) Overview posted live
• November 1997 (bp, sd) Original submission
## Author History
Stephen P Daiger, PhD (2000-present)Abigail Fahim, MD, PhD (2013-present)Roberta A Pagon, MD; University of Washington (2000-2013)Richard G Weleber, MD, DABMG, FACMG (2013-present)
## Revision History
6 April 2023 (gm) Revision: information about likely pathogenic variants in noncoding regions detected by genome sequencing added to
19 January 2017 (bp) Comprehensive update posted live
21 March 2013 (me) Comprehensive update posted live
16 September 2005 (me) Comprehensive update posted live
23 June 2003 (me) Comprehensive update posted live
4 August 2000 (bp, me) Overview posted live
November 1997 (bp, sd) Original submission
• 6 April 2023 (gm) Revision: information about likely pathogenic variants in noncoding regions detected by genome sequencing added to
• 19 January 2017 (bp) Comprehensive update posted live
• 21 March 2013 (me) Comprehensive update posted live
• 16 September 2005 (me) Comprehensive update posted live
• 23 June 2003 (me) Comprehensive update posted live
• 4 August 2000 (bp, me) Overview posted live
• November 1997 (bp, sd) Original submission
## References
## Literature Cited
|
[] |
4/8/2000
|
19/1/2017
|
6/4/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
rpe65-lca
|
rpe65-lca
|
[
"RPE65-Related LCA/EOSRD",
"RPE65-Related LCA / EOSRD",
"Retinoid isomerohydrolase",
"RPE65",
"RPE65-Related Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy"
] |
Daniel L Chao, Amanda Burr, Mark Pennesi
|
Summary The diagnosis of Subretinal gene augmentation, an FDA-approved therapy, compensates for loss-of-function
|
## Diagnosis
Symptomatic onset between birth and age five years
Roving eye movements or nystagmus
Poor pupillary light responses in some
Profound nyctalopia
Oculodigital sign (i.e., poking, rubbing or pressing on the eye in order to stimulate phosphenes for visual perception). Once considered pathognomonic for LCA, the oculodigital sign is also found in other types of severe visual impairment and is not typically observed in
Central visual acuity decreased to the 20/100 range (which can be variably preserved if initial manifestations are between ages 1 and 5 years). Generally, central visual acuity is worse when onset is before age one year compared to onset between ages one and five years.
Fundus examination that can be quite variable and can appear normal at presentation. Associated findings include RPE mottling, pigmentary retinopathy with attenuated vessels, optic nerve pallor, white spots at the level of the RPE, parafoveal RPE loss as a bull's eye maculopathy, and optic disc drusen (see
Note: While two studies suggest that OCT in
The diagnosis of
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 of the extensive genetic heterogeneity of LCA/EOSRD (see
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 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 deletion of exons 1-7 has been reported by
• Symptomatic onset between birth and age five years
• Roving eye movements or nystagmus
• Poor pupillary light responses in some
• Profound nyctalopia
• Oculodigital sign (i.e., poking, rubbing or pressing on the eye in order to stimulate phosphenes for visual perception). Once considered pathognomonic for LCA, the oculodigital sign is also found in other types of severe visual impairment and is not typically observed in
• Central visual acuity decreased to the 20/100 range (which can be variably preserved if initial manifestations are between ages 1 and 5 years). Generally, central visual acuity is worse when onset is before age one year compared to onset between ages one and five years.
• Fundus examination that can be quite variable and can appear normal at presentation. Associated findings include RPE mottling, pigmentary retinopathy with attenuated vessels, optic nerve pallor, white spots at the level of the RPE, parafoveal RPE loss as a bull's eye maculopathy, and optic disc drusen (see
• Note: While two studies suggest that OCT in
## Suggestive Findings
Symptomatic onset between birth and age five years
Roving eye movements or nystagmus
Poor pupillary light responses in some
Profound nyctalopia
Oculodigital sign (i.e., poking, rubbing or pressing on the eye in order to stimulate phosphenes for visual perception). Once considered pathognomonic for LCA, the oculodigital sign is also found in other types of severe visual impairment and is not typically observed in
Central visual acuity decreased to the 20/100 range (which can be variably preserved if initial manifestations are between ages 1 and 5 years). Generally, central visual acuity is worse when onset is before age one year compared to onset between ages one and five years.
Fundus examination that can be quite variable and can appear normal at presentation. Associated findings include RPE mottling, pigmentary retinopathy with attenuated vessels, optic nerve pallor, white spots at the level of the RPE, parafoveal RPE loss as a bull's eye maculopathy, and optic disc drusen (see
Note: While two studies suggest that OCT in
• Symptomatic onset between birth and age five years
• Roving eye movements or nystagmus
• Poor pupillary light responses in some
• Profound nyctalopia
• Oculodigital sign (i.e., poking, rubbing or pressing on the eye in order to stimulate phosphenes for visual perception). Once considered pathognomonic for LCA, the oculodigital sign is also found in other types of severe visual impairment and is not typically observed in
• Central visual acuity decreased to the 20/100 range (which can be variably preserved if initial manifestations are between ages 1 and 5 years). Generally, central visual acuity is worse when onset is before age one year compared to onset between ages one and five years.
• Fundus examination that can be quite variable and can appear normal at presentation. Associated findings include RPE mottling, pigmentary retinopathy with attenuated vessels, optic nerve pallor, white spots at the level of the RPE, parafoveal RPE loss as a bull's eye maculopathy, and optic disc drusen (see
• Note: While two studies suggest that OCT in
## Establishing the Diagnosis
The diagnosis of
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 of the extensive genetic heterogeneity of LCA/EOSRD (see
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 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 deletion of exons 1-7 has been reported by
## Option 1
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 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 deletion of exons 1-7 has been reported by
## Clinical Characteristics
(
Late-stage findings can include keratoconus and cataract.
Refractive error is common; most affected individuals are myopic [
Although numerous
It has been suggested that the severity of
Leber congenital amaurosis (LCA) and early-onset severe retinal degeneration (EOSRD) are clinical diagnoses that do not have well agreed-upon definitions; consequently, different designations may be variably applied to an affected individual. With nomenclature moving away from clinical descriptive terms to gene-based terms,
It is estimated that between 1,000 and 2,000 individuals in the United States have
The incidence of LCA ranges from 2:100,000 to 3:100,000 [
• Late-stage findings can include keratoconus and cataract.
• Refractive error is common; most affected individuals are myopic [
## Clinical Description
(
Late-stage findings can include keratoconus and cataract.
Refractive error is common; most affected individuals are myopic [
• Late-stage findings can include keratoconus and cataract.
• Refractive error is common; most affected individuals are myopic [
## Genotype-Phenotype Correlations
Although numerous
It has been suggested that the severity of
## Nomenclature
Leber congenital amaurosis (LCA) and early-onset severe retinal degeneration (EOSRD) are clinical diagnoses that do not have well agreed-upon definitions; consequently, different designations may be variably applied to an affected individual. With nomenclature moving away from clinical descriptive terms to gene-based terms,
## Prevalence
It is estimated that between 1,000 and 2,000 individuals in the United States have
The incidence of LCA ranges from 2:100,000 to 3:100,000 [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
RP type 20 is thought to account for up to 1%-2% of autosomal recessive RP; the estimated incidence of autosomal recessive RP is 1:3000 – 1:5000 (see
## Differential Diagnosis
See
## Management
To establish the extent of disease and needs of individuals diagnosed with
Individuals with
Incl motor, adaptive, cognitive & speech/language evaluation.
Evaluate for early intervention/special education.
Use of community vision services through Early Intervention or School District
Use of community or online resources such as Parent To Parent
Need for social work involvement for parental support and to connect families with local resources
Kinetic visual field testing uses moving targets of various light sizes and intensities to map out the entire visual field, as well as the blind spot and any scotomas (decreased areas of vision). This type of testing is useful for mapping visual field sensitivity boundaries (
Static visual field testing systematically plots the field of vision using threshold testing with flashing light presentations of various intensities. This type of testing allows the determination of retinal sensitivity in any given location (
Children with
Advice on learning / intellectual disability / educational issues will vary from country to country, or even region to region within a country, depending on support services available. Overarching principles should include the following:
Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers/schools for the visually impaired
Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable Braille display
As patients grow older, identifying further assistance including financial and/or employment (available in some countries through certification/registration processes)
Registration with services to record population data on the causes and effects of visual impairment (available in some countries)
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability / educational issues in the United States.
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 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 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.
Children who are legally blind may have difficulty integrating and socializing with peers in school. 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 (ADHD), when necessary.
In one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
Of note, differences observed in the outcome of these trials may be due to differences in viral vectors and/or delivery protocols or the outcome measures used to assess change over time.
For data on preclinical testing in animal models click
Available from
Administered through qualified
Age between 12 months and 65 years
Presence of biallelic
Ophthalmic evaluation that includes many of the evaluations in
Meeting eligibility requirements for treatment
Prior authorization from the third party payer to approve coverage of this treatment
Determination of the amount of the cost covered by the third party payor versus the amount covered by the patient / patient's family
Recommended Surveillance for Individuals with
Children should be discouraged whenever possible from repeatedly poking and pressing on their eyes, which may cause damage to the cornea and/or retina.
It is appropriate to clarify the genetic status of sibs of an individual with
See
A Phase I clinical trial was conducted using oral supplementation of QLT091001 (synthetic
In a Phase Ib follow-up multicenter trial, 18 patients with either
A Phase III trial for this oral retinoid is being planned. In addition to potentially serving as a monotherapy for inherited retinal diseases with defects in the visual cycle, this oral retinoid could also be combined with gene therapy to provide a potentially synergistic effect.
Search
• Incl motor, adaptive, cognitive & speech/language evaluation.
• Evaluate for early intervention/special education.
• Use of community vision services through Early Intervention or School District
• Use of community or online resources such as Parent To Parent
• Need for social work involvement for parental support and to connect families with local resources
• Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers/schools for the visually impaired
• Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable Braille display
• As patients grow older, identifying further assistance including financial and/or employment (available in some countries through certification/registration processes)
• Registration with services to record population data on the causes and effects of visual impairment (available in some countries)
• 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 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 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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 one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
• In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
• In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
• Of note, differences observed in the outcome of these trials may be due to differences in viral vectors and/or delivery protocols or the outcome measures used to assess change over time.
• In one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
• In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
• In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
• For data on preclinical testing in animal models click
• In one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
• In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
• In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
• Available from
• Administered through qualified
• Age between 12 months and 65 years
• Presence of biallelic
• Ophthalmic evaluation that includes many of the evaluations in
• Meeting eligibility requirements for treatment
• Prior authorization from the third party payer to approve coverage of this treatment
• Determination of the amount of the cost covered by the third party payor versus the amount covered by the patient / patient's family
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of individuals diagnosed with
Individuals with
Incl motor, adaptive, cognitive & speech/language evaluation.
Evaluate for early intervention/special education.
Use of community vision services through Early Intervention or School District
Use of community or online resources such as Parent To Parent
Need for social work involvement for parental support and to connect families with local resources
Kinetic visual field testing uses moving targets of various light sizes and intensities to map out the entire visual field, as well as the blind spot and any scotomas (decreased areas of vision). This type of testing is useful for mapping visual field sensitivity boundaries (
Static visual field testing systematically plots the field of vision using threshold testing with flashing light presentations of various intensities. This type of testing allows the determination of retinal sensitivity in any given location (
• Incl motor, adaptive, cognitive & speech/language evaluation.
• Evaluate for early intervention/special education.
• Use of community vision services through Early Intervention or School District
• Use of community or online resources such as Parent To Parent
• Need for social work involvement for parental support and to connect families with local resources
## Treatment of Manifestations
Children with
Advice on learning / intellectual disability / educational issues will vary from country to country, or even region to region within a country, depending on support services available. Overarching principles should include the following:
Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers/schools for the visually impaired
Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable Braille display
As patients grow older, identifying further assistance including financial and/or employment (available in some countries through certification/registration processes)
Registration with services to record population data on the causes and effects of visual impairment (available in some countries)
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability / educational issues in the United States.
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 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 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.
Children who are legally blind may have difficulty integrating and socializing with peers in school. 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 (ADHD), when necessary.
In one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
Of note, differences observed in the outcome of these trials may be due to differences in viral vectors and/or delivery protocols or the outcome measures used to assess change over time.
For data on preclinical testing in animal models click
Available from
Administered through qualified
Age between 12 months and 65 years
Presence of biallelic
Ophthalmic evaluation that includes many of the evaluations in
Meeting eligibility requirements for treatment
Prior authorization from the third party payer to approve coverage of this treatment
Determination of the amount of the cost covered by the third party payor versus the amount covered by the patient / patient's family
• Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers/schools for the visually impaired
• Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable Braille display
• As patients grow older, identifying further assistance including financial and/or employment (available in some countries through certification/registration processes)
• Registration with services to record population data on the causes and effects of visual impairment (available in some countries)
• 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 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 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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 one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
• In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
• In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
• Of note, differences observed in the outcome of these trials may be due to differences in viral vectors and/or delivery protocols or the outcome measures used to assess change over time.
• In one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
• In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
• In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
• For data on preclinical testing in animal models click
• In one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
• In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
• In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
• Available from
• Administered through qualified
• Age between 12 months and 65 years
• Presence of biallelic
• Ophthalmic evaluation that includes many of the evaluations in
• Meeting eligibility requirements for treatment
• Prior authorization from the third party payer to approve coverage of this treatment
• Determination of the amount of the cost covered by the third party payor versus the amount covered by the patient / patient's family
## For All Individuals with
## Developmental Delay / Intellectual Disability Management Issues
Children with
Advice on learning / intellectual disability / educational issues will vary from country to country, or even region to region within a country, depending on support services available. Overarching principles should include the following:
Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers/schools for the visually impaired
Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable Braille display
As patients grow older, identifying further assistance including financial and/or employment (available in some countries through certification/registration processes)
Registration with services to record population data on the causes and effects of visual impairment (available in some countries)
The following information represents typical management recommendations for individuals with developmental delay / intellectual disability / educational issues in the United States.
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 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 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.
• Involving child development and educational specialists at the earliest available opportunity, often with specialist teachers/schools for the visually impaired
• Early referral to low vision services to access low visual aids, especially with improving technologies, such as the refreshable Braille display
• As patients grow older, identifying further assistance including financial and/or employment (available in some countries through certification/registration processes)
• Registration with services to record population data on the causes and effects of visual impairment (available in some countries)
• 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 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 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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.
• Special education law requires that children participating in 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 teen years, a transition plan should 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 Concerns
Children who are legally blind may have difficulty integrating and socializing with peers in school. 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 (ADHD), when necessary.
## Subretinal Gene Supplementation Therapy
In one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
Of note, differences observed in the outcome of these trials may be due to differences in viral vectors and/or delivery protocols or the outcome measures used to assess change over time.
For data on preclinical testing in animal models click
Available from
Administered through qualified
Age between 12 months and 65 years
Presence of biallelic
Ophthalmic evaluation that includes many of the evaluations in
Meeting eligibility requirements for treatment
Prior authorization from the third party payer to approve coverage of this treatment
Determination of the amount of the cost covered by the third party payor versus the amount covered by the patient / patient's family
• In one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
• In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
• In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
• Of note, differences observed in the outcome of these trials may be due to differences in viral vectors and/or delivery protocols or the outcome measures used to assess change over time.
• In one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
• In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
• In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
• For data on preclinical testing in animal models click
• In one trial, visual sensitivity (determined with static perimetry) initially improved but then declined three to five years later, with evidence of continued retinal degeneration in the treated eye [
• In another trial, static visual perimetry improved at year one post treatment, but then declined to baseline by years two to three post treatment [
• In other Phase II trials the duration of more sustained visual improvement in children (as measured by best corrected visual acuity) was at three years post treatment [
• Available from
• Administered through qualified
• Age between 12 months and 65 years
• Presence of biallelic
• Ophthalmic evaluation that includes many of the evaluations in
• Meeting eligibility requirements for treatment
• Prior authorization from the third party payer to approve coverage of this treatment
• Determination of the amount of the cost covered by the third party payor versus the amount covered by the patient / patient's family
## Surveillance
Recommended Surveillance for Individuals with
## Agents/Circumstances to Avoid
Children should be discouraged whenever possible from repeatedly poking and pressing on their eyes, which may cause damage to the cornea and/or retina.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of sibs of an individual with
See
## Therapies Under Investigation
A Phase I clinical trial was conducted using oral supplementation of QLT091001 (synthetic
In a Phase Ib follow-up multicenter trial, 18 patients with either
A Phase III trial for this oral retinoid is being planned. In addition to potentially serving as a monotherapy for inherited retinal diseases with defects in the visual cycle, this oral retinoid could also be combined with gene therapy to provide a potentially synergistic effect.
Search
## Genetic Counseling
The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are not at risk of developing LCA/EOSRD.
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 not at risk of developing LCA/EOSRD.
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 not at risk of developing LCA/EOSRD.
• 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 not at risk of developing LCA/EOSRD.
• 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 individual are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are not at risk of developing LCA/EOSRD.
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 not at risk of developing LCA/EOSRD.
• The parents of an affected individual are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are not at risk of developing LCA/EOSRD.
• 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 not at risk of developing LCA/EOSRD.
## 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, 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
Ireland
•
•
•
•
•
•
•
• Ireland
•
## Molecular Genetics
RPE65-Related Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for RPE65-Related Leber Congenital Amaurosis / Early-Onset Severe Retinal Dystrophy (
Normally, photoreceptors sense light through the isomerization of the visual chromophore
Therefore, without RPE65 function
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
Normally, photoreceptors sense light through the isomerization of the visual chromophore
Therefore, without RPE65 function
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## References
## Literature Cited
## Chapter Notes
Daniel Chao is an Assistant Professor of Ophthalmology at the Shiley Eye Institute, Viterbi Department of Ophthalmology at University of California, San Diego. He is a vitreoretinal surgeon and runs a translational research program focused on developing new therapeutics for retinal diseases. He has a strong interest in inherited retinal diseases, and is a part-time fellow in ocular genetics at the Casey Eye Institute, Oregon Health & Science University.
Amanda Burr is a Genetic Counselor at Oregon Health & Science University's Casey Eye Institute in Portland, Oregon. She specializes in genetic counseling for individuals suspected or known to have inherited retinal disorders.
Dr Mark Pennesi is an Associate Professor of Ophthalmology at Oregon Health & Science University's Casey Eye Institute in Portland, Oregon. He is the chief of the Ophthalmic Genetics Division and an inherited retinal degeneration specialist.
14 November 2019 (bp) Review posted live
26 March 2019 (dc) Original submission
• 14 November 2019 (bp) Review posted live
• 26 March 2019 (dc) Original submission
## Author Notes
Daniel Chao is an Assistant Professor of Ophthalmology at the Shiley Eye Institute, Viterbi Department of Ophthalmology at University of California, San Diego. He is a vitreoretinal surgeon and runs a translational research program focused on developing new therapeutics for retinal diseases. He has a strong interest in inherited retinal diseases, and is a part-time fellow in ocular genetics at the Casey Eye Institute, Oregon Health & Science University.
Amanda Burr is a Genetic Counselor at Oregon Health & Science University's Casey Eye Institute in Portland, Oregon. She specializes in genetic counseling for individuals suspected or known to have inherited retinal disorders.
Dr Mark Pennesi is an Associate Professor of Ophthalmology at Oregon Health & Science University's Casey Eye Institute in Portland, Oregon. He is the chief of the Ophthalmic Genetics Division and an inherited retinal degeneration specialist.
## Revision History
14 November 2019 (bp) Review posted live
26 March 2019 (dc) Original submission
• 14 November 2019 (bp) Review posted live
• 26 March 2019 (dc) Original submission
|
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"H Morimura, GA Fishman, SA Grover, AB Fulton, EL Berson, TP Dryja. Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa or leber congenital amaurosis.. Proc Natl Acad Sci U S A. 1998;95:3088-93",
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"C Ripamonti, GB Henning, RR Ali, JW Bainbridge, SJ Robbie, V Sundaram, VA Luong, I Van Den Born, I Casteels, TJL De Ravel, AT Moore, A Stockman. Nature of the visual loss in observers with Leber's congenital amaurosis caused by specific mutations in RPE65.. Invest Ophthalmol Vis Sci. 2014;55:6817-28",
"S Russell, J Bennett, JA Wellman, DC Chung, ZF Yu, A Tillman, J Wittes, J Pappas, O Elci, S Mccague, D Cross, KA Marshall, J Walshire, TL Kehoe, H Reichert, M Davis, L Raffini, LA George, FP Hudson, L Dingfield, X Zhu, JA Haller, EH Sohn, VB Mahajan, W Pfeifer, M Weckmann, C Johnson, D Gewaily, A Drack, E Stone, K Wachtel, F Simonelli, BP Leroy, JF Wright, KA High, AM Maguire. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial.. Lancet. 2017;390:849-60",
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"JP Van Hooser, TS Aleman, YG He, AV Cideciyan, V Kuksa, SJ Pittler, EM Stone, SG Jacobson, K Palczewski. Rapid restoration of visual pigment and function with oral retinoid in a mouse model of childhood blindness.. Proc Natl Acad Sci U S A. 2000;97:8623-8",
"JP Van Hooser, Y Liang, T Maeda, V Kuksa, GF Jang, YG He, F Rieke, HK Fong, PB Detwiler, K Palczewski. Recovery of visual functions in a mouse model of Leber congenital amaurosis.. J Biol Chem. 2002;277:19173-82",
"A Verma, V Perumalsamy, S Shetty, M Kulm, P. Sundaresan. Mutational screening of LCA genes emphasizing RPE65 in South Indian cohort of patients.. PLoS One. 2013;8",
"RG Weleber, ME Pennesi, DJ Wilson, S Kaushal, LR Erker, L Jensen, MT Mcbride, TR Flotte, M Humphries, R Calcedo, WW Hauswirth, JD Chulay, JT Stout. Results at 2 years after gene therapy for RPE65-deficient Leber congenital amaurosis and severe early-childhood-onset retinal dystrophy.. Ophthalmology. 2016;123:1606-20",
"S Yzer, LI Van Den Born, J Schuil, HY Kroes, MM Van Genderen, FN Boonstra, B Van Den Helm, HG Brunner, RK Koenekoop, FPM Cremers. Tyr368His RPE65 founder mutation is associated with variable expression and progression of early onset retinal dystrophy in 10 families of a genetically isolated population.. J Med Genet. 2003;40:709-13"
] |
14/11/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
rrm2b-mtddepl
|
rrm2b-mtddepl
|
[
"RRM2B Autosomal Recessive Progressive External Ophthalmoplegia (arPEO)",
"RRM2B Encephalomyopathic Mitochondrial DNA Maintenance Defects (MDMD)",
"RRM2B Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE)",
"RRM2B Autosomal Dominant Progressive External Ophthalmoplegia (adPEO)",
"Ribonucleoside-diphosphate reductase subunit M2 B",
"RRM2B",
"RRM2B Mitochondrial DNA Maintenance Defects"
] |
Albert Z Lim, Robert McFarland, Robert W Taylor, Gráinne S Gorman
|
Summary Four phenotypes comprise the To date, 78 individuals from 52 families with a molecularly confirmed The diagnosis of an With the exception of autosomal dominant progressive external ophthalmoplegia, Once the
|
COX = cytochrome
No true epidemiologic study is available to assess the exact prevalence for each of these disorders.
Previously referred to as mtDNA depletion syndrome 8A (encephalomyopathic type with renal tubulopathy) or
Previously referred to as mtDNA depletion syndrome 8B
## Diagnosis
Note: While muscle biopsy is not required to consider this diagnosis, muscle biopsy findings – in the event that one was obtained for other reasons – may include cytochrome
Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
CNS findings including seizures, developmental delay, microcephaly, faltering growth
Sensorineural hearing loss
Proximal renal tubulopathy with nephrocalcinosis
Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
Progressive external ophthalmoplegia
Ptosis of variable severity
Sensorineural hearing loss
Proximal muscle weakness and fatigue
Bulbar dysfunction
Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
Sensory axonal peripheral neuropathy
Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
Note: Absence of a known family history does not preclude the diagnosis.
The diagnosis of an
The identification of biallelic
The identification of a heterozygous
* Note: The authors of this chapter have offered to review
Molecular genetic testing approaches can include a combination of
Note: Single-gene testing (sequence analysis 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
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.
•
• Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
• CNS findings including seizures, developmental delay, microcephaly, faltering growth
• Sensorineural hearing loss
• Proximal renal tubulopathy with nephrocalcinosis
• Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
• Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
• CNS findings including seizures, developmental delay, microcephaly, faltering growth
• Sensorineural hearing loss
• Proximal renal tubulopathy with nephrocalcinosis
• Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
• Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
• CNS findings including seizures, developmental delay, microcephaly, faltering growth
• Sensorineural hearing loss
• Proximal renal tubulopathy with nephrocalcinosis
• Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
•
• Progressive external ophthalmoplegia
• Ptosis of variable severity
• Sensorineural hearing loss
• Proximal muscle weakness and fatigue
• Bulbar dysfunction
• Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
• CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
• Sensory axonal peripheral neuropathy
• Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
• Progressive external ophthalmoplegia
• Ptosis of variable severity
• Sensorineural hearing loss
• Proximal muscle weakness and fatigue
• Bulbar dysfunction
• Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
• CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
• Sensory axonal peripheral neuropathy
• Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
• Note: Absence of a known family history does not preclude the diagnosis.
• Progressive external ophthalmoplegia
• Ptosis of variable severity
• Sensorineural hearing loss
• Proximal muscle weakness and fatigue
• Bulbar dysfunction
• Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
• CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
• Sensory axonal peripheral neuropathy
• Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
• The identification of biallelic
• The identification of a heterozygous
## Suggestive Findings
Note: While muscle biopsy is not required to consider this diagnosis, muscle biopsy findings – in the event that one was obtained for other reasons – may include cytochrome
Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
CNS findings including seizures, developmental delay, microcephaly, faltering growth
Sensorineural hearing loss
Proximal renal tubulopathy with nephrocalcinosis
Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
Progressive external ophthalmoplegia
Ptosis of variable severity
Sensorineural hearing loss
Proximal muscle weakness and fatigue
Bulbar dysfunction
Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
Sensory axonal peripheral neuropathy
Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
Note: Absence of a known family history does not preclude the diagnosis.
•
• Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
• CNS findings including seizures, developmental delay, microcephaly, faltering growth
• Sensorineural hearing loss
• Proximal renal tubulopathy with nephrocalcinosis
• Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
• Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
• CNS findings including seizures, developmental delay, microcephaly, faltering growth
• Sensorineural hearing loss
• Proximal renal tubulopathy with nephrocalcinosis
• Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
• Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
• CNS findings including seizures, developmental delay, microcephaly, faltering growth
• Sensorineural hearing loss
• Proximal renal tubulopathy with nephrocalcinosis
• Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
•
• Progressive external ophthalmoplegia
• Ptosis of variable severity
• Sensorineural hearing loss
• Proximal muscle weakness and fatigue
• Bulbar dysfunction
• Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
• CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
• Sensory axonal peripheral neuropathy
• Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
• Progressive external ophthalmoplegia
• Ptosis of variable severity
• Sensorineural hearing loss
• Proximal muscle weakness and fatigue
• Bulbar dysfunction
• Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
• CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
• Sensory axonal peripheral neuropathy
• Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
• Note: Absence of a known family history does not preclude the diagnosis.
• Progressive external ophthalmoplegia
• Ptosis of variable severity
• Sensorineural hearing loss
• Proximal muscle weakness and fatigue
• Bulbar dysfunction
• Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
• CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
• Sensory axonal peripheral neuropathy
• Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
## Common Phenotypes
Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
CNS findings including seizures, developmental delay, microcephaly, faltering growth
Sensorineural hearing loss
Proximal renal tubulopathy with nephrocalcinosis
Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
Progressive external ophthalmoplegia
Ptosis of variable severity
Sensorineural hearing loss
Proximal muscle weakness and fatigue
Bulbar dysfunction
Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
Sensory axonal peripheral neuropathy
Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
Note: Absence of a known family history does not preclude the diagnosis.
•
• Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
• CNS findings including seizures, developmental delay, microcephaly, faltering growth
• Sensorineural hearing loss
• Proximal renal tubulopathy with nephrocalcinosis
• Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
• Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
• CNS findings including seizures, developmental delay, microcephaly, faltering growth
• Sensorineural hearing loss
• Proximal renal tubulopathy with nephrocalcinosis
• Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
• Myopathy manifesting as muscle hypotonia and weakness, often associated with respiratory insufficiency/failure
• CNS findings including seizures, developmental delay, microcephaly, faltering growth
• Sensorineural hearing loss
• Proximal renal tubulopathy with nephrocalcinosis
• Gastrointestinal disturbance manifesting as dysmotility or feeding difficulties
•
• Progressive external ophthalmoplegia
• Ptosis of variable severity
• Sensorineural hearing loss
• Proximal muscle weakness and fatigue
• Bulbar dysfunction
• Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
• CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
• Sensory axonal peripheral neuropathy
• Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
• Progressive external ophthalmoplegia
• Ptosis of variable severity
• Sensorineural hearing loss
• Proximal muscle weakness and fatigue
• Bulbar dysfunction
• Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
• CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
• Sensory axonal peripheral neuropathy
• Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
• Note: Absence of a known family history does not preclude the diagnosis.
• Progressive external ophthalmoplegia
• Ptosis of variable severity
• Sensorineural hearing loss
• Proximal muscle weakness and fatigue
• Bulbar dysfunction
• Gastrointestinal issues, including irritable bowel syndrome-like symptoms and low body mass index, cachexia
• CNS findings either absent or minimal (including ataxia, cognitive dysfunction, and mood disturbance)
• Sensory axonal peripheral neuropathy
• Endocrinopathy (including hypothyroidism, hypoparathyroidism, diabetes mellitus, and hypogonadism)
## Rare Phenotypes
## Establishing the Diagnosis
The diagnosis of an
The identification of biallelic
The identification of a heterozygous
* Note: The authors of this chapter have offered to review
Molecular genetic testing approaches can include a combination of
Note: Single-gene testing (sequence analysis 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
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 identification of biallelic
• The identification of a heterozygous
## 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.
## Clinical Characteristics
The two common forms of
The two rare phenotypes –
Phenotypic Spectrum of
AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; MDMD = mitochondrial DNA maintenance defects; MOI = mode of inheritance; MNGIE = mitochondrial neurogastrointestinal encephalopathy; PEO = progressive external ophthalmoplegia
For review of the adPEO and arPEO phenotypes, see
Accumulation of clonally expanded (multiple) mtDNA deletions causes tissue-specific cytochrome
For review of the MNGIE phenotype, see
For review of the Kearns-Sayre syndrome phenotype, see
Select Clinical Features of
Based on
PEO = progressive external ophthalmoplegia; UMN = upper motor neuron
n = 31
Onset is typically in the first few months of life; affected children succumb in early childhood. Disease characteristics include myopathy manifesting as hypotonia, weakness associated with respiratory insufficiency, faltering growth (failure to thrive), and proximal renal tubulopathy.
Central nervous system (CNS) features can include encephalopathy (15 affected individuals), gross motor delay (15), feeding difficulties (14), seizures (12), and sensorineural hearing loss (11). Other less frequently reported CNS manifestations include cerebral atrophy, and generalized central hypomyelination.
Given the multisystem involvement, most infants with the encephalomyopathic phenotype have faltering growth and a poor prognosis.
Select Features of
Based on
PEO = progressive external ophthalmoplegia
n = 42
The first individuals reported were from two large, unrelated families with autosomal dominant PEO [
A homozygous missense pathogenic variant in
Kearns-Sayre-like syndrome (KSS) was reported in two individuals with onset before age 20 years of PEO-plus / Kearns-Sayre syndrome (PEO, pigmentary retinopathy, sensorineural hearing loss, and increased CSF protein documented in one and renal tubulopathy in the other, similar to single mtDNA deletion disorders) [
Defining the genotype-phenotype correlations in
The prevalence of
## Clinical Description
The two common forms of
The two rare phenotypes –
Phenotypic Spectrum of
AD = autosomal dominant; AR = autosomal recessive; GI = gastrointestinal; MDMD = mitochondrial DNA maintenance defects; MOI = mode of inheritance; MNGIE = mitochondrial neurogastrointestinal encephalopathy; PEO = progressive external ophthalmoplegia
For review of the adPEO and arPEO phenotypes, see
Accumulation of clonally expanded (multiple) mtDNA deletions causes tissue-specific cytochrome
For review of the MNGIE phenotype, see
For review of the Kearns-Sayre syndrome phenotype, see
Select Clinical Features of
Based on
PEO = progressive external ophthalmoplegia; UMN = upper motor neuron
n = 31
Onset is typically in the first few months of life; affected children succumb in early childhood. Disease characteristics include myopathy manifesting as hypotonia, weakness associated with respiratory insufficiency, faltering growth (failure to thrive), and proximal renal tubulopathy.
Central nervous system (CNS) features can include encephalopathy (15 affected individuals), gross motor delay (15), feeding difficulties (14), seizures (12), and sensorineural hearing loss (11). Other less frequently reported CNS manifestations include cerebral atrophy, and generalized central hypomyelination.
Given the multisystem involvement, most infants with the encephalomyopathic phenotype have faltering growth and a poor prognosis.
Select Features of
Based on
PEO = progressive external ophthalmoplegia
n = 42
The first individuals reported were from two large, unrelated families with autosomal dominant PEO [
A homozygous missense pathogenic variant in
Kearns-Sayre-like syndrome (KSS) was reported in two individuals with onset before age 20 years of PEO-plus / Kearns-Sayre syndrome (PEO, pigmentary retinopathy, sensorineural hearing loss, and increased CSF protein documented in one and renal tubulopathy in the other, similar to single mtDNA deletion disorders) [
Select Clinical Features of
Based on
PEO = progressive external ophthalmoplegia; UMN = upper motor neuron
n = 31
Onset is typically in the first few months of life; affected children succumb in early childhood. Disease characteristics include myopathy manifesting as hypotonia, weakness associated with respiratory insufficiency, faltering growth (failure to thrive), and proximal renal tubulopathy.
Central nervous system (CNS) features can include encephalopathy (15 affected individuals), gross motor delay (15), feeding difficulties (14), seizures (12), and sensorineural hearing loss (11). Other less frequently reported CNS manifestations include cerebral atrophy, and generalized central hypomyelination.
Given the multisystem involvement, most infants with the encephalomyopathic phenotype have faltering growth and a poor prognosis.
Select Features of
Based on
PEO = progressive external ophthalmoplegia
n = 42
The first individuals reported were from two large, unrelated families with autosomal dominant PEO [
## Rare Forms of
A homozygous missense pathogenic variant in
Kearns-Sayre-like syndrome (KSS) was reported in two individuals with onset before age 20 years of PEO-plus / Kearns-Sayre syndrome (PEO, pigmentary retinopathy, sensorineural hearing loss, and increased CSF protein documented in one and renal tubulopathy in the other, similar to single mtDNA deletion disorders) [
## Genotype-Phenotype Correlations
Defining the genotype-phenotype correlations in
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
To date, pathogenic variants in 20 nuclear genes are known to be associated with mtDNA maintenance defects (see
Note: As is apparent in
Categories of mtDNA Maintenance Defects: Genes and Primary Presenting Features
MNGIE = mitochondrial neurogastrointestinal encephalopathy; Mt = Mitochondrial
## Management
No clinical guidelines specific to
The management of the two common phenotypes,
For management of the two rare phenotypes, mitochondrial neurogastrointestinal encephalopathy (MNGIE)-like disease and Kearns-Sayre syndrome-like, see
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis of
Assess functional neurologic status.
EEG & brain imaging if seizures suspected
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Need for adaptive devices
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gastroenterology / nutrition / feeding team eval
To incl eval for gastrointestinal dysmotility, aspiration risk & nutritional status
Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk.
Bedside fundoscopy
Visual acuity testing
Ptosis & CPEO assessment
Early ophthalmology involvement
Clinical photographs for comparison of ptosis
Community resources &
Social work involvement for parental support;
Home nursing referral.
Assess healthcare decisions in the context of the best interest of the child & values & preferences of the family.
For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
MOI = mode of inheritance
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis of
Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
Consider need for corrective measures incl prisms &/or surgery
Nutritional status;
Aspiration risk.
Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
PT needs
Small motor function (e.g., hands, feet, face, fingers, toes)
ADL
CCAS Scale to evaluate cognitive & emotional involvement;
Psychiatrist, psychologist, neuropsychologist if needed.
Measure height & weight.
Calculate BMI.
Serial weight measurement
Community resources &
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; BAEP = brain stem auditory evoked potentials; BARS = Brief Ataxia Rating Scale; BMI = body mass index; CCAS = cerebellar cognitive affective syndrome; ICARS = International Co-operative Ataxia Rating Scale; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
To date, there are no known cures and few effective treatments for any forms of mitochondrial disease, including
Treatment of Manifestations of
To maintain muscle strength & mobility; prevent contractures
Consider need for adaptive positioning devices.
Certain ASMs require monitoring of levels.
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.
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
See
Treatment of Manifestations of
Speech & language therapy
Parenteral feeding to avoid aspiration
Hearing aids
Cochlear implants
Consider regular assessments for insidious onset.
Require ENT surgeon for cochlear implant.
Dietary modifications to improve bowel movements
Laxatives
PEG/PEJ insertion (if clinically indicated)
TPN (very rare)
Regular BMI measurement
Ensure appropriate growth based on centiles of children.
Correction of blood sugar w/oral medication or insulin
Targeted treatment based on clinical features & blood results
BMI = body mass index; OT = occupational therapy; PEG/J = percutaneous endoscopic gastrostomy/jejunostomy; PEO = progressive external ophthalmoplegia; PT = physical therapy; TPN = total parenteral nutrition
Because most infants and young children with the encephalomyopathic form are severely affected and are hospitalized for prolonged periods from the onset of disease manifestations, they should be reviewed regularly by senior clinical specialists if they are hospitalized. The recommendations regarding frequency in
Recommended Surveillance of
Quarterly
W/o seizure correlates, routine EEG is not indicated.
Quarterly
Assessment of feeding
Monitor stool frequency.
Dietary assessment to maintain adequate nutrition & growth
BMI = body mass index; OT = occupational therapy; PT = physical therapy
Recommended Surveillance of
ADL = activities of daily living; BMI = body mass index; GI = gastrointestinal; OT = occupational therapy; PEO = progressive external ophthalmoplegia; PT = physical therapy
Valproic acid should be used only in exceptional circumstances.
Decisions related to drug prescribing should always be tailored to the affected individual's specific needs and risks [
It is safe to use metformin in primary mitochondrial disease.
If indicated, linezolid could be used in mitochondrial disease with careful lactate monitoring, particularly in children and other individuals with preexisting lactic acidemia.
Although historically there have been largely theoretic concerns regarding general anesthetic use in individuals with mitochondrial disease, adverse events are exceptionally rare. Catabolism should be prevented by minimizing preoperative fasting and administering intravenous glucose perioperatively during prolonged anesthesia, unless the individual is on a ketogenic diet.
It is appropriate to clarify the genetic status of at-risk relatives of an affected family member so that those with the
See
Search
• Assess functional neurologic status.
• EEG & brain imaging if seizures suspected
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Need for adaptive devices
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• To incl eval for gastrointestinal dysmotility, aspiration risk & nutritional status
• Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk.
• Bedside fundoscopy
• Visual acuity testing
• Ptosis & CPEO assessment
• Early ophthalmology involvement
• Clinical photographs for comparison of ptosis
• Community resources &
• Social work involvement for parental support;
• Home nursing referral.
• Assess healthcare decisions in the context of the best interest of the child & values & preferences of the family.
• For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
• Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
• Consider need for corrective measures incl prisms &/or surgery
• Nutritional status;
• Aspiration risk.
• Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• PT needs
• Small motor function (e.g., hands, feet, face, fingers, toes)
• ADL
• CCAS Scale to evaluate cognitive & emotional involvement;
• Psychiatrist, psychologist, neuropsychologist if needed.
• Measure height & weight.
• Calculate BMI.
• Serial weight measurement
• Community resources &
• Social work involvement for parental support;
• Home nursing referral.
• To maintain muscle strength & mobility; prevent contractures
• Consider need for adaptive positioning devices.
• Certain ASMs require monitoring of levels.
• 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.
• Speech & language therapy
• Parenteral feeding to avoid aspiration
• Hearing aids
• Cochlear implants
• Consider regular assessments for insidious onset.
• Require ENT surgeon for cochlear implant.
• Dietary modifications to improve bowel movements
• Laxatives
• PEG/PEJ insertion (if clinically indicated)
• TPN (very rare)
• Regular BMI measurement
• Ensure appropriate growth based on centiles of children.
• Correction of blood sugar w/oral medication or insulin
• Targeted treatment based on clinical features & blood results
• Quarterly
• W/o seizure correlates, routine EEG is not indicated.
• Assessment of feeding
• Monitor stool frequency.
• Dietary assessment to maintain adequate nutrition & growth
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis of
Assess functional neurologic status.
EEG & brain imaging if seizures suspected
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Need for adaptive devices
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gastroenterology / nutrition / feeding team eval
To incl eval for gastrointestinal dysmotility, aspiration risk & nutritional status
Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk.
Bedside fundoscopy
Visual acuity testing
Ptosis & CPEO assessment
Early ophthalmology involvement
Clinical photographs for comparison of ptosis
Community resources &
Social work involvement for parental support;
Home nursing referral.
Assess healthcare decisions in the context of the best interest of the child & values & preferences of the family.
For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
MOI = mode of inheritance
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis of
Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
Consider need for corrective measures incl prisms &/or surgery
Nutritional status;
Aspiration risk.
Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
PT needs
Small motor function (e.g., hands, feet, face, fingers, toes)
ADL
CCAS Scale to evaluate cognitive & emotional involvement;
Psychiatrist, psychologist, neuropsychologist if needed.
Measure height & weight.
Calculate BMI.
Serial weight measurement
Community resources &
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; BAEP = brain stem auditory evoked potentials; BARS = Brief Ataxia Rating Scale; BMI = body mass index; CCAS = cerebellar cognitive affective syndrome; ICARS = International Co-operative Ataxia Rating Scale; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
• Assess functional neurologic status.
• EEG & brain imaging if seizures suspected
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Need for adaptive devices
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• To incl eval for gastrointestinal dysmotility, aspiration risk & nutritional status
• Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk.
• Bedside fundoscopy
• Visual acuity testing
• Ptosis & CPEO assessment
• Early ophthalmology involvement
• Clinical photographs for comparison of ptosis
• Community resources &
• Social work involvement for parental support;
• Home nursing referral.
• Assess healthcare decisions in the context of the best interest of the child & values & preferences of the family.
• For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
• Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
• Consider need for corrective measures incl prisms &/or surgery
• Nutritional status;
• Aspiration risk.
• Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• PT needs
• Small motor function (e.g., hands, feet, face, fingers, toes)
• ADL
• CCAS Scale to evaluate cognitive & emotional involvement;
• Psychiatrist, psychologist, neuropsychologist if needed.
• Measure height & weight.
• Calculate BMI.
• Serial weight measurement
• Community resources &
• Social work involvement for parental support;
• Home nursing referral.
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis of
Assess functional neurologic status.
EEG & brain imaging if seizures suspected
Gross motor & fine motor skills
Contractures, clubfoot, & kyphoscoliosis
Need for adaptive devices
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Gastroenterology / nutrition / feeding team eval
To incl eval for gastrointestinal dysmotility, aspiration risk & nutritional status
Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk.
Bedside fundoscopy
Visual acuity testing
Ptosis & CPEO assessment
Early ophthalmology involvement
Clinical photographs for comparison of ptosis
Community resources &
Social work involvement for parental support;
Home nursing referral.
Assess healthcare decisions in the context of the best interest of the child & values & preferences of the family.
For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
MOI = mode of inheritance
• Assess functional neurologic status.
• EEG & brain imaging if seizures suspected
• Gross motor & fine motor skills
• Contractures, clubfoot, & kyphoscoliosis
• Need for adaptive devices
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• To incl eval for gastrointestinal dysmotility, aspiration risk & nutritional status
• Consider eval for gastric tube placement in persons w/dysphagia &/or aspiration risk.
• Bedside fundoscopy
• Visual acuity testing
• Ptosis & CPEO assessment
• Early ophthalmology involvement
• Clinical photographs for comparison of ptosis
• Community resources &
• Social work involvement for parental support;
• Home nursing referral.
• Assess healthcare decisions in the context of the best interest of the child & values & preferences of the family.
• For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis of
Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
Consider need for corrective measures incl prisms &/or surgery
Nutritional status;
Aspiration risk.
Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores
Need for adaptive devices
Footwear needs
PT needs
Small motor function (e.g., hands, feet, face, fingers, toes)
ADL
CCAS Scale to evaluate cognitive & emotional involvement;
Psychiatrist, psychologist, neuropsychologist if needed.
Measure height & weight.
Calculate BMI.
Serial weight measurement
Community resources &
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; BAEP = brain stem auditory evoked potentials; BARS = Brief Ataxia Rating Scale; BMI = body mass index; CCAS = cerebellar cognitive affective syndrome; ICARS = International Co-operative Ataxia Rating Scale; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
• Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
• Consider need for corrective measures incl prisms &/or surgery
• Nutritional status;
• Aspiration risk.
• Muscle tone; joint range of motion; posture; mobility; strength, coordination & endurance; pain; bedsores
• Need for adaptive devices
• Footwear needs
• PT needs
• Small motor function (e.g., hands, feet, face, fingers, toes)
• ADL
• CCAS Scale to evaluate cognitive & emotional involvement;
• Psychiatrist, psychologist, neuropsychologist if needed.
• Measure height & weight.
• Calculate BMI.
• Serial weight measurement
• Community resources &
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
To date, there are no known cures and few effective treatments for any forms of mitochondrial disease, including
Treatment of Manifestations of
To maintain muscle strength & mobility; prevent contractures
Consider need for adaptive positioning devices.
Certain ASMs require monitoring of levels.
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.
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
See
Treatment of Manifestations of
Speech & language therapy
Parenteral feeding to avoid aspiration
Hearing aids
Cochlear implants
Consider regular assessments for insidious onset.
Require ENT surgeon for cochlear implant.
Dietary modifications to improve bowel movements
Laxatives
PEG/PEJ insertion (if clinically indicated)
TPN (very rare)
Regular BMI measurement
Ensure appropriate growth based on centiles of children.
Correction of blood sugar w/oral medication or insulin
Targeted treatment based on clinical features & blood results
BMI = body mass index; OT = occupational therapy; PEG/J = percutaneous endoscopic gastrostomy/jejunostomy; PEO = progressive external ophthalmoplegia; PT = physical therapy; TPN = total parenteral nutrition
• To maintain muscle strength & mobility; prevent contractures
• Consider need for adaptive positioning devices.
• Certain ASMs require monitoring of levels.
• 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.
• Speech & language therapy
• Parenteral feeding to avoid aspiration
• Hearing aids
• Cochlear implants
• Consider regular assessments for insidious onset.
• Require ENT surgeon for cochlear implant.
• Dietary modifications to improve bowel movements
• Laxatives
• PEG/PEJ insertion (if clinically indicated)
• TPN (very rare)
• Regular BMI measurement
• Ensure appropriate growth based on centiles of children.
• Correction of blood sugar w/oral medication or insulin
• Targeted treatment based on clinical features & blood results
Treatment of Manifestations of
To maintain muscle strength & mobility; prevent contractures
Consider need for adaptive positioning devices.
Certain ASMs require monitoring of levels.
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.
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
See
• To maintain muscle strength & mobility; prevent contractures
• Consider need for adaptive positioning devices.
• Certain ASMs require monitoring of levels.
• 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.
Treatment of Manifestations of
Speech & language therapy
Parenteral feeding to avoid aspiration
Hearing aids
Cochlear implants
Consider regular assessments for insidious onset.
Require ENT surgeon for cochlear implant.
Dietary modifications to improve bowel movements
Laxatives
PEG/PEJ insertion (if clinically indicated)
TPN (very rare)
Regular BMI measurement
Ensure appropriate growth based on centiles of children.
Correction of blood sugar w/oral medication or insulin
Targeted treatment based on clinical features & blood results
BMI = body mass index; OT = occupational therapy; PEG/J = percutaneous endoscopic gastrostomy/jejunostomy; PEO = progressive external ophthalmoplegia; PT = physical therapy; TPN = total parenteral nutrition
• Speech & language therapy
• Parenteral feeding to avoid aspiration
• Hearing aids
• Cochlear implants
• Consider regular assessments for insidious onset.
• Require ENT surgeon for cochlear implant.
• Dietary modifications to improve bowel movements
• Laxatives
• PEG/PEJ insertion (if clinically indicated)
• TPN (very rare)
• Regular BMI measurement
• Ensure appropriate growth based on centiles of children.
• Correction of blood sugar w/oral medication or insulin
• Targeted treatment based on clinical features & blood results
## Surveillance
Because most infants and young children with the encephalomyopathic form are severely affected and are hospitalized for prolonged periods from the onset of disease manifestations, they should be reviewed regularly by senior clinical specialists if they are hospitalized. The recommendations regarding frequency in
Recommended Surveillance of
Quarterly
W/o seizure correlates, routine EEG is not indicated.
Quarterly
Assessment of feeding
Monitor stool frequency.
Dietary assessment to maintain adequate nutrition & growth
BMI = body mass index; OT = occupational therapy; PT = physical therapy
Recommended Surveillance of
ADL = activities of daily living; BMI = body mass index; GI = gastrointestinal; OT = occupational therapy; PEO = progressive external ophthalmoplegia; PT = physical therapy
• Quarterly
• W/o seizure correlates, routine EEG is not indicated.
• Assessment of feeding
• Monitor stool frequency.
• Dietary assessment to maintain adequate nutrition & growth
Because most infants and young children with the encephalomyopathic form are severely affected and are hospitalized for prolonged periods from the onset of disease manifestations, they should be reviewed regularly by senior clinical specialists if they are hospitalized. The recommendations regarding frequency in
Recommended Surveillance of
Quarterly
W/o seizure correlates, routine EEG is not indicated.
Quarterly
Assessment of feeding
Monitor stool frequency.
Dietary assessment to maintain adequate nutrition & growth
BMI = body mass index; OT = occupational therapy; PT = physical therapy
• Quarterly
• W/o seizure correlates, routine EEG is not indicated.
• Assessment of feeding
• Monitor stool frequency.
• Dietary assessment to maintain adequate nutrition & growth
Recommended Surveillance of
ADL = activities of daily living; BMI = body mass index; GI = gastrointestinal; OT = occupational therapy; PEO = progressive external ophthalmoplegia; PT = physical therapy
## Agents/Circumstances to Avoid
Valproic acid should be used only in exceptional circumstances.
Decisions related to drug prescribing should always be tailored to the affected individual's specific needs and risks [
It is safe to use metformin in primary mitochondrial disease.
If indicated, linezolid could be used in mitochondrial disease with careful lactate monitoring, particularly in children and other individuals with preexisting lactic acidemia.
Although historically there have been largely theoretic concerns regarding general anesthetic use in individuals with mitochondrial disease, adverse events are exceptionally rare. Catabolism should be prevented by minimizing preoperative fasting and administering intravenous glucose perioperatively during prolonged anesthesia, unless the individual is on a ketogenic diet.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of at-risk relatives of an affected family member so that those with the
See
## Therapies Under Investigation
Search
## Genetic Counseling
With the exception of autosomal dominant progressive external ophthalmoplegia (adPEO),
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 (carriers) for autosomal recessive
If both parents are known to be heterozygous for an
A wide range of intrafamilial variability in symptomatology, age of onset, and severity is observed among sibs who inherit biallelic
Heterozygotes (carriers) for autosomal recessive
Individuals with
The offspring of individuals with less severe manifestations of an autosomal recessive
Most individuals diagnosed with an autosomal dominant
Some individuals diagnosed with an
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, 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 a mtDNA maintenance defect may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
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 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, 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 (carriers) for 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
• A wide range of intrafamilial variability in symptomatology, age of onset, and severity is observed among sibs who inherit biallelic
• Heterozygotes (carriers) for autosomal recessive
• Individuals with
• The offspring of individuals with less severe manifestations of an autosomal recessive
• Most individuals diagnosed with an autosomal dominant
• Some individuals diagnosed with an
• 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, 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 a mtDNA maintenance defect may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• 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
• 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 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, are carriers, or are at risk of being carriers.
## Mode of Inheritance
With the exception of autosomal dominant progressive external ophthalmoplegia (adPEO),
## 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.
Heterozygotes (carriers) for autosomal recessive
If both parents are known to be heterozygous for an
A wide range of intrafamilial variability in symptomatology, age of onset, and severity is observed among sibs who inherit biallelic
Heterozygotes (carriers) for autosomal recessive
Individuals with
The offspring of individuals with less severe manifestations of an autosomal recessive
• 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 (carriers) for 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
• A wide range of intrafamilial variability in symptomatology, age of onset, and severity is observed among sibs who inherit biallelic
• Heterozygotes (carriers) for autosomal recessive
• Individuals with
• The offspring of individuals with less severe manifestations of an autosomal recessive
## Autosomal Dominant Inheritance – Risk to Family Members
Most individuals diagnosed with an autosomal dominant
Some individuals diagnosed with an
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, 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 a mtDNA maintenance defect may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
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 parents have not been tested for the
• Most individuals diagnosed with an autosomal dominant
• Some individuals diagnosed with an
• 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, 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 a mtDNA maintenance defect may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the pathogenic variant identified in the proband.
• 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
• 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 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, 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
Australia
United Kingdom
United Kingdom
•
• Australia
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
RRM2B Mitochondrial DNA Maintenance Defects: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for RRM2B Mitochondrial DNA Maintenance Defects (
Abnormal p53R2 function results in disruption of mtDNA maintenance (replication and repair), leading to qualitative (accumulation of multiple mtDNA deletions) and/or quantitative (depletion of mtDNA copy number) downstream mitochondrial genomic effects.
Truncating variants in the last exon in unrelated individuals with familial autosomal dominant PEO result in abnormal mRNA that escapes nonsense-mediated decay and production of a truncated protein. A dominant-negative or gain-of-function effect on the heterotetrameric structure of the RNR enzyme has been suggested [
## Molecular Pathogenesis
Abnormal p53R2 function results in disruption of mtDNA maintenance (replication and repair), leading to qualitative (accumulation of multiple mtDNA deletions) and/or quantitative (depletion of mtDNA copy number) downstream mitochondrial genomic effects.
Truncating variants in the last exon in unrelated individuals with familial autosomal dominant PEO result in abnormal mRNA that escapes nonsense-mediated decay and production of a truncated protein. A dominant-negative or gain-of-function effect on the heterotetrameric structure of the RNR enzyme has been suggested [
## Chapter Notes
The authors of this chapter have offered to review
Work in Newcastle is supported by the Wellcome Centre for Mitochondrial Research (203105); Newcastle University Centre for Ageing and Vitality (supported by the Biotechnology and Biological Sciences Research Council and Medical Research Council [L016354]); UK National Institute for Health Research (NIHR) Biomedical Research Centre for Ageing and Age‐Related Disease award to the Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust; NIHR; the Lily Foundation; and the UK NHS Specialist Commissioners, which funds the Rare Mitochondrial Disorders of Adults and Children Diagnostic Service in Newcastle upon Tyne (
24 June 2021 (bp) Comprehensive update posted live
17 April 2014 (me) Review posted live
31 May 2013 (gg) Original submission
• 24 June 2021 (bp) Comprehensive update posted live
• 17 April 2014 (me) Review posted live
• 31 May 2013 (gg) Original submission
## Author Notes
The authors of this chapter have offered to review
## Acknowledgments
Work in Newcastle is supported by the Wellcome Centre for Mitochondrial Research (203105); Newcastle University Centre for Ageing and Vitality (supported by the Biotechnology and Biological Sciences Research Council and Medical Research Council [L016354]); UK National Institute for Health Research (NIHR) Biomedical Research Centre for Ageing and Age‐Related Disease award to the Newcastle upon Tyne Hospitals National Health Service (NHS) Foundation Trust; NIHR; the Lily Foundation; and the UK NHS Specialist Commissioners, which funds the Rare Mitochondrial Disorders of Adults and Children Diagnostic Service in Newcastle upon Tyne (
## Revision History
24 June 2021 (bp) Comprehensive update posted live
17 April 2014 (me) Review posted live
31 May 2013 (gg) Original submission
• 24 June 2021 (bp) Comprehensive update posted live
• 17 April 2014 (me) Review posted live
• 31 May 2013 (gg) Original submission
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Schematic representation of the
|
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"A Spinazzola, F Invernizzi, F Carrara, E Lamantea, A Donati, M Dirocco, I Giordano, M Meznaric-Petrusa, E Baruffini, I Ferrero, M. Zeviani. Clinical and molecular features of mitochondrial DNA depletion syndromes.. J Inherit Metab Dis. 2009;32:143-58",
"V Stojanovic, JA Mayr, W Sperl, N Barišić, A Doronjski, G Milak. Infantile peripheral neuropathy, deafness, and proximal tubulopathy associated with a novel mutation of the RRM2B gene: case study.. Croat Med J. 2013;54:579-84",
"A Takata, M Kato, M Nakamura, T Yoshikawa, S Kanba, A Sano, T Kato. Exome sequencing identifies a novel missense variant in RRM2B associated with autosomal recessive progressive external ophthalmoplegia.. Genome Biol. 2011;12:R92",
"H Tyynismaa, E Ylikallio, M Patel, MJ Molnar, RG Haller, A Suomalainen. A heterozygous truncating mutation in RRM2B causes autosomal-dominant progressive external ophthalmoplegia with multiple mtDNA deletions.. Am J Hum Genet. 2009;85:290-5"
] |
17/4/2014
|
24/6/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
rss
|
rss
|
[
"Russell-Silver Syndrome",
"Russell-Silver Syndrome",
"Cyclin-dependent kinase inhibitor 1C",
"High mobility group protein HMGI-C",
"Insulin-like growth factor 2",
"Zinc finger protein PLAG1",
"CDKN1C",
"H19",
"HMGA2",
"IGF2",
"PLAG1",
"Silver-Russell Syndrome"
] |
Silver-Russell Syndrome
|
Howard M Saal, Madeleine D Harbison, Irene Netchine
|
Summary Silver-Russell Syndrome (SRS) is typically characterized by gestational growth restriction resulting in affected individuals being born small for gestational age, with relative macrocephaly at birth (head circumference ≥1.5 standard deviations [SD] above birth weight and/or length), prominent forehead with frontal bossing, and frequently body asymmetry. This is typically followed by postnatal growth failure, and in some cases progressive limb length discrepancy and feeding difficulties. Additional clinical features include triangular facies, fifth finger clinodactyly, and micrognathia with narrow chin. Except for the limb length asymmetry, growth failure is proportionate and head growth typically normal. The average adult height in untreated individuals is ~3.1±1.4 SD below the mean. The Netchine-Harbison Clinical Scoring System (NH-CSS) is a sensitive diagnostic scoring system. Clinical diagnosis can be established in an individual who meets at least four of the NH-CSS clinical criteria – prominent forehead/frontal bossing and relative macrocephaly at birth plus two additional findings – and in whom other disorders have been ruled out. SRS is a genetically heterogeneous condition. Genetic testing confirms clinical diagnosis in approximately 60% of affected individuals. 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. There are a small number of individuals with SRS who have duplications, deletions, or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, affected individuals with pathogenic variants in
|
## Diagnosis
Consensus clinical diagnostic criteria for Silver-Russell syndrome (SRS) have been published [
SRS
Small for gestational age (birth weight and/or length two or more standard deviations [SD] below the mean for gestational age)
Postnatal growth failure (length/height two or more SD below the mean for age and sex at age 24 months)
Relative macrocephaly at birth (head circumference more than 1.5 SD above birth weight and/or length)
Frontal bossing or prominent forehead (forehead projecting beyond the facial plane on a side view at age one to three years)
Body asymmetry (limb length discrepancy ≥0.5 cm, or <0.5 cm with ≥2 other asymmetric body parts)
Feeding difficulties, or body mass index two or more SD below the mean at age two years, or current use of a feeding tube or cyproheptadine for appetite stimulation
Rarely, individuals meeting three of the six criteria have had positive molecular confirmation of SRS.
The clinical diagnosis of SRS
Note: Molecular genetic testing is recommended in all individuals with suspected SRS to provide accurate recurrence risk information.
SRS is an etiologically heterogeneous condition. In the international consensus statement for the diagnosis and management of SRS [
The clinical diagnosis of SRS can be established in a proband with at least four of the six NH-CSS clinical diagnostic criteria (see
Two of the criteria must be relative macrocephaly at birth and frontal bossing or prominent forehead.
Other disorders with growth restriction must be ruled out either based on clinical features or molecular testing [
Note: In older children and adults, frontal bossing or a prominent forehead may disappear. Therefore, a clinical diagnosis of SRS in older children and adults may require assessment of profile photographs from age two years or younger.
The molecular diagnosis of SRS can be established in a proband with one of the following identified on molecular genetic testing (see
An international expert consensus algorithm for the molecular investigation of SRS has been published [
Note: (1) Detection of an abnormality is dependent on the mechanism of disease and testing methodology used (see
Note: (1) The genes included in various multigene panels and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Silver-Russell Syndrome
chr = chromosome; SNP = single-nucleotide polymorphisms; STR = short tandem repeat; upd(7)mat = maternal uniparental disomy of chromosome 7; upd(11)mat = maternal uniparental disomy of chromosome 11
See
Assays developed to be methylation sensitive such as multiplex ligation probe analysis (MS-MLPA), quantitative PCR (MS-qPCR), or Southern blotting (mainly historical testing) allow detection of epigenetic and genomic alterations of 11p15.5. Methylation-sensitive assays can diagnose SRS resulting from DNA methylation alterations, deletions, and duplications, or uniparental disomy (UPD). Interpretation of methylation data should consider results of copy number testing because copy number variants that alter the relative dosage of parental contributions (e.g., paternal duplication) are associated with abnormal methylation status. Note that MLPA testing may be followed by microarray testing to define breakpoints of deletions or duplications. Other methods to confirm maternal UPD at 11p15.5 include short tandem repeat (STR) analysis or SNP analysis [
A small number of individuals have hypomethylation of only
False negatives may occur because of mosaicism as 11p15.5 hypomethylation occurs post fertilization. Testing tissues from a second source (e.g., buccal cells or fibroblasts) should be performed.
Both isodisomy and heterodisomy [
A
A
Note: SNP array analysis will detect maternal UPD only in those with isodisomy; 28.8% of upd(7)mat (2%-3% of all individuals with SRS) are a result of isodisomy [
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, partial-, whole-, or multigene 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.
Several reports, including one four-generation family segregating a
One family with SRS and a paternally transmitted
Heterozygous loss-of-function
Heterozygous loss-of-function
Approximately 40% of individuals with at least four of the six Netchine-Harbison clinical diagnostic criteria will have nondiagnostic laboratory studies.
• Small for gestational age (birth weight and/or length two or more standard deviations [SD] below the mean for gestational age)
• Postnatal growth failure (length/height two or more SD below the mean for age and sex at age 24 months)
• Relative macrocephaly at birth (head circumference more than 1.5 SD above birth weight and/or length)
• Frontal bossing or prominent forehead (forehead projecting beyond the facial plane on a side view at age one to three years)
• Body asymmetry (limb length discrepancy ≥0.5 cm, or <0.5 cm with ≥2 other asymmetric body parts)
• Feeding difficulties, or body mass index two or more SD below the mean at age two years, or current use of a feeding tube or cyproheptadine for appetite stimulation
• Two of the criteria must be relative macrocephaly at birth and frontal bossing or prominent forehead.
• Other disorders with growth restriction must be ruled out either based on clinical features or molecular testing [
•
•
• Note: (1) Detection of an abnormality is dependent on the mechanism of disease and testing methodology used (see
• Note: (1) The genes included in various multigene panels and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
• For an introduction to multigene panels click
•
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
SRS
Small for gestational age (birth weight and/or length two or more standard deviations [SD] below the mean for gestational age)
Postnatal growth failure (length/height two or more SD below the mean for age and sex at age 24 months)
Relative macrocephaly at birth (head circumference more than 1.5 SD above birth weight and/or length)
Frontal bossing or prominent forehead (forehead projecting beyond the facial plane on a side view at age one to three years)
Body asymmetry (limb length discrepancy ≥0.5 cm, or <0.5 cm with ≥2 other asymmetric body parts)
Feeding difficulties, or body mass index two or more SD below the mean at age two years, or current use of a feeding tube or cyproheptadine for appetite stimulation
Rarely, individuals meeting three of the six criteria have had positive molecular confirmation of SRS.
• Small for gestational age (birth weight and/or length two or more standard deviations [SD] below the mean for gestational age)
• Postnatal growth failure (length/height two or more SD below the mean for age and sex at age 24 months)
• Relative macrocephaly at birth (head circumference more than 1.5 SD above birth weight and/or length)
• Frontal bossing or prominent forehead (forehead projecting beyond the facial plane on a side view at age one to three years)
• Body asymmetry (limb length discrepancy ≥0.5 cm, or <0.5 cm with ≥2 other asymmetric body parts)
• Feeding difficulties, or body mass index two or more SD below the mean at age two years, or current use of a feeding tube or cyproheptadine for appetite stimulation
## Establishing the Diagnosis
The clinical diagnosis of SRS
Note: Molecular genetic testing is recommended in all individuals with suspected SRS to provide accurate recurrence risk information.
SRS is an etiologically heterogeneous condition. In the international consensus statement for the diagnosis and management of SRS [
The clinical diagnosis of SRS can be established in a proband with at least four of the six NH-CSS clinical diagnostic criteria (see
Two of the criteria must be relative macrocephaly at birth and frontal bossing or prominent forehead.
Other disorders with growth restriction must be ruled out either based on clinical features or molecular testing [
Note: In older children and adults, frontal bossing or a prominent forehead may disappear. Therefore, a clinical diagnosis of SRS in older children and adults may require assessment of profile photographs from age two years or younger.
The molecular diagnosis of SRS can be established in a proband with one of the following identified on molecular genetic testing (see
An international expert consensus algorithm for the molecular investigation of SRS has been published [
Note: (1) Detection of an abnormality is dependent on the mechanism of disease and testing methodology used (see
Note: (1) The genes included in various multigene panels and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Silver-Russell Syndrome
chr = chromosome; SNP = single-nucleotide polymorphisms; STR = short tandem repeat; upd(7)mat = maternal uniparental disomy of chromosome 7; upd(11)mat = maternal uniparental disomy of chromosome 11
See
Assays developed to be methylation sensitive such as multiplex ligation probe analysis (MS-MLPA), quantitative PCR (MS-qPCR), or Southern blotting (mainly historical testing) allow detection of epigenetic and genomic alterations of 11p15.5. Methylation-sensitive assays can diagnose SRS resulting from DNA methylation alterations, deletions, and duplications, or uniparental disomy (UPD). Interpretation of methylation data should consider results of copy number testing because copy number variants that alter the relative dosage of parental contributions (e.g., paternal duplication) are associated with abnormal methylation status. Note that MLPA testing may be followed by microarray testing to define breakpoints of deletions or duplications. Other methods to confirm maternal UPD at 11p15.5 include short tandem repeat (STR) analysis or SNP analysis [
A small number of individuals have hypomethylation of only
False negatives may occur because of mosaicism as 11p15.5 hypomethylation occurs post fertilization. Testing tissues from a second source (e.g., buccal cells or fibroblasts) should be performed.
Both isodisomy and heterodisomy [
A
A
Note: SNP array analysis will detect maternal UPD only in those with isodisomy; 28.8% of upd(7)mat (2%-3% of all individuals with SRS) are a result of isodisomy [
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, partial-, whole-, or multigene 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.
Several reports, including one four-generation family segregating a
One family with SRS and a paternally transmitted
Heterozygous loss-of-function
Heterozygous loss-of-function
Approximately 40% of individuals with at least four of the six Netchine-Harbison clinical diagnostic criteria will have nondiagnostic laboratory studies.
• Two of the criteria must be relative macrocephaly at birth and frontal bossing or prominent forehead.
• Other disorders with growth restriction must be ruled out either based on clinical features or molecular testing [
•
•
• Note: (1) Detection of an abnormality is dependent on the mechanism of disease and testing methodology used (see
• Note: (1) The genes included in various multigene panels and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
• For an introduction to multigene panels click
•
• For an introduction to comprehensive genomic testing click
## Clinical Diagnosis
SRS is an etiologically heterogeneous condition. In the international consensus statement for the diagnosis and management of SRS [
The clinical diagnosis of SRS can be established in a proband with at least four of the six NH-CSS clinical diagnostic criteria (see
Two of the criteria must be relative macrocephaly at birth and frontal bossing or prominent forehead.
Other disorders with growth restriction must be ruled out either based on clinical features or molecular testing [
Note: In older children and adults, frontal bossing or a prominent forehead may disappear. Therefore, a clinical diagnosis of SRS in older children and adults may require assessment of profile photographs from age two years or younger.
• Two of the criteria must be relative macrocephaly at birth and frontal bossing or prominent forehead.
• Other disorders with growth restriction must be ruled out either based on clinical features or molecular testing [
## Molecular Diagnosis
The molecular diagnosis of SRS can be established in a proband with one of the following identified on molecular genetic testing (see
An international expert consensus algorithm for the molecular investigation of SRS has been published [
Note: (1) Detection of an abnormality is dependent on the mechanism of disease and testing methodology used (see
Note: (1) The genes included in various multigene panels and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Silver-Russell Syndrome
chr = chromosome; SNP = single-nucleotide polymorphisms; STR = short tandem repeat; upd(7)mat = maternal uniparental disomy of chromosome 7; upd(11)mat = maternal uniparental disomy of chromosome 11
See
Assays developed to be methylation sensitive such as multiplex ligation probe analysis (MS-MLPA), quantitative PCR (MS-qPCR), or Southern blotting (mainly historical testing) allow detection of epigenetic and genomic alterations of 11p15.5. Methylation-sensitive assays can diagnose SRS resulting from DNA methylation alterations, deletions, and duplications, or uniparental disomy (UPD). Interpretation of methylation data should consider results of copy number testing because copy number variants that alter the relative dosage of parental contributions (e.g., paternal duplication) are associated with abnormal methylation status. Note that MLPA testing may be followed by microarray testing to define breakpoints of deletions or duplications. Other methods to confirm maternal UPD at 11p15.5 include short tandem repeat (STR) analysis or SNP analysis [
A small number of individuals have hypomethylation of only
False negatives may occur because of mosaicism as 11p15.5 hypomethylation occurs post fertilization. Testing tissues from a second source (e.g., buccal cells or fibroblasts) should be performed.
Both isodisomy and heterodisomy [
A
A
Note: SNP array analysis will detect maternal UPD only in those with isodisomy; 28.8% of upd(7)mat (2%-3% of all individuals with SRS) are a result of isodisomy [
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, partial-, whole-, or multigene 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.
Several reports, including one four-generation family segregating a
One family with SRS and a paternally transmitted
Heterozygous loss-of-function
Heterozygous loss-of-function
Approximately 40% of individuals with at least four of the six Netchine-Harbison clinical diagnostic criteria will have nondiagnostic laboratory studies.
•
•
• Note: (1) Detection of an abnormality is dependent on the mechanism of disease and testing methodology used (see
• Note: (1) The genes included in various multigene panels and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
• For an introduction to multigene panels click
•
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Silver-Russell Syndrome (SRS) is characterized by intrauterine growth restriction resulting in affected individuals being born small for gestational age with relative macrocephaly (head circumference ≥1.5 standard deviations [SD] above birth weight and/or length), a prominent forehead usually with frontal bossing, and frequently body asymmetry. This is followed by postnatal growth failure and, in some individuals, progressive limb length discrepancy and severe feeding difficulties in the first few years of life. Additional clinical features include triangular facies, fifth finger clinodactyly, and micrognathia with a small chin. Except for the limb length asymmetry, growth failure is usually proportionate but with normal head growth. The average adult height in untreated individuals is ~3.1±1.4 SD below the mean.
To date, more than 1,000 individuals have been diagnosed with SRS [
Silver-Russell Syndrome: Frequency of Select Features
Based on
In two European series of untreated adults with SRS, height ranged from 3.7 to 3.5 SD below the mean for males and 4.2 to 2.5 SD below the mean for females [
Growth charts for European children with SRS have been published [
The goals of GH treatment are multifaceted, including improving growth velocity, body composition (especially lean body mass), psychomotor development, and appetite, as well as reducing the risk of hypoglycemia and optimizing overall linear growth [
Note: Many children with SRS do not achieve normal stature even with administration of human GH if rapid bone age advancement during puberty is not managed (see
Testing for GH deficiency by fasting is contraindicated because of the risk for inducing hypoglycemia [
Treatment with GH in SRS is indicated regardless of the presence or absence of GH deficiency.
Gastrointestinal disorders should be treated early and adequately. It is critical that attention to growth and nutrition begin in infancy. Aggressive feeding measures are often required, including use of nasogastric tubes or, less frequently, gastrostomy tube placement (see
Limb length asymmetry, caused by hypoplasia or hemihypoplasia with diminished growth of the affected side
Fifth finger clinodactyly and/or brachydactyly. These are among the most frequently described skeletal anomalies (albeit minor) in individuals with SRS.
Scoliosis, which has been reported in up to 36% of individuals with SRS in some studies [
In a review of a large cohort of children with SRS with either 11p15 methylation defects or upd(7)mat, developmental delay was seen in 34% of individuals; the majority had mild delays. Developmental delays were more commonly seen in those with maternal upd(7)mat than those with 11p15 methylation defects (65% vs 20%). Speech delays were common in both groups [
A study surveying adults with SRS reported that 64.5% had motor delays and 38.7% had speech delay, with most of the subjects having attended mainstream education and 21.2% receiving special education support. For individuals older than 21 years, 40% obtained university degrees [
Several genotype-phenotype correlations have been observed in individuals with SRS.
Using methylation-sensitive restriction enzymes to measure the degree of methylation of
A study by
In another study, children with SRS due to upd(7)mat attained more linear growth (or height) with GH therapy compared to children with 11p15.5 ICR1 hypomethylation, possibly because children with 11p15.5 methylation abnormalities showed elevated levels of insulin-like growth factor 1 (IGF-1, the product of
A series of children with SRS with 11p15.5 loss of methylation (LOM), upd(7)mat, and SRS with no identified epigenetic or genetic variants showed genotype-phenotype correlations comparable to children with SRS reported in earlier publications. There were more individuals who were small for gestational age in the 11p15.5 LOM group and SRS group with no identified epigenetic/genetic etiology compared to those with upd(7)mat. Triangular face and frontal bossing were more common in individuals with 11p15.5 LOM and no epigenetic/genetic etiology cases compared to those with upd(7)mat. Facial and limb asymmetry were more common in individuals with 11p15.5 LOM compared to the upd(7)mat and SRS with no epigenetic/genetic abnormalities groups [
Another study comparing individuals with SRS due to 11p15.5 LOM to individuals with SRS due to upd(7)mat showed similar body weight at diagnosis (3 and 3.2 SD below the mean, respectively), but heights were greater in individuals with 11p15.5 LOM (3.0 SD below the mean) compared to those with upd(7)mat (3.8 SD below the mean). Asymmetry was seen in 76% of individuals with 11p15.5 LOM vs 50% of individuals with upd(7)mat. Most cases in both groups had normal neurocognitive development (86% of individuals with 11p15.5 LOM and 80% of individuals with upd(7)mat). Triangular facies were reported in 89% of individuals with 11p15.5 LOM vs 50% of those with upd(7)mat. Also of note, clinodactyly was more frequently reported in individuals with 11p11.5 LOM (68%) compared to those with upd(7)mat (20%). Genital anomalies were seen in 19% of individuals with 11p15.5 LOM and none of the individuals with upd(7)mat [
Penetrance for SRS is estimated to be 100% for males and females. Sex-limited penetrance is observed in individuals with
The prevalence of SRS is unknown and was previously estimated at 1:30,000-100,000 (A Toutain,
• Testing for GH deficiency by fasting is contraindicated because of the risk for inducing hypoglycemia [
• Treatment with GH in SRS is indicated regardless of the presence or absence of GH deficiency.
• Limb length asymmetry, caused by hypoplasia or hemihypoplasia with diminished growth of the affected side
• Fifth finger clinodactyly and/or brachydactyly. These are among the most frequently described skeletal anomalies (albeit minor) in individuals with SRS.
• Scoliosis, which has been reported in up to 36% of individuals with SRS in some studies [
## Clinical Description
Silver-Russell Syndrome (SRS) is characterized by intrauterine growth restriction resulting in affected individuals being born small for gestational age with relative macrocephaly (head circumference ≥1.5 standard deviations [SD] above birth weight and/or length), a prominent forehead usually with frontal bossing, and frequently body asymmetry. This is followed by postnatal growth failure and, in some individuals, progressive limb length discrepancy and severe feeding difficulties in the first few years of life. Additional clinical features include triangular facies, fifth finger clinodactyly, and micrognathia with a small chin. Except for the limb length asymmetry, growth failure is usually proportionate but with normal head growth. The average adult height in untreated individuals is ~3.1±1.4 SD below the mean.
To date, more than 1,000 individuals have been diagnosed with SRS [
Silver-Russell Syndrome: Frequency of Select Features
Based on
In two European series of untreated adults with SRS, height ranged from 3.7 to 3.5 SD below the mean for males and 4.2 to 2.5 SD below the mean for females [
Growth charts for European children with SRS have been published [
The goals of GH treatment are multifaceted, including improving growth velocity, body composition (especially lean body mass), psychomotor development, and appetite, as well as reducing the risk of hypoglycemia and optimizing overall linear growth [
Note: Many children with SRS do not achieve normal stature even with administration of human GH if rapid bone age advancement during puberty is not managed (see
Testing for GH deficiency by fasting is contraindicated because of the risk for inducing hypoglycemia [
Treatment with GH in SRS is indicated regardless of the presence or absence of GH deficiency.
Gastrointestinal disorders should be treated early and adequately. It is critical that attention to growth and nutrition begin in infancy. Aggressive feeding measures are often required, including use of nasogastric tubes or, less frequently, gastrostomy tube placement (see
Limb length asymmetry, caused by hypoplasia or hemihypoplasia with diminished growth of the affected side
Fifth finger clinodactyly and/or brachydactyly. These are among the most frequently described skeletal anomalies (albeit minor) in individuals with SRS.
Scoliosis, which has been reported in up to 36% of individuals with SRS in some studies [
In a review of a large cohort of children with SRS with either 11p15 methylation defects or upd(7)mat, developmental delay was seen in 34% of individuals; the majority had mild delays. Developmental delays were more commonly seen in those with maternal upd(7)mat than those with 11p15 methylation defects (65% vs 20%). Speech delays were common in both groups [
A study surveying adults with SRS reported that 64.5% had motor delays and 38.7% had speech delay, with most of the subjects having attended mainstream education and 21.2% receiving special education support. For individuals older than 21 years, 40% obtained university degrees [
• Testing for GH deficiency by fasting is contraindicated because of the risk for inducing hypoglycemia [
• Treatment with GH in SRS is indicated regardless of the presence or absence of GH deficiency.
• Limb length asymmetry, caused by hypoplasia or hemihypoplasia with diminished growth of the affected side
• Fifth finger clinodactyly and/or brachydactyly. These are among the most frequently described skeletal anomalies (albeit minor) in individuals with SRS.
• Scoliosis, which has been reported in up to 36% of individuals with SRS in some studies [
## Genotype-Phenotype Correlations
Several genotype-phenotype correlations have been observed in individuals with SRS.
Using methylation-sensitive restriction enzymes to measure the degree of methylation of
A study by
In another study, children with SRS due to upd(7)mat attained more linear growth (or height) with GH therapy compared to children with 11p15.5 ICR1 hypomethylation, possibly because children with 11p15.5 methylation abnormalities showed elevated levels of insulin-like growth factor 1 (IGF-1, the product of
A series of children with SRS with 11p15.5 loss of methylation (LOM), upd(7)mat, and SRS with no identified epigenetic or genetic variants showed genotype-phenotype correlations comparable to children with SRS reported in earlier publications. There were more individuals who were small for gestational age in the 11p15.5 LOM group and SRS group with no identified epigenetic/genetic etiology compared to those with upd(7)mat. Triangular face and frontal bossing were more common in individuals with 11p15.5 LOM and no epigenetic/genetic etiology cases compared to those with upd(7)mat. Facial and limb asymmetry were more common in individuals with 11p15.5 LOM compared to the upd(7)mat and SRS with no epigenetic/genetic abnormalities groups [
Another study comparing individuals with SRS due to 11p15.5 LOM to individuals with SRS due to upd(7)mat showed similar body weight at diagnosis (3 and 3.2 SD below the mean, respectively), but heights were greater in individuals with 11p15.5 LOM (3.0 SD below the mean) compared to those with upd(7)mat (3.8 SD below the mean). Asymmetry was seen in 76% of individuals with 11p15.5 LOM vs 50% of individuals with upd(7)mat. Most cases in both groups had normal neurocognitive development (86% of individuals with 11p15.5 LOM and 80% of individuals with upd(7)mat). Triangular facies were reported in 89% of individuals with 11p15.5 LOM vs 50% of those with upd(7)mat. Also of note, clinodactyly was more frequently reported in individuals with 11p11.5 LOM (68%) compared to those with upd(7)mat (20%). Genital anomalies were seen in 19% of individuals with 11p15.5 LOM and none of the individuals with upd(7)mat [
## Penetrance
Penetrance for SRS is estimated to be 100% for males and females. Sex-limited penetrance is observed in individuals with
## Prevalence
The prevalence of SRS is unknown and was previously estimated at 1:30,000-100,000 (A Toutain,
## Genetically Related (Allelic) Disorders
Allelic Disorders
Abnormal regulation of gene transcription in the imprinted domain on chr 11p15.5 (i.e., the BWS critical region)
Maternally inherited loss-of-function pathogenic variant in
Loss of methylation at the ICR2
Gain of methylation at the ICR1
Paternal UPD of chr 11p15
Hypermethylation at the ICR1
Paternal UPD of chr 11p15.5
Genomic abnormalities incl deletions & insertions
chr = chromosome; ICR = imprinting control region; UPD = uniparental disomy
• Abnormal regulation of gene transcription in the imprinted domain on chr 11p15.5 (i.e., the BWS critical region)
• Maternally inherited loss-of-function pathogenic variant in
• Loss of methylation at the ICR2
• Gain of methylation at the ICR1
• Paternal UPD of chr 11p15
• Hypermethylation at the ICR1
• Paternal UPD of chr 11p15.5
• Genomic abnormalities incl deletions & insertions
## Differential Diagnosis
Note: Bone age may be delayed in children with SRS; however, delayed bone age is a nonspecific finding frequently seen in children with intrauterine growth restriction of many etiologies.
Disorders with intrauterine growth restriction and poor postnatal growth of interest in the differential diagnosis of SRS are listed in
Monogenic Disorders with IUGR and Poor Postnatal Growth to Consider in the Differential Diagnosis of Silver-Russell Syndrome
Abnormal sister chromatid exchange
Microcephaly
↑ chromosome breakage
Absent thumb(s) or thumb hypoplasia
Microcephaly
Radial anomalies
↑ malignancy risk
Fifth finger clinodactyly
Relatively large head
Triangular facies
Short broad neck
No limb or facial asymmetry
Frontal bossing
Small mouth
Absent patellae
Microcephaly
Microtia
Frontal bossing
Genital abnormalities
Adrenal hypoplasia
Adrenal insufficiency
Metaphyseal dysplasia
Blue sclerae
Relatively large head
Triangular face
Extremely delayed growth in progressively deforming OI
Fractures w/minimal or absent trauma
Dentinogenesis imperfecta
Hearing loss (in adult years)
↑ chromosome breakage
Hearing loss
Microcephaly
Clinodactyly
Dental anomalies
Global DD
Microcephaly
Synophrys
Chromosome instability
Microcephaly
Sloping forehead
Disproportionate short stature w/mesomelic shortening
Microcephaly
Skeletal anomalies
Dysmorphic facial features
Clinodactyly
High-pitched voice
Male genital anomalies
Wide mouth
Prominent nose
Clavicular abnormalities
Cone-shaped epiphyses
Broad thumbs & great toes
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; IUGR = intrauterine growth restriction; MOI = mode of inheritance; XL = X-linked
Typically a
Chromosomal Abnormalities Associated with IUGR and Poor Postnatal Growth to Consider in the Differential Diagnosis of Silver-Russell Syndrome
Global DD
Microcephaly
Triangular face
Frontal bossing
Clinodactyly
No asymmetry
No relative macrocephaly
No postnatal growth restriction; catch-up growth seen in many persons
Challenging to distinguish on clinical basis
Later in life, affected persons are overweight w/truncal obesity.
Triangular face
Feeding difficulties
Clinodactyly
Cryptorchidism
Hypotonia
No relative macrocephaly
No asymmetry
chr = chromosome; DD = developmental delay; IUGR = intrauterine growth restriction; LOM = loss of methylation; UPD = uniparental disomy
For individuals with methylation alterations in the 11p15 imprinted domain as well as other imprinted loci, review of the maternal history should be undertaken for findings such as recurrent pregnancy loss or molar pregnancy. In these situations, consideration should be given to testing for pathogenic variants in maternal effect genes that lead to SRS. If a pathogenic variant in a maternal effect gene is detected in the proband and mother, information regarding the increased risk for reproductive complications such as preeclampsia, recurrent pregnancy loss, and molar pregnancy as well as the significant risk for having children with imprinting disorders should be addressed through genetic counseling [
Eleven individuals with SRS tested using MS-MLPA assays were found to have MLID with methylation disturbances at up to nine imprinted differentially methylated regions (iDMRs) per person. In addition to imprinting control region 1 (ICR1), the most frequent loci involved were ICR2 and
Note: It is not yet clear if oligogenic or multifactorial causes are relevant in MLID. While it appears that some heterozygous variants in SCMC genes may be disease causing, such cases may also be associated with unidentified pathogenic variants in the second allele or pathogenic variants in other SCMC genes. In addition, the potential interaction of pathogenic variants with interventions such as assisted reproductive technology will be an important area of future work.
• Abnormal sister chromatid exchange
• Microcephaly
• ↑ chromosome breakage
• Absent thumb(s) or thumb hypoplasia
• Microcephaly
• Radial anomalies
• ↑ malignancy risk
• Fifth finger clinodactyly
• Relatively large head
• Triangular facies
• Short broad neck
• No limb or facial asymmetry
• Frontal bossing
• Small mouth
• Absent patellae
• Microcephaly
• Microtia
• Frontal bossing
• Genital abnormalities
• Adrenal hypoplasia
• Adrenal insufficiency
• Metaphyseal dysplasia
• Blue sclerae
• Relatively large head
• Triangular face
• Extremely delayed growth in progressively deforming OI
• Fractures w/minimal or absent trauma
• Dentinogenesis imperfecta
• Hearing loss (in adult years)
• ↑ chromosome breakage
• Hearing loss
• Microcephaly
• Clinodactyly
• Dental anomalies
• Global DD
• Microcephaly
• Synophrys
• Chromosome instability
• Microcephaly
• Sloping forehead
• Disproportionate short stature w/mesomelic shortening
• Microcephaly
• Skeletal anomalies
• Dysmorphic facial features
• Clinodactyly
• High-pitched voice
• Male genital anomalies
• Wide mouth
• Prominent nose
• Clavicular abnormalities
• Cone-shaped epiphyses
• Broad thumbs & great toes
• Global DD
• Microcephaly
• Triangular face
• Frontal bossing
• Clinodactyly
• No asymmetry
• No relative macrocephaly
• No postnatal growth restriction; catch-up growth seen in many persons
• Challenging to distinguish on clinical basis
• Later in life, affected persons are overweight w/truncal obesity.
• Triangular face
• Feeding difficulties
• Clinodactyly
• Cryptorchidism
• Hypotonia
• No relative macrocephaly
• No asymmetry
## Management
International consensus management guidelines for Silver-Russell Syndrome (SRS) have been published [
To establish the extent of disease and needs in an individual diagnosed with SRS, the evaluations summarized in
Silver-Russell Syndrome: Recommended Evaluations Following Initial Diagnosis
For children suspected of having GERD, eval for esophagitis incl video swallow studies, gastric emptying studies, pH probe, & endoscopy are recommended.
Intestinal malrotation has been reported & needs to be ruled out in those w/feeding disorders, constipation, & delayed gastric emptying.
Physical exam for cleft palate & bifid uvula w/submucous cleft palate
Referral to craniofacial center for further eval & mgmt
Community or
Social work involvement for parental support
Home nursing referral
GERD = gastroesophageal reflux disease; GH = growth hormone; MOI = mode of inheritance; SRS = Silver-Russell syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for SRS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists including an endocrinologist, gastroenterologist, dietician, clinical geneticist and genetic counselor, craniofacial team, orthopedic surgeon, neurologist, speech-language therapist, and psychologist (see
Silver-Russell Syndrome: Treatment of Manifestations
Frequent feeding, avoidance of prolonged fasting between feeds (≤4 hours in infants), & complex carbohydrates are recommended.
Monitoring for urinary ketones after prolonged fasting (incl when infants start sleeping through the night) or w/excess physical activity or illness is recommended.
Measures incl nutritional & caloric supplements; treatment of GERD; speech &/or occupational therapy for oral motor problems & oral aversion; appetite stimulants such as cyproheptadine; enteral feeding w/gastrostomy or jejunostomy tube for extreme cases of feeding aversion &/or GERD w/ or w/o fundoplication
With non-volitional feeding, too rapid & excessive weight gain must be avoided.
Initial treatment of limb length discrepancy can incl use of a shoe lift. In older children, limb lengthening w/distraction osteogenesis is a commonly used procedure. When single-segment limb lengthening is sufficient, limb lengthening w/femoral internal distracters is generally done prior to completion of growth but close to final attainment of height. For young children w/leg length discrepancy >4 cm, lengthening is done in the lower segment (tibia) w/external fixators.
Scoliosis & kyphosis should be monitored & early bracing is recommended. Many individuals will need corrective surgery.
Dental hygiene & dental crowding is managed routinely by pediatric dentist &/or orthodontist.
Early dental care, orthodontia for dental crowding, & maxillofacial surgery may be needed in older children once growth is completed.
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
DSD = disorders of sex development; GH = growth hormone; GI = gastrointestinal; GnRH = gonadotropin-releasing hormone
Children with SRS have benefited from GH supplementation [
Many children with SRS do not achieve normal stature even with administration of human GH if rapid bone age advancement during puberty is not managed.
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.
Surveillance guidelines for children with SRS are outlined in
Silver-Russell Syndrome: Recommended Surveillance
Monitor for ketotic hypoglycemia (urine ketones & blood glucose) during infancy & in older children w/macrocephaly, lean body habitus, & poor appetite.
Monitor urine ketones to prevent hypoglycemia in infants when frequency of feeding is being ↓ & in children who are acutely ill w/↓ feeding or fever & in older children at time of ↑ physical activity.
Monitor for early signs of puberty incl early adrenarche due to risk of rapid bone age advancement & reduced final height despite GH therapy.
Eval of nutritional status & safety of oral intake
Monitor & manage nasogastric feeding or gastrostomy tube, if needed.
Monitor for constipation.
Exam & measurement of limb length discrepancy. Measurement of infant lengths & both legs recorded, & longer limb entered on a growth curve. For measuring height in older children, an appropriate-sized lift sufficient to level the hips should be placed under the foot of the shorter lower extremity.
Eval of scoliosis
Monitor developmental progress & educational needs.
Monitor speech articulation & language.
GH = growth hormone; GI = gastrointestinal; OT = occupational therapy; PT = physical therapy
Avoid prolonged fasting in infants and young children because of the risk of inducing hypoglycemia. For this reason, testing for GH deficiency by fasting is contraindicated [
Avoid elective surgery whenever possible. If surgery is unavoidable, physicians must be aware of the risk for hypoglycemia, hypothermia, difficult healing, and difficult intubation (due to abnormal tooth distribution and micrognathia, which can affect airway visualization and the intubation process).
See
Search
• For children suspected of having GERD, eval for esophagitis incl video swallow studies, gastric emptying studies, pH probe, & endoscopy are recommended.
• Intestinal malrotation has been reported & needs to be ruled out in those w/feeding disorders, constipation, & delayed gastric emptying.
• Physical exam for cleft palate & bifid uvula w/submucous cleft palate
• Referral to craniofacial center for further eval & mgmt
• Community or
• Social work involvement for parental support
• Home nursing referral
• Frequent feeding, avoidance of prolonged fasting between feeds (≤4 hours in infants), & complex carbohydrates are recommended.
• Monitoring for urinary ketones after prolonged fasting (incl when infants start sleeping through the night) or w/excess physical activity or illness is recommended.
• Measures incl nutritional & caloric supplements; treatment of GERD; speech &/or occupational therapy for oral motor problems & oral aversion; appetite stimulants such as cyproheptadine; enteral feeding w/gastrostomy or jejunostomy tube for extreme cases of feeding aversion &/or GERD w/ or w/o fundoplication
• With non-volitional feeding, too rapid & excessive weight gain must be avoided.
• Initial treatment of limb length discrepancy can incl use of a shoe lift. In older children, limb lengthening w/distraction osteogenesis is a commonly used procedure. When single-segment limb lengthening is sufficient, limb lengthening w/femoral internal distracters is generally done prior to completion of growth but close to final attainment of height. For young children w/leg length discrepancy >4 cm, lengthening is done in the lower segment (tibia) w/external fixators.
• Scoliosis & kyphosis should be monitored & early bracing is recommended. Many individuals will need corrective surgery.
• Dental hygiene & dental crowding is managed routinely by pediatric dentist &/or orthodontist.
• Early dental care, orthodontia for dental crowding, & maxillofacial surgery may be needed in older children once growth is completed.
• 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.
• Monitor for ketotic hypoglycemia (urine ketones & blood glucose) during infancy & in older children w/macrocephaly, lean body habitus, & poor appetite.
• Monitor urine ketones to prevent hypoglycemia in infants when frequency of feeding is being ↓ & in children who are acutely ill w/↓ feeding or fever & in older children at time of ↑ physical activity.
• Monitor for early signs of puberty incl early adrenarche due to risk of rapid bone age advancement & reduced final height despite GH therapy.
• Eval of nutritional status & safety of oral intake
• Monitor & manage nasogastric feeding or gastrostomy tube, if needed.
• Monitor for constipation.
• Exam & measurement of limb length discrepancy. Measurement of infant lengths & both legs recorded, & longer limb entered on a growth curve. For measuring height in older children, an appropriate-sized lift sufficient to level the hips should be placed under the foot of the shorter lower extremity.
• Eval of scoliosis
• Monitor developmental progress & educational needs.
• Monitor speech articulation & language.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SRS, the evaluations summarized in
Silver-Russell Syndrome: Recommended Evaluations Following Initial Diagnosis
For children suspected of having GERD, eval for esophagitis incl video swallow studies, gastric emptying studies, pH probe, & endoscopy are recommended.
Intestinal malrotation has been reported & needs to be ruled out in those w/feeding disorders, constipation, & delayed gastric emptying.
Physical exam for cleft palate & bifid uvula w/submucous cleft palate
Referral to craniofacial center for further eval & mgmt
Community or
Social work involvement for parental support
Home nursing referral
GERD = gastroesophageal reflux disease; GH = growth hormone; MOI = mode of inheritance; SRS = Silver-Russell syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• For children suspected of having GERD, eval for esophagitis incl video swallow studies, gastric emptying studies, pH probe, & endoscopy are recommended.
• Intestinal malrotation has been reported & needs to be ruled out in those w/feeding disorders, constipation, & delayed gastric emptying.
• Physical exam for cleft palate & bifid uvula w/submucous cleft palate
• Referral to craniofacial center for further eval & mgmt
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for SRS. Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists including an endocrinologist, gastroenterologist, dietician, clinical geneticist and genetic counselor, craniofacial team, orthopedic surgeon, neurologist, speech-language therapist, and psychologist (see
Silver-Russell Syndrome: Treatment of Manifestations
Frequent feeding, avoidance of prolonged fasting between feeds (≤4 hours in infants), & complex carbohydrates are recommended.
Monitoring for urinary ketones after prolonged fasting (incl when infants start sleeping through the night) or w/excess physical activity or illness is recommended.
Measures incl nutritional & caloric supplements; treatment of GERD; speech &/or occupational therapy for oral motor problems & oral aversion; appetite stimulants such as cyproheptadine; enteral feeding w/gastrostomy or jejunostomy tube for extreme cases of feeding aversion &/or GERD w/ or w/o fundoplication
With non-volitional feeding, too rapid & excessive weight gain must be avoided.
Initial treatment of limb length discrepancy can incl use of a shoe lift. In older children, limb lengthening w/distraction osteogenesis is a commonly used procedure. When single-segment limb lengthening is sufficient, limb lengthening w/femoral internal distracters is generally done prior to completion of growth but close to final attainment of height. For young children w/leg length discrepancy >4 cm, lengthening is done in the lower segment (tibia) w/external fixators.
Scoliosis & kyphosis should be monitored & early bracing is recommended. Many individuals will need corrective surgery.
Dental hygiene & dental crowding is managed routinely by pediatric dentist &/or orthodontist.
Early dental care, orthodontia for dental crowding, & maxillofacial surgery may be needed in older children once growth is completed.
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
DSD = disorders of sex development; GH = growth hormone; GI = gastrointestinal; GnRH = gonadotropin-releasing hormone
Children with SRS have benefited from GH supplementation [
Many children with SRS do not achieve normal stature even with administration of human GH if rapid bone age advancement during puberty is not managed.
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.
• Frequent feeding, avoidance of prolonged fasting between feeds (≤4 hours in infants), & complex carbohydrates are recommended.
• Monitoring for urinary ketones after prolonged fasting (incl when infants start sleeping through the night) or w/excess physical activity or illness is recommended.
• Measures incl nutritional & caloric supplements; treatment of GERD; speech &/or occupational therapy for oral motor problems & oral aversion; appetite stimulants such as cyproheptadine; enteral feeding w/gastrostomy or jejunostomy tube for extreme cases of feeding aversion &/or GERD w/ or w/o fundoplication
• With non-volitional feeding, too rapid & excessive weight gain must be avoided.
• Initial treatment of limb length discrepancy can incl use of a shoe lift. In older children, limb lengthening w/distraction osteogenesis is a commonly used procedure. When single-segment limb lengthening is sufficient, limb lengthening w/femoral internal distracters is generally done prior to completion of growth but close to final attainment of height. For young children w/leg length discrepancy >4 cm, lengthening is done in the lower segment (tibia) w/external fixators.
• Scoliosis & kyphosis should be monitored & early bracing is recommended. Many individuals will need corrective surgery.
• Dental hygiene & dental crowding is managed routinely by pediatric dentist &/or orthodontist.
• Early dental care, orthodontia for dental crowding, & maxillofacial surgery may be needed in older children once growth is completed.
• 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.
## Motor Dysfunction
## Surveillance
Surveillance guidelines for children with SRS are outlined in
Silver-Russell Syndrome: Recommended Surveillance
Monitor for ketotic hypoglycemia (urine ketones & blood glucose) during infancy & in older children w/macrocephaly, lean body habitus, & poor appetite.
Monitor urine ketones to prevent hypoglycemia in infants when frequency of feeding is being ↓ & in children who are acutely ill w/↓ feeding or fever & in older children at time of ↑ physical activity.
Monitor for early signs of puberty incl early adrenarche due to risk of rapid bone age advancement & reduced final height despite GH therapy.
Eval of nutritional status & safety of oral intake
Monitor & manage nasogastric feeding or gastrostomy tube, if needed.
Monitor for constipation.
Exam & measurement of limb length discrepancy. Measurement of infant lengths & both legs recorded, & longer limb entered on a growth curve. For measuring height in older children, an appropriate-sized lift sufficient to level the hips should be placed under the foot of the shorter lower extremity.
Eval of scoliosis
Monitor developmental progress & educational needs.
Monitor speech articulation & language.
GH = growth hormone; GI = gastrointestinal; OT = occupational therapy; PT = physical therapy
• Monitor for ketotic hypoglycemia (urine ketones & blood glucose) during infancy & in older children w/macrocephaly, lean body habitus, & poor appetite.
• Monitor urine ketones to prevent hypoglycemia in infants when frequency of feeding is being ↓ & in children who are acutely ill w/↓ feeding or fever & in older children at time of ↑ physical activity.
• Monitor for early signs of puberty incl early adrenarche due to risk of rapid bone age advancement & reduced final height despite GH therapy.
• Eval of nutritional status & safety of oral intake
• Monitor & manage nasogastric feeding or gastrostomy tube, if needed.
• Monitor for constipation.
• Exam & measurement of limb length discrepancy. Measurement of infant lengths & both legs recorded, & longer limb entered on a growth curve. For measuring height in older children, an appropriate-sized lift sufficient to level the hips should be placed under the foot of the shorter lower extremity.
• Eval of scoliosis
• Monitor developmental progress & educational needs.
• Monitor speech articulation & language.
## Agents/Circumstances to Avoid
Avoid prolonged fasting in infants and young children because of the risk of inducing hypoglycemia. For this reason, testing for GH deficiency by fasting is contraindicated [
Avoid elective surgery whenever possible. If surgery is unavoidable, physicians must be aware of the risk for hypoglycemia, hypothermia, difficult healing, and difficult intubation (due to abnormal tooth distribution and micrognathia, which can affect airway visualization and the intubation process).
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The following recurrence risk information pertains to individuals who have Silver-Russell syndrome (SRS) without other imprinting disorders, such as multilocus imprinting disturbances (MLID) (see
In most families, a proband with SRS represents a simplex case (a single affected family member) and has SRS as a result of an apparent
The majority of individuals with chromosome 11p15.5-related SRS have the disorder as the result of 11p15.5 hypomethylation at the paternal imprinting control region 1 (ICR1) that occurred as a postzygotic event.
Rarely, a parent of an individual with 11p15.5-related SRS has a predisposing genetic alteration that results in an SRS-causing genetic alteration when transmitted to offspring. Rare familial cases of chromosome 11p15.5-related SRS have been reported due to predisposing genetic alterations including the following:
Maternally inherited 11p15 duplication
Maternally inherited
Paternally inherited
Paternally inherited small deletion close to the boundaries of the ICR1
To allow reliable recurrence risk counseling, the following testing is recommended:
The family history of some individuals diagnosed with
If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low (empiric data are not available) but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration (paternal germline mosaicism for an
If a parent has a CNV involving the 11p15.5 region, the risk to sibs is variable and can be as high as 50% depending on the size of the affected fragment [
If a parent has a translocation or inversion involving the 11p15.5 region, the risk to sibs is increased and depends on the specific chromosomal rearrangement and other variables.
If the mother of the proband has a
If no underlying 11p15.5 genetic alteration is identified in the proband, the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline (empiric data are not available). There is also a low recurrence risk associated with the possibility of unidentified molecular alterations or MLID (see
If the proband has a CNV or chromosomal rearrangement, the risk to offspring of SRS may be as high as 50% depending on the sex of the proband and the specific genetic alteration.
If the proband has a pathogenic variant in
Offspring who inherit a
Offspring who inherit an
If the proband has somatic mosaicism for maternal uniparental disomy of chromosome 11 (upd(11)mat), the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline.
In most individuals with SRS caused by maternal uniparental disomy of chromosome 7 (upd(7)mat), the genetic alteration occurred as a
Rarely, a parent of a proband with upd(7)mat has a predisposing genetic alteration. Such predisposing genetic alterations include the following:
CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
A translocation involving chromosome 7
To allow reliable recurrence risk counseling, the following testing is recommended for the proband and parents of the proband:
If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration and the possibility that a parent has a pathogenic variant in a gene associated with MLID (see
If the father of the proband has a deletion involving 7q32 (
If a parent has a translocation involving chromosome 7, the risk to sibs is increased and depends on the specific chromosome rearrangement and the other variables.
Some individuals with
Some individuals with
To allow reliable recurrence risk counseling, the following testing is recommended:
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 genetic alteration 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 an
Familial SRS recurrence due to
Both maternal and paternal transmission of genetic alterations involving
If the
The recurrence risk to sibs of a proband and offspring of a proband is likely low. However, the risk may be increased if the proband has a genetic alteration that is not detected by current genetic testing platforms or a pathogenic variant in an MLID-related gene (see
Note: The preimplantation genetic diagnosis or prenatal finding of a genetic alteration consistent with SRS cannot be used to reliably predict clinical outcome [
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 majority of individuals with chromosome 11p15.5-related SRS have the disorder as the result of 11p15.5 hypomethylation at the paternal imprinting control region 1 (ICR1) that occurred as a postzygotic event.
• Rarely, a parent of an individual with 11p15.5-related SRS has a predisposing genetic alteration that results in an SRS-causing genetic alteration when transmitted to offspring. Rare familial cases of chromosome 11p15.5-related SRS have been reported due to predisposing genetic alterations including the following:
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Paternally inherited small deletion close to the boundaries of the ICR1
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Paternally inherited small deletion close to the boundaries of the ICR1
• To allow reliable recurrence risk counseling, the following testing is recommended:
• The family history of some individuals diagnosed with
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Paternally inherited small deletion close to the boundaries of the ICR1
• If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low (empiric data are not available) but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration (paternal germline mosaicism for an
• If a parent has a CNV involving the 11p15.5 region, the risk to sibs is variable and can be as high as 50% depending on the size of the affected fragment [
• If a parent has a translocation or inversion involving the 11p15.5 region, the risk to sibs is increased and depends on the specific chromosomal rearrangement and other variables.
• If the mother of the proband has a
• If no underlying 11p15.5 genetic alteration is identified in the proband, the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline (empiric data are not available). There is also a low recurrence risk associated with the possibility of unidentified molecular alterations or MLID (see
• If the proband has a CNV or chromosomal rearrangement, the risk to offspring of SRS may be as high as 50% depending on the sex of the proband and the specific genetic alteration.
• If the proband has a pathogenic variant in
• Offspring who inherit a
• Offspring who inherit an
• Offspring who inherit a
• Offspring who inherit an
• If the proband has somatic mosaicism for maternal uniparental disomy of chromosome 11 (upd(11)mat), the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline.
• Offspring who inherit a
• Offspring who inherit an
• In most individuals with SRS caused by maternal uniparental disomy of chromosome 7 (upd(7)mat), the genetic alteration occurred as a
• Rarely, a parent of a proband with upd(7)mat has a predisposing genetic alteration. Such predisposing genetic alterations include the following:
• CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
• A translocation involving chromosome 7
• CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
• A translocation involving chromosome 7
• To allow reliable recurrence risk counseling, the following testing is recommended for the proband and parents of the proband:
• CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
• A translocation involving chromosome 7
• If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration and the possibility that a parent has a pathogenic variant in a gene associated with MLID (see
• If the father of the proband has a deletion involving 7q32 (
• If a parent has a translocation involving chromosome 7, the risk to sibs is increased and depends on the specific chromosome rearrangement and the other variables.
• Some individuals with
• Some individuals with
• To allow reliable recurrence risk counseling, the following testing is recommended:
• 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 genetic alteration 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 genetic alteration 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 genetic alteration 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 an
• Familial SRS recurrence due to
• Both maternal and paternal transmission of genetic alterations involving
• Familial SRS recurrence due to
• Both maternal and paternal transmission of genetic alterations involving
• If the
• Familial SRS recurrence due to
• Both maternal and paternal transmission of genetic alterations involving
## Mode of Inheritance
The following recurrence risk information pertains to individuals who have Silver-Russell syndrome (SRS) without other imprinting disorders, such as multilocus imprinting disturbances (MLID) (see
In most families, a proband with SRS represents a simplex case (a single affected family member) and has SRS as a result of an apparent
The majority of individuals with chromosome 11p15.5-related SRS have the disorder as the result of 11p15.5 hypomethylation at the paternal imprinting control region 1 (ICR1) that occurred as a postzygotic event.
Rarely, a parent of an individual with 11p15.5-related SRS has a predisposing genetic alteration that results in an SRS-causing genetic alteration when transmitted to offspring. Rare familial cases of chromosome 11p15.5-related SRS have been reported due to predisposing genetic alterations including the following:
Maternally inherited 11p15 duplication
Maternally inherited
Paternally inherited
Paternally inherited small deletion close to the boundaries of the ICR1
To allow reliable recurrence risk counseling, the following testing is recommended:
The family history of some individuals diagnosed with
If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low (empiric data are not available) but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration (paternal germline mosaicism for an
If a parent has a CNV involving the 11p15.5 region, the risk to sibs is variable and can be as high as 50% depending on the size of the affected fragment [
If a parent has a translocation or inversion involving the 11p15.5 region, the risk to sibs is increased and depends on the specific chromosomal rearrangement and other variables.
If the mother of the proband has a
If no underlying 11p15.5 genetic alteration is identified in the proband, the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline (empiric data are not available). There is also a low recurrence risk associated with the possibility of unidentified molecular alterations or MLID (see
If the proband has a CNV or chromosomal rearrangement, the risk to offspring of SRS may be as high as 50% depending on the sex of the proband and the specific genetic alteration.
If the proband has a pathogenic variant in
Offspring who inherit a
Offspring who inherit an
If the proband has somatic mosaicism for maternal uniparental disomy of chromosome 11 (upd(11)mat), the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline.
In most individuals with SRS caused by maternal uniparental disomy of chromosome 7 (upd(7)mat), the genetic alteration occurred as a
Rarely, a parent of a proband with upd(7)mat has a predisposing genetic alteration. Such predisposing genetic alterations include the following:
CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
A translocation involving chromosome 7
To allow reliable recurrence risk counseling, the following testing is recommended for the proband and parents of the proband:
If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration and the possibility that a parent has a pathogenic variant in a gene associated with MLID (see
If the father of the proband has a deletion involving 7q32 (
If a parent has a translocation involving chromosome 7, the risk to sibs is increased and depends on the specific chromosome rearrangement and the other variables.
Some individuals with
Some individuals with
To allow reliable recurrence risk counseling, the following testing is recommended:
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 genetic alteration 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 an
Familial SRS recurrence due to
Both maternal and paternal transmission of genetic alterations involving
If the
The recurrence risk to sibs of a proband and offspring of a proband is likely low. However, the risk may be increased if the proband has a genetic alteration that is not detected by current genetic testing platforms or a pathogenic variant in an MLID-related gene (see
• The majority of individuals with chromosome 11p15.5-related SRS have the disorder as the result of 11p15.5 hypomethylation at the paternal imprinting control region 1 (ICR1) that occurred as a postzygotic event.
• Rarely, a parent of an individual with 11p15.5-related SRS has a predisposing genetic alteration that results in an SRS-causing genetic alteration when transmitted to offspring. Rare familial cases of chromosome 11p15.5-related SRS have been reported due to predisposing genetic alterations including the following:
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Paternally inherited small deletion close to the boundaries of the ICR1
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Paternally inherited small deletion close to the boundaries of the ICR1
• To allow reliable recurrence risk counseling, the following testing is recommended:
• The family history of some individuals diagnosed with
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Paternally inherited small deletion close to the boundaries of the ICR1
• If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low (empiric data are not available) but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration (paternal germline mosaicism for an
• If a parent has a CNV involving the 11p15.5 region, the risk to sibs is variable and can be as high as 50% depending on the size of the affected fragment [
• If a parent has a translocation or inversion involving the 11p15.5 region, the risk to sibs is increased and depends on the specific chromosomal rearrangement and other variables.
• If the mother of the proband has a
• If no underlying 11p15.5 genetic alteration is identified in the proband, the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline (empiric data are not available). There is also a low recurrence risk associated with the possibility of unidentified molecular alterations or MLID (see
• If the proband has a CNV or chromosomal rearrangement, the risk to offspring of SRS may be as high as 50% depending on the sex of the proband and the specific genetic alteration.
• If the proband has a pathogenic variant in
• Offspring who inherit a
• Offspring who inherit an
• Offspring who inherit a
• Offspring who inherit an
• If the proband has somatic mosaicism for maternal uniparental disomy of chromosome 11 (upd(11)mat), the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline.
• Offspring who inherit a
• Offspring who inherit an
• In most individuals with SRS caused by maternal uniparental disomy of chromosome 7 (upd(7)mat), the genetic alteration occurred as a
• Rarely, a parent of a proband with upd(7)mat has a predisposing genetic alteration. Such predisposing genetic alterations include the following:
• CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
• A translocation involving chromosome 7
• CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
• A translocation involving chromosome 7
• To allow reliable recurrence risk counseling, the following testing is recommended for the proband and parents of the proband:
• CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
• A translocation involving chromosome 7
• If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration and the possibility that a parent has a pathogenic variant in a gene associated with MLID (see
• If the father of the proband has a deletion involving 7q32 (
• If a parent has a translocation involving chromosome 7, the risk to sibs is increased and depends on the specific chromosome rearrangement and the other variables.
• Some individuals with
• Some individuals with
• To allow reliable recurrence risk counseling, the following testing is recommended:
• 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 genetic alteration 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 genetic alteration 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 genetic alteration 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 an
• Familial SRS recurrence due to
• Both maternal and paternal transmission of genetic alterations involving
• Familial SRS recurrence due to
• Both maternal and paternal transmission of genetic alterations involving
• If the
• Familial SRS recurrence due to
• Both maternal and paternal transmission of genetic alterations involving
## Chromosome 11p15.5-Related SRS – Risk to Family Members
The majority of individuals with chromosome 11p15.5-related SRS have the disorder as the result of 11p15.5 hypomethylation at the paternal imprinting control region 1 (ICR1) that occurred as a postzygotic event.
Rarely, a parent of an individual with 11p15.5-related SRS has a predisposing genetic alteration that results in an SRS-causing genetic alteration when transmitted to offspring. Rare familial cases of chromosome 11p15.5-related SRS have been reported due to predisposing genetic alterations including the following:
Maternally inherited 11p15 duplication
Maternally inherited
Paternally inherited
Paternally inherited small deletion close to the boundaries of the ICR1
To allow reliable recurrence risk counseling, the following testing is recommended:
The family history of some individuals diagnosed with
If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low (empiric data are not available) but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration (paternal germline mosaicism for an
If a parent has a CNV involving the 11p15.5 region, the risk to sibs is variable and can be as high as 50% depending on the size of the affected fragment [
If a parent has a translocation or inversion involving the 11p15.5 region, the risk to sibs is increased and depends on the specific chromosomal rearrangement and other variables.
If the mother of the proband has a
If no underlying 11p15.5 genetic alteration is identified in the proband, the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline (empiric data are not available). There is also a low recurrence risk associated with the possibility of unidentified molecular alterations or MLID (see
If the proband has a CNV or chromosomal rearrangement, the risk to offspring of SRS may be as high as 50% depending on the sex of the proband and the specific genetic alteration.
If the proband has a pathogenic variant in
Offspring who inherit a
Offspring who inherit an
If the proband has somatic mosaicism for maternal uniparental disomy of chromosome 11 (upd(11)mat), the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline.
• The majority of individuals with chromosome 11p15.5-related SRS have the disorder as the result of 11p15.5 hypomethylation at the paternal imprinting control region 1 (ICR1) that occurred as a postzygotic event.
• Rarely, a parent of an individual with 11p15.5-related SRS has a predisposing genetic alteration that results in an SRS-causing genetic alteration when transmitted to offspring. Rare familial cases of chromosome 11p15.5-related SRS have been reported due to predisposing genetic alterations including the following:
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Paternally inherited small deletion close to the boundaries of the ICR1
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Paternally inherited small deletion close to the boundaries of the ICR1
• To allow reliable recurrence risk counseling, the following testing is recommended:
• The family history of some individuals diagnosed with
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Paternally inherited small deletion close to the boundaries of the ICR1
• If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low (empiric data are not available) but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration (paternal germline mosaicism for an
• If a parent has a CNV involving the 11p15.5 region, the risk to sibs is variable and can be as high as 50% depending on the size of the affected fragment [
• If a parent has a translocation or inversion involving the 11p15.5 region, the risk to sibs is increased and depends on the specific chromosomal rearrangement and other variables.
• If the mother of the proband has a
• If no underlying 11p15.5 genetic alteration is identified in the proband, the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline (empiric data are not available). There is also a low recurrence risk associated with the possibility of unidentified molecular alterations or MLID (see
• If the proband has a CNV or chromosomal rearrangement, the risk to offspring of SRS may be as high as 50% depending on the sex of the proband and the specific genetic alteration.
• If the proband has a pathogenic variant in
• Offspring who inherit a
• Offspring who inherit an
• Offspring who inherit a
• Offspring who inherit an
• If the proband has somatic mosaicism for maternal uniparental disomy of chromosome 11 (upd(11)mat), the risk to offspring of SRS is presumed to be low, as the imprint is normally reset in the germline.
• Offspring who inherit a
• Offspring who inherit an
## Chromosome 7-Related SRS – Risk to Family Members
In most individuals with SRS caused by maternal uniparental disomy of chromosome 7 (upd(7)mat), the genetic alteration occurred as a
Rarely, a parent of a proband with upd(7)mat has a predisposing genetic alteration. Such predisposing genetic alterations include the following:
CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
A translocation involving chromosome 7
To allow reliable recurrence risk counseling, the following testing is recommended for the proband and parents of the proband:
If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration and the possibility that a parent has a pathogenic variant in a gene associated with MLID (see
If the father of the proband has a deletion involving 7q32 (
If a parent has a translocation involving chromosome 7, the risk to sibs is increased and depends on the specific chromosome rearrangement and the other variables.
• In most individuals with SRS caused by maternal uniparental disomy of chromosome 7 (upd(7)mat), the genetic alteration occurred as a
• Rarely, a parent of a proband with upd(7)mat has a predisposing genetic alteration. Such predisposing genetic alterations include the following:
• CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
• A translocation involving chromosome 7
• CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
• A translocation involving chromosome 7
• To allow reliable recurrence risk counseling, the following testing is recommended for the proband and parents of the proband:
• CNV in the critical imprinted region on chromosome 7 (e.g., paternally inherited deletion or maternally inherited duplication involving 7q32 [
• A translocation involving chromosome 7
• If neither parent of the proband is found to have a predisposing genetic alteration, the risk to sibs is presumed to be low but still increased compared to the general population because of the possibility of parental germline mosaicism for a predisposing genetic alteration and the possibility that a parent has a pathogenic variant in a gene associated with MLID (see
• If the father of the proband has a deletion involving 7q32 (
• If a parent has a translocation involving chromosome 7, the risk to sibs is increased and depends on the specific chromosome rearrangement and the other variables.
Some individuals with
Some individuals with
To allow reliable recurrence risk counseling, the following testing is recommended:
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 genetic alteration 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 an
Familial SRS recurrence due to
Both maternal and paternal transmission of genetic alterations involving
If the
• Some individuals with
• Some individuals with
• To allow reliable recurrence risk counseling, the following testing is recommended:
• 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 genetic alteration 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 genetic alteration 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 genetic alteration 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 an
• Familial SRS recurrence due to
• Both maternal and paternal transmission of genetic alterations involving
• Familial SRS recurrence due to
• Both maternal and paternal transmission of genetic alterations involving
• If the
• Familial SRS recurrence due to
• Both maternal and paternal transmission of genetic alterations involving
## Proband with No SRS-Causing Genetic Alteration Identified – Risk to Family Members
The recurrence risk to sibs of a proband and offspring of a proband is likely low. However, the risk may be increased if the proband has a genetic alteration that is not detected by current genetic testing platforms or a pathogenic variant in an MLID-related gene (see
## Related Genetic Counseling Issues
## Prenatal Testing and Preimplantation Genetic Testing
Note: The preimplantation genetic diagnosis or prenatal finding of a genetic alteration consistent with SRS cannot be used to reliably predict clinical outcome [
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
Italy
Belgium
France
Leinestrasse 2
28199 Bremen
Germany
United Kingdom
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• Italy
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• Belgium
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• France
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• Leinestrasse 2
• 28199 Bremen
• Germany
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• United Kingdom
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## Molecular Genetics
Silver-Russell Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Silver-Russell Syndrome (
Imprinted genes often occur in clusters that include a regulatory imprinting control region (ICR). The importance of imprinted genes at chromosome 11p15.5 for fetal growth is known [
See
Abnormal methylation at 11p15.5 can occur through several mechanisms:
Note: (1) Because 11p15.5 hypomethylation at the paternal ICR1 is usually a postzygotic event, most individuals with SRS have a somatic distribution of abnormal methylation patterns (see
A small number of individuals with SRS have a duplication involving the maternal 11p15.5 region. Larger duplications, which can involve translocations and inversions, are detectable by cytogenetic analysis [
Rare familial cases of SRS have been reported with underlying mechanisms including the following:
Maternally inherited 11p15 duplication
Maternally inherited
Paternally inherited
Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
In these families, the risk of recurrence can be as high as 50%. Investigation for underlying CNVs in individuals with 11p15.5 loss of methylation is therefore important [
The genetic loci responsible for maternal uniparental disomy of chromosome 7 (upd(7)mat) imprinting appear to include at least
Maternal isodisomy or heterodisomy [
Mosaicism for upd(7)mat [
Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
46,XY/46,XY and upd(7)mat mosaicism [
Maternal segmental isodisomy of 86.51 Mb of chromosome 7q11q36 and absence of heterozygosity has been reported in a female with SRS who also had congenital chloride diarrhea caused by homozygous pathogenic variants in
Several deletions of 7q32.2 including the paternal
Deletions of the
Loss-of-function pathogenic variants have been identified in several individuals, five of which were identified by next-generation sequencing [
A 77-kb deletion of 8q12.1 involving
Loss-of-function pathogenic variants have been reported in several individuals.
• Note: (1) Because 11p15.5 hypomethylation at the paternal ICR1 is usually a postzygotic event, most individuals with SRS have a somatic distribution of abnormal methylation patterns (see
• A small number of individuals with SRS have a duplication involving the maternal 11p15.5 region. Larger duplications, which can involve translocations and inversions, are detectable by cytogenetic analysis [
• Rare familial cases of SRS have been reported with underlying mechanisms including the following:
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
• Maternal isodisomy or heterodisomy [
• Mosaicism for upd(7)mat [
• Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
• Maternal isodisomy or heterodisomy [
• Mosaicism for upd(7)mat [
• Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
• Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
• Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
• 46,XY/46,XY and upd(7)mat mosaicism [
• Maternal segmental isodisomy of 86.51 Mb of chromosome 7q11q36 and absence of heterozygosity has been reported in a female with SRS who also had congenital chloride diarrhea caused by homozygous pathogenic variants in
• Several deletions of 7q32.2 including the paternal
• Maternal isodisomy or heterodisomy [
• Mosaicism for upd(7)mat [
• Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
• Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
## Molecular Pathogenesis
Imprinted genes often occur in clusters that include a regulatory imprinting control region (ICR). The importance of imprinted genes at chromosome 11p15.5 for fetal growth is known [
See
Abnormal methylation at 11p15.5 can occur through several mechanisms:
Note: (1) Because 11p15.5 hypomethylation at the paternal ICR1 is usually a postzygotic event, most individuals with SRS have a somatic distribution of abnormal methylation patterns (see
A small number of individuals with SRS have a duplication involving the maternal 11p15.5 region. Larger duplications, which can involve translocations and inversions, are detectable by cytogenetic analysis [
Rare familial cases of SRS have been reported with underlying mechanisms including the following:
Maternally inherited 11p15 duplication
Maternally inherited
Paternally inherited
Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
In these families, the risk of recurrence can be as high as 50%. Investigation for underlying CNVs in individuals with 11p15.5 loss of methylation is therefore important [
The genetic loci responsible for maternal uniparental disomy of chromosome 7 (upd(7)mat) imprinting appear to include at least
Maternal isodisomy or heterodisomy [
Mosaicism for upd(7)mat [
Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
46,XY/46,XY and upd(7)mat mosaicism [
Maternal segmental isodisomy of 86.51 Mb of chromosome 7q11q36 and absence of heterozygosity has been reported in a female with SRS who also had congenital chloride diarrhea caused by homozygous pathogenic variants in
Several deletions of 7q32.2 including the paternal
Deletions of the
Loss-of-function pathogenic variants have been identified in several individuals, five of which were identified by next-generation sequencing [
A 77-kb deletion of 8q12.1 involving
Loss-of-function pathogenic variants have been reported in several individuals.
• Note: (1) Because 11p15.5 hypomethylation at the paternal ICR1 is usually a postzygotic event, most individuals with SRS have a somatic distribution of abnormal methylation patterns (see
• A small number of individuals with SRS have a duplication involving the maternal 11p15.5 region. Larger duplications, which can involve translocations and inversions, are detectable by cytogenetic analysis [
• Rare familial cases of SRS have been reported with underlying mechanisms including the following:
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
• Maternal isodisomy or heterodisomy [
• Mosaicism for upd(7)mat [
• Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
• Maternal isodisomy or heterodisomy [
• Mosaicism for upd(7)mat [
• Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
• Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
• Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
• 46,XY/46,XY and upd(7)mat mosaicism [
• Maternal segmental isodisomy of 86.51 Mb of chromosome 7q11q36 and absence of heterozygosity has been reported in a female with SRS who also had congenital chloride diarrhea caused by homozygous pathogenic variants in
• Several deletions of 7q32.2 including the paternal
• Maternal isodisomy or heterodisomy [
• Mosaicism for upd(7)mat [
• Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
• Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
## Chromosome 11p15.5-Related Silver-Russell Syndrome (SRS)
Imprinted genes often occur in clusters that include a regulatory imprinting control region (ICR). The importance of imprinted genes at chromosome 11p15.5 for fetal growth is known [
See
Abnormal methylation at 11p15.5 can occur through several mechanisms:
Note: (1) Because 11p15.5 hypomethylation at the paternal ICR1 is usually a postzygotic event, most individuals with SRS have a somatic distribution of abnormal methylation patterns (see
A small number of individuals with SRS have a duplication involving the maternal 11p15.5 region. Larger duplications, which can involve translocations and inversions, are detectable by cytogenetic analysis [
Rare familial cases of SRS have been reported with underlying mechanisms including the following:
Maternally inherited 11p15 duplication
Maternally inherited
Paternally inherited
Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
In these families, the risk of recurrence can be as high as 50%. Investigation for underlying CNVs in individuals with 11p15.5 loss of methylation is therefore important [
• Note: (1) Because 11p15.5 hypomethylation at the paternal ICR1 is usually a postzygotic event, most individuals with SRS have a somatic distribution of abnormal methylation patterns (see
• A small number of individuals with SRS have a duplication involving the maternal 11p15.5 region. Larger duplications, which can involve translocations and inversions, are detectable by cytogenetic analysis [
• Rare familial cases of SRS have been reported with underlying mechanisms including the following:
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
• Maternally inherited 11p15 duplication
• Maternally inherited
• Paternally inherited
• Small paternally inherited deletions adjacent to the 11p15.5 ICR1.
## Chromosome 7-Related SRS
The genetic loci responsible for maternal uniparental disomy of chromosome 7 (upd(7)mat) imprinting appear to include at least
Maternal isodisomy or heterodisomy [
Mosaicism for upd(7)mat [
Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
46,XY/46,XY and upd(7)mat mosaicism [
Maternal segmental isodisomy of 86.51 Mb of chromosome 7q11q36 and absence of heterozygosity has been reported in a female with SRS who also had congenital chloride diarrhea caused by homozygous pathogenic variants in
Several deletions of 7q32.2 including the paternal
• Maternal isodisomy or heterodisomy [
• Mosaicism for upd(7)mat [
• Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
• Maternal isodisomy or heterodisomy [
• Mosaicism for upd(7)mat [
• Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
• Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
• Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
• 46,XY/46,XY and upd(7)mat mosaicism [
• Maternal segmental isodisomy of 86.51 Mb of chromosome 7q11q36 and absence of heterozygosity has been reported in a female with SRS who also had congenital chloride diarrhea caused by homozygous pathogenic variants in
• Several deletions of 7q32.2 including the paternal
• Maternal isodisomy or heterodisomy [
• Mosaicism for upd(7)mat [
• Segmental upd(7)mat has been reported: one individual with upd(7)mat for 7q31-qter [
• Mosaic trisomy 7 with maternal heterodisomy has been reported in two children [
## Deletions and Intragenic Pathogenic Variants Involving
Deletions of the
Loss-of-function pathogenic variants have been identified in several individuals, five of which were identified by next-generation sequencing [
## Deletions and Intragenic Pathogenic Variants Involving
A 77-kb deletion of 8q12.1 involving
Loss-of-function pathogenic variants have been reported in several individuals.
## Chapter Notes
Howard M Saal, MD, FACMG, is Director of Clinical Genetics at Cincinnati Children's Hospital Medical Center. He directs the Cleft and Craniofacial Center and the Skeletal Dysplasia Clinic. Dr Saal is actively involved in clinical research regarding individuals with growth disorders, skeletal dysplasias, bone mineralization disorders, and orofacial cleft and craniofacial disorders. He is happy to communicate with persons who have any questions regarding the diagnosis of Silver-Russell syndrome or other related considerations. He can be contacted at
9 January 2025 (gm) Revision: added blue sclera as a feature of SRS in
9 May 2024 (gm) Comprehensive update posted live
21 October 2019 (ha) Comprehensive update posted live
2 June 2011 (me) Comprehensive update posted live
7 September 2006 (me) Comprehensive update posted live
5 March 2004 (me) Comprehensive update posted live
2 November 2001 (me) Review posted live
February 2001 (hs) Original submission
• 9 January 2025 (gm) Revision: added blue sclera as a feature of SRS in
• 9 May 2024 (gm) Comprehensive update posted live
• 21 October 2019 (ha) Comprehensive update posted live
• 2 June 2011 (me) Comprehensive update posted live
• 7 September 2006 (me) Comprehensive update posted live
• 5 March 2004 (me) Comprehensive update posted live
• 2 November 2001 (me) Review posted live
• February 2001 (hs) Original submission
## Author Notes
Howard M Saal, MD, FACMG, is Director of Clinical Genetics at Cincinnati Children's Hospital Medical Center. He directs the Cleft and Craniofacial Center and the Skeletal Dysplasia Clinic. Dr Saal is actively involved in clinical research regarding individuals with growth disorders, skeletal dysplasias, bone mineralization disorders, and orofacial cleft and craniofacial disorders. He is happy to communicate with persons who have any questions regarding the diagnosis of Silver-Russell syndrome or other related considerations. He can be contacted at
## Revision History
9 January 2025 (gm) Revision: added blue sclera as a feature of SRS in
9 May 2024 (gm) Comprehensive update posted live
21 October 2019 (ha) Comprehensive update posted live
2 June 2011 (me) Comprehensive update posted live
7 September 2006 (me) Comprehensive update posted live
5 March 2004 (me) Comprehensive update posted live
2 November 2001 (me) Review posted live
February 2001 (hs) Original submission
• 9 January 2025 (gm) Revision: added blue sclera as a feature of SRS in
• 9 May 2024 (gm) Comprehensive update posted live
• 21 October 2019 (ha) Comprehensive update posted live
• 2 June 2011 (me) Comprehensive update posted live
• 7 September 2006 (me) Comprehensive update posted live
• 5 March 2004 (me) Comprehensive update posted live
• 2 November 2001 (me) Review posted live
• February 2001 (hs) Original submission
## References
American College of Medical Genetics Statement on diagnostic testing for uniparental disomy. Available
Eggermann K, Bliek J, Brioude F, Algar E, Buiting K, Russo S, Tümer Z, Monk D, Moore G, Antoniadi T, Macdonald F, Netchine I, Lombardi P, Soellner L, Begemann M, Prawitt D, Maher ER, Mannens M, Riccio A, Weksberg R, Lapunzina P, Grønskov K, Mackay DJ, Eggermann T. EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver-Russell and Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2016;24:1377-87. [
Eggermann T, Brioude F, Russo S, Lombardi MP, Bliek J, Maher ER, Larizza L, Prawitt D, Netchine I, Gonzales M, Grønskov K, Tümer Z, Monk D, Mannens M, Chrzanowska K, Walasek MK, Begemann M, Soellner L, Eggermann K, Tenorio J, Nevado J, Moore GE, Mackay DJ, Temple K, Gillessen-Kaesbach G, Ogata T, Weksberg R, Algar E, Lapunzina P. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur J Hum Genet. 2016;24:784-93. [
Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, Canton AP, Chrzanowska KH, Davies JH, Dias RP, Dubern B, Elbracht M, Giabicani E, Grimberg A, Grønskov K, Hokken-Koelega AC, Jorge AA, Kagami M, Linglart A, Maghnie M, Mohnike K, Monk D, Moore GE, Murray PG, Ogata T, Petit IO, Russo S, Said E, Toumba M, Tümer Z, Binder G, Eggermann T, Harbison MD, Temple IK, Mackay DJ, Netchine I. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13:105-24. [
• American College of Medical Genetics Statement on diagnostic testing for uniparental disomy. Available
• Eggermann K, Bliek J, Brioude F, Algar E, Buiting K, Russo S, Tümer Z, Monk D, Moore G, Antoniadi T, Macdonald F, Netchine I, Lombardi P, Soellner L, Begemann M, Prawitt D, Maher ER, Mannens M, Riccio A, Weksberg R, Lapunzina P, Grønskov K, Mackay DJ, Eggermann T. EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver-Russell and Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2016;24:1377-87. [
• Eggermann T, Brioude F, Russo S, Lombardi MP, Bliek J, Maher ER, Larizza L, Prawitt D, Netchine I, Gonzales M, Grønskov K, Tümer Z, Monk D, Mannens M, Chrzanowska K, Walasek MK, Begemann M, Soellner L, Eggermann K, Tenorio J, Nevado J, Moore GE, Mackay DJ, Temple K, Gillessen-Kaesbach G, Ogata T, Weksberg R, Algar E, Lapunzina P. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur J Hum Genet. 2016;24:784-93. [
• Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, Canton AP, Chrzanowska KH, Davies JH, Dias RP, Dubern B, Elbracht M, Giabicani E, Grimberg A, Grønskov K, Hokken-Koelega AC, Jorge AA, Kagami M, Linglart A, Maghnie M, Mohnike K, Monk D, Moore GE, Murray PG, Ogata T, Petit IO, Russo S, Said E, Toumba M, Tümer Z, Binder G, Eggermann T, Harbison MD, Temple IK, Mackay DJ, Netchine I. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13:105-24. [
## Published Guidelines / Consensus Statements
American College of Medical Genetics Statement on diagnostic testing for uniparental disomy. Available
Eggermann K, Bliek J, Brioude F, Algar E, Buiting K, Russo S, Tümer Z, Monk D, Moore G, Antoniadi T, Macdonald F, Netchine I, Lombardi P, Soellner L, Begemann M, Prawitt D, Maher ER, Mannens M, Riccio A, Weksberg R, Lapunzina P, Grønskov K, Mackay DJ, Eggermann T. EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver-Russell and Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2016;24:1377-87. [
Eggermann T, Brioude F, Russo S, Lombardi MP, Bliek J, Maher ER, Larizza L, Prawitt D, Netchine I, Gonzales M, Grønskov K, Tümer Z, Monk D, Mannens M, Chrzanowska K, Walasek MK, Begemann M, Soellner L, Eggermann K, Tenorio J, Nevado J, Moore GE, Mackay DJ, Temple K, Gillessen-Kaesbach G, Ogata T, Weksberg R, Algar E, Lapunzina P. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur J Hum Genet. 2016;24:784-93. [
Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, Canton AP, Chrzanowska KH, Davies JH, Dias RP, Dubern B, Elbracht M, Giabicani E, Grimberg A, Grønskov K, Hokken-Koelega AC, Jorge AA, Kagami M, Linglart A, Maghnie M, Mohnike K, Monk D, Moore GE, Murray PG, Ogata T, Petit IO, Russo S, Said E, Toumba M, Tümer Z, Binder G, Eggermann T, Harbison MD, Temple IK, Mackay DJ, Netchine I. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13:105-24. [
• American College of Medical Genetics Statement on diagnostic testing for uniparental disomy. Available
• Eggermann K, Bliek J, Brioude F, Algar E, Buiting K, Russo S, Tümer Z, Monk D, Moore G, Antoniadi T, Macdonald F, Netchine I, Lombardi P, Soellner L, Begemann M, Prawitt D, Maher ER, Mannens M, Riccio A, Weksberg R, Lapunzina P, Grønskov K, Mackay DJ, Eggermann T. EMQN best practice guidelines for the molecular genetic testing and reporting of chromosome 11p15 imprinting disorders: Silver-Russell and Beckwith-Wiedemann syndrome. Eur J Hum Genet. 2016;24:1377-87. [
• Eggermann T, Brioude F, Russo S, Lombardi MP, Bliek J, Maher ER, Larizza L, Prawitt D, Netchine I, Gonzales M, Grønskov K, Tümer Z, Monk D, Mannens M, Chrzanowska K, Walasek MK, Begemann M, Soellner L, Eggermann K, Tenorio J, Nevado J, Moore GE, Mackay DJ, Temple K, Gillessen-Kaesbach G, Ogata T, Weksberg R, Algar E, Lapunzina P. Prenatal molecular testing for Beckwith-Wiedemann and Silver-Russell syndromes: a challenge for molecular analysis and genetic counseling. Eur J Hum Genet. 2016;24:784-93. [
• Wakeling EL, Brioude F, Lokulo-Sodipe O, O'Connell SM, Salem J, Bliek J, Canton AP, Chrzanowska KH, Davies JH, Dias RP, Dubern B, Elbracht M, Giabicani E, Grimberg A, Grønskov K, Hokken-Koelega AC, Jorge AA, Kagami M, Linglart A, Maghnie M, Mohnike K, Monk D, Moore GE, Murray PG, Ogata T, Petit IO, Russo S, Said E, Toumba M, Tümer Z, Binder G, Eggermann T, Harbison MD, Temple IK, Mackay DJ, Netchine I. Diagnosis and management of Silver-Russell syndrome: first international consensus statement. Nat Rev Endocrinol. 2017;13:105-24. [
## Literature Cited
Flowchart for investigation and diagnosis of Silver-Russell syndrome
Adapted from
Paternal hypomethylation of the imprinting control region 1 (ICR1; also called
Adapted from
|
[] |
2/11/2002
|
9/5/2024
|
9/1/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
rsts
|
rsts
|
[
"Broad Thumb-Hallux Syndrome",
"Broad Thumbs-Hallux Syndrome",
"CREB-binding protein",
"Histone acetyltransferase p300",
"CREBBP",
"EP300",
"Rubinstein-Taybi Syndrome"
] |
Rubinstein-Taybi Syndrome
|
Cathy A Stevens
|
Summary Rubinstein-Taybi syndrome (RSTS) is characterized by distinctive facial features, broad and often angulated thumbs and halluces, short stature, and moderate-to-severe intellectual disability. Characteristic craniofacial features include downslanted palpebral fissures, low-hanging columella, high palate, grimacing smile, and talon cusps. Prenatal growth is often normal, then height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Obesity may develop in childhood or adolescence. Average IQ ranges between 35 and 50; however, developmental outcome varies considerably. Some individuals with The diagnosis of RSTS is established in a proband with characteristic clinical features. A heterozygous pathogenic variant in RSTS is inherited in an autosomal dominant manner. Most individuals diagnosed with RSTS have the disorder as the result of a
|
## Diagnosis
Rubinstein-Taybi syndrome (RSTS)
Craniofacial appearance (See
Downslanted palpebral fissures
Convex nasal ridge with low-hanging columella
High palate
Grimacing smile
Talon cusps (an accessory cusp-like structure on the lingual side of the tooth), usually occurring on the maxillary incisors of the permanent dentition
The thumbs and halluces are almost always broad and often angulated.
The distal phalanges of the fingers may appear broad.
The proximal phalanges may be abnormally shaped. Radiographs of the hands and feet in individuals with RSTS are unusual but not necessarily diagnostic.
Most males have undescended testes.
Structural abnormalities of the urinary tract are common.
Congenital heart defects of various types occur in approximately one third of individuals.
While prenatal growth is often normal, height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Absence of the pubertal growth spurt adds to the reduced final height for males and females.
Microcephaly is present within the first few months of life and typically persists into adulthood.
Obesity may develop, particularly in adolescence or adulthood.
The diagnosis of RSTS
A heterozygous pathogenic (or likely pathogenic) variant in
A heterozygous deletion of chromosome 16p13.3 (
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. Because the phenotype of RSTS is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of RSTS, molecular genetic testing approaches can include a
For an introduction to multigene panels click
Note: (1) Since a significant proportion of
For an introduction to CMA click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Rubinstein-Taybi Syndrome
RSTS = Rubinstein-Taybi 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. 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 may not be detected by these methods (see
RSTS may be caused by pathogenic variants in other genes in up to 30% of individuals [
• Craniofacial appearance (See
• Downslanted palpebral fissures
• Convex nasal ridge with low-hanging columella
• High palate
• Grimacing smile
• Talon cusps (an accessory cusp-like structure on the lingual side of the tooth), usually occurring on the maxillary incisors of the permanent dentition
• The thumbs and halluces are almost always broad and often angulated.
• The distal phalanges of the fingers may appear broad.
• The proximal phalanges may be abnormally shaped. Radiographs of the hands and feet in individuals with RSTS are unusual but not necessarily diagnostic.
• Most males have undescended testes.
• Structural abnormalities of the urinary tract are common.
• Congenital heart defects of various types occur in approximately one third of individuals.
• While prenatal growth is often normal, height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Absence of the pubertal growth spurt adds to the reduced final height for males and females.
• Microcephaly is present within the first few months of life and typically persists into adulthood.
• Obesity may develop, particularly in adolescence or adulthood.
• A heterozygous pathogenic (or likely pathogenic) variant in
• A heterozygous deletion of chromosome 16p13.3 (
• For an introduction to multigene panels click
• Note: (1) Since a significant proportion of
• For an introduction to CMA click
## Suggestive Findings
Rubinstein-Taybi syndrome (RSTS)
Craniofacial appearance (See
Downslanted palpebral fissures
Convex nasal ridge with low-hanging columella
High palate
Grimacing smile
Talon cusps (an accessory cusp-like structure on the lingual side of the tooth), usually occurring on the maxillary incisors of the permanent dentition
The thumbs and halluces are almost always broad and often angulated.
The distal phalanges of the fingers may appear broad.
The proximal phalanges may be abnormally shaped. Radiographs of the hands and feet in individuals with RSTS are unusual but not necessarily diagnostic.
Most males have undescended testes.
Structural abnormalities of the urinary tract are common.
Congenital heart defects of various types occur in approximately one third of individuals.
While prenatal growth is often normal, height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Absence of the pubertal growth spurt adds to the reduced final height for males and females.
Microcephaly is present within the first few months of life and typically persists into adulthood.
Obesity may develop, particularly in adolescence or adulthood.
• Craniofacial appearance (See
• Downslanted palpebral fissures
• Convex nasal ridge with low-hanging columella
• High palate
• Grimacing smile
• Talon cusps (an accessory cusp-like structure on the lingual side of the tooth), usually occurring on the maxillary incisors of the permanent dentition
• The thumbs and halluces are almost always broad and often angulated.
• The distal phalanges of the fingers may appear broad.
• The proximal phalanges may be abnormally shaped. Radiographs of the hands and feet in individuals with RSTS are unusual but not necessarily diagnostic.
• Most males have undescended testes.
• Structural abnormalities of the urinary tract are common.
• Congenital heart defects of various types occur in approximately one third of individuals.
• While prenatal growth is often normal, height, weight, and head circumference percentiles rapidly drop in the first few months of life. Short stature is typical in adulthood. Absence of the pubertal growth spurt adds to the reduced final height for males and females.
• Microcephaly is present within the first few months of life and typically persists into adulthood.
• Obesity may develop, particularly in adolescence or adulthood.
## Establishing the Diagnosis
The diagnosis of RSTS
A heterozygous pathogenic (or likely pathogenic) variant in
A heterozygous deletion of chromosome 16p13.3 (
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. Because the phenotype of RSTS is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of RSTS, molecular genetic testing approaches can include a
For an introduction to multigene panels click
Note: (1) Since a significant proportion of
For an introduction to CMA click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Rubinstein-Taybi Syndrome
RSTS = Rubinstein-Taybi 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. 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 may not be detected by these methods (see
RSTS may be caused by pathogenic variants in other genes in up to 30% of individuals [
• A heterozygous pathogenic (or likely pathogenic) variant in
• A heterozygous deletion of chromosome 16p13.3 (
• For an introduction to multigene panels click
• Note: (1) Since a significant proportion of
• For an introduction to CMA click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of RSTS, molecular genetic testing approaches can include a
For an introduction to multigene panels click
Note: (1) Since a significant proportion of
For an introduction to CMA click
• For an introduction to multigene panels click
• Note: (1) Since a significant proportion of
• For an introduction to CMA click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Rubinstein-Taybi Syndrome
RSTS = Rubinstein-Taybi 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. 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 may not be detected by these methods (see
RSTS may be caused by pathogenic variants in other genes in up to 30% of individuals [
## Clinical Characteristics
Rubinstein-Taybi syndrome (RSTS) is a multisystem disorder characterized by short stature, variable structural abnormalities, characteristic facial appearance, broad thumbs and halluces, and variable degrees of intellectual disability. The most consistent craniofacial features are microcephaly, highly arched eyebrows, downslanted palpebral fissures, convex nasal ridge, low-hanging columella, and grimacing smile. The thumbs and halluces are broad and often angulated [
RSTS is frequently recognized at birth or in infancy because of the striking facial features and characteristic hand and foot findings. Problems in early life include respiratory difficulties, feeding issues, poor weight gain, recurrent infections, and severe constipation.
To date, at least 600 individuals have been identified with a pathogenic variant in
Select Features of Rubinstein-Taybi Syndrome
While body mass index is normal for males at age 21, it is increased for females at this age. Many adults develop obesity of unclear etiology [
Average height for adult males is 162.6 cm and for adult females is 151.0 cm [
The average IQ of affected individuals in one study was 51 and in another study 36 [
In one study of adults with RSTS, families reported a decline in developmental abilities over time in 32%, including decreased social interaction, more limited speech, and worsening stamina and mobility [
It is unknown whether life span in RSTS is abnormal. One reported individual is alive at age 67 years [
The type and location of pathogenic variants in
Mosaic microdeletions of
See
The birth prevalence RSTS in the Netherlands has been estimated to be between 1:100,000 and 1:125,000 [
## Clinical Description
Rubinstein-Taybi syndrome (RSTS) is a multisystem disorder characterized by short stature, variable structural abnormalities, characteristic facial appearance, broad thumbs and halluces, and variable degrees of intellectual disability. The most consistent craniofacial features are microcephaly, highly arched eyebrows, downslanted palpebral fissures, convex nasal ridge, low-hanging columella, and grimacing smile. The thumbs and halluces are broad and often angulated [
RSTS is frequently recognized at birth or in infancy because of the striking facial features and characteristic hand and foot findings. Problems in early life include respiratory difficulties, feeding issues, poor weight gain, recurrent infections, and severe constipation.
To date, at least 600 individuals have been identified with a pathogenic variant in
Select Features of Rubinstein-Taybi Syndrome
While body mass index is normal for males at age 21, it is increased for females at this age. Many adults develop obesity of unclear etiology [
Average height for adult males is 162.6 cm and for adult females is 151.0 cm [
The average IQ of affected individuals in one study was 51 and in another study 36 [
In one study of adults with RSTS, families reported a decline in developmental abilities over time in 32%, including decreased social interaction, more limited speech, and worsening stamina and mobility [
It is unknown whether life span in RSTS is abnormal. One reported individual is alive at age 67 years [
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
The type and location of pathogenic variants in
Mosaic microdeletions of
See
## Prevalence
The birth prevalence RSTS in the Netherlands has been estimated to be between 1:100,000 and 1:125,000 [
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
For individuals with the distinctive facial features and hand and foot abnormalities, the diagnosis of Rubinstein-Taybi syndrome (RSTS) is usually straightforward.
Broad/angulated thumbs and halluces may be seen in the
Genes of Interest in the Differential Diagnosis of Rubinstein-Taybi Syndrome
Bicoronal craniosynostosis or cloverleaf skull
Distinctive facial features
Preaxial polydactyly or mixed pre- & postaxial polydactyly, widely spaced eyes, & macrocephaly
Persons w/mild GCPS may have subtle craniofacial findings.
Persons w/severe GCPS may have seizures, hydrocephalus, & ID.
Hearing loss
Characteristic facial features
Facial features (e.g., low-hanging columella)
Short thumbs & broad fingertips
Short stature
Normal OFC
Absence of downslanting palpebral fissures
Thumbs not usually deviated & halluces not broad
Coronal synostosis (unilateral or bilateral), facial asymmetry, ptosis, & characteristic appearance of ear (small pinna w/prominent crus)
Syndactyly of digits 2 & 3 of hand variably present
Mild-to-moderate DD & ID reported; normal intelligence is more common.
AD = autosomal dominant; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; OFC = occipital frontal circumference; RSTS = Rubinstein-Taybi syndrome
Greig cephalopolysyndactyly syndrome is associated with either a heterozygous pathogenic variant of
Floating-Harbor syndrome is caused by a pathogenic variant in
• Bicoronal craniosynostosis or cloverleaf skull
• Distinctive facial features
• Preaxial polydactyly or mixed pre- & postaxial polydactyly, widely spaced eyes, & macrocephaly
• Persons w/mild GCPS may have subtle craniofacial findings.
• Persons w/severe GCPS may have seizures, hydrocephalus, & ID.
• Hearing loss
• Characteristic facial features
• Facial features (e.g., low-hanging columella)
• Short thumbs & broad fingertips
• Short stature
• Normal OFC
• Absence of downslanting palpebral fissures
• Thumbs not usually deviated & halluces not broad
• Coronal synostosis (unilateral or bilateral), facial asymmetry, ptosis, & characteristic appearance of ear (small pinna w/prominent crus)
• Syndactyly of digits 2 & 3 of hand variably present
• Mild-to-moderate DD & ID reported; normal intelligence is more common.
## Management
Clinical practice guidelines for Rubinstein-Taybi Syndrome (RSTS) have been published by
To establish the extent of disease and needs in an individual diagnosed with RSTS, the evaluations summarized in
Rubinstein-Taybi Syndrome: Recommended Evaluations Following Initial Diagnosis
Neurologic eval
Ultrasound of spinal canal in neonatal period should be considered to screen for tethered cord.
MRI of spinal canal should be performed in older children if symptomatic.
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Thumbs & halluces, joints, & spine
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 eval of aspiration risk & nutritional status
Assess for gastroesophageal reflux as warranted.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Assess for constipation.
Upper GI study if symptoms of malrotation
Assess for hearing loss.
Auditory brain stem response testing is recommended (see
Eval by cardiologist for structural heart defects
Echocardiogram
Renal ultrasound exam
Consider VCUG.
Assess for presence of cryptorchidism in males.
Refer to urologist for undescended testes by age 6-12 mos.
Community or online
Social work involvement for parental support
Home nursing referral
Based on
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; RSTS = Rubinstein-Taybi syndrome; VCUG = voiding cystourethrogram
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for RSTS.
Rubinstein-Taybi Syndrome: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Consider need for positioning & mobility devices, disability parking placard.
For significantly angulated thumbs or duplicated halluces, surgical repair per orthopedist. Recurrence of deviation may occur after surgery. Decision reg surgery may need to be postponed until function of hands can be accurately evaluated (typically age 3-4 yrs).
Standard mgmt of gastroesophageal reflux & constipation
Consider tube feeding as needed for failure to thrive.
Stool softeners, prokinetics, osmotic agents, dietary changes, or laxatives as needed
Children: through early intervention programs and/or school district
Adults: low vision clinic &/or community vision services/occupational therapy/mobility services
Monitoring by echocardiogram; surgery if necessary
The frequency of hypertension is not ↑ in adults.
Treatment as in general population
Standard treatment of cryptorchidism
Provide developmentally appropriate sex education/contraception as needed.
No treatment protocols for keloids but options incl steroid injection, laser, radiation, cryotherapy, & surgery.
Pilomatrixomas can be surgically removed if symptomatic.
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 home nursing support
Consider involvement in adaptive sports or
ASM = anti-seizure medication; CPAP = continuous positive airway pressure; 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 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, 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
Rubinstein-Taybi Syndrome: Recommended Surveillance
Frequently during 1st yr of life & at regular checkups.
If growth differs from expected, assess for growth hormone deficiency.
Physical medicine, OT/PT assessment of mobility, self-help skills
Eval of gait
Bone density study if recurrent fractures
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Vaccinations per general population
If recurrent infections, baseline immune workup
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy; RSTS = Rubinstein-Taybi syndrome
See
Preeclampsia was reported in 12/52 mothers whose fetus had
Search
• Neurologic eval
• Ultrasound of spinal canal in neonatal period should be considered to screen for tethered cord.
• MRI of spinal canal should be performed in older children if symptomatic.
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Thumbs & halluces, joints, & spine
• 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 eval of aspiration risk & nutritional status
• Assess for gastroesophageal reflux as warranted.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Upper GI study if symptoms of malrotation
• Assess for hearing loss.
• Auditory brain stem response testing is recommended (see
• Eval by cardiologist for structural heart defects
• Echocardiogram
• Renal ultrasound exam
• Consider VCUG.
• Assess for presence of cryptorchidism in males.
• Refer to urologist for undescended testes by age 6-12 mos.
• Community or online
• Social work involvement for parental support
• Home nursing referral
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Consider need for positioning & mobility devices, disability parking placard.
• For significantly angulated thumbs or duplicated halluces, surgical repair per orthopedist. Recurrence of deviation may occur after surgery. Decision reg surgery may need to be postponed until function of hands can be accurately evaluated (typically age 3-4 yrs).
• Standard mgmt of gastroesophageal reflux & constipation
• Consider tube feeding as needed for failure to thrive.
• Stool softeners, prokinetics, osmotic agents, dietary changes, or laxatives as needed
• Children: through early intervention programs and/or school district
• Adults: low vision clinic &/or community vision services/occupational therapy/mobility services
• Monitoring by echocardiogram; surgery if necessary
• The frequency of hypertension is not ↑ in adults.
• Treatment as in general population
• Standard treatment of cryptorchidism
• Provide developmentally appropriate sex education/contraception as needed.
• No treatment protocols for keloids but options incl steroid injection, laser, radiation, cryotherapy, & surgery.
• Pilomatrixomas can be surgically removed if symptomatic.
• 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 home nursing support
• 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
• Frequently during 1st yr of life & at regular checkups.
• If growth differs from expected, assess for growth hormone deficiency.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Eval of gait
• Bone density study if recurrent fractures
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Vaccinations per general population
• If recurrent infections, baseline immune workup
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with RSTS, the evaluations summarized in
Rubinstein-Taybi Syndrome: Recommended Evaluations Following Initial Diagnosis
Neurologic eval
Ultrasound of spinal canal in neonatal period should be considered to screen for tethered cord.
MRI of spinal canal should be performed in older children if symptomatic.
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Thumbs & halluces, joints, & spine
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 eval of aspiration risk & nutritional status
Assess for gastroesophageal reflux as warranted.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Assess for constipation.
Upper GI study if symptoms of malrotation
Assess for hearing loss.
Auditory brain stem response testing is recommended (see
Eval by cardiologist for structural heart defects
Echocardiogram
Renal ultrasound exam
Consider VCUG.
Assess for presence of cryptorchidism in males.
Refer to urologist for undescended testes by age 6-12 mos.
Community or online
Social work involvement for parental support
Home nursing referral
Based on
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; GI = gastrointestinal; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; RSTS = Rubinstein-Taybi syndrome; VCUG = voiding cystourethrogram
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Neurologic eval
• Ultrasound of spinal canal in neonatal period should be considered to screen for tethered cord.
• MRI of spinal canal should be performed in older children if symptomatic.
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Thumbs & halluces, joints, & spine
• 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 eval of aspiration risk & nutritional status
• Assess for gastroesophageal reflux as warranted.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Assess for constipation.
• Upper GI study if symptoms of malrotation
• Assess for hearing loss.
• Auditory brain stem response testing is recommended (see
• Eval by cardiologist for structural heart defects
• Echocardiogram
• Renal ultrasound exam
• Consider VCUG.
• Assess for presence of cryptorchidism in males.
• Refer to urologist for undescended testes by age 6-12 mos.
• Community or online
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for RSTS.
Rubinstein-Taybi Syndrome: Treatment of Manifestations
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Consider need for positioning & mobility devices, disability parking placard.
For significantly angulated thumbs or duplicated halluces, surgical repair per orthopedist. Recurrence of deviation may occur after surgery. Decision reg surgery may need to be postponed until function of hands can be accurately evaluated (typically age 3-4 yrs).
Standard mgmt of gastroesophageal reflux & constipation
Consider tube feeding as needed for failure to thrive.
Stool softeners, prokinetics, osmotic agents, dietary changes, or laxatives as needed
Children: through early intervention programs and/or school district
Adults: low vision clinic &/or community vision services/occupational therapy/mobility services
Monitoring by echocardiogram; surgery if necessary
The frequency of hypertension is not ↑ in adults.
Treatment as in general population
Standard treatment of cryptorchidism
Provide developmentally appropriate sex education/contraception as needed.
No treatment protocols for keloids but options incl steroid injection, laser, radiation, cryotherapy, & surgery.
Pilomatrixomas can be surgically removed if symptomatic.
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 home nursing support
Consider involvement in adaptive sports or
ASM = anti-seizure medication; CPAP = continuous positive airway pressure; 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 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, 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.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Consider need for positioning & mobility devices, disability parking placard.
• For significantly angulated thumbs or duplicated halluces, surgical repair per orthopedist. Recurrence of deviation may occur after surgery. Decision reg surgery may need to be postponed until function of hands can be accurately evaluated (typically age 3-4 yrs).
• Standard mgmt of gastroesophageal reflux & constipation
• Consider tube feeding as needed for failure to thrive.
• Stool softeners, prokinetics, osmotic agents, dietary changes, or laxatives as needed
• Children: through early intervention programs and/or school district
• Adults: low vision clinic &/or community vision services/occupational therapy/mobility services
• Monitoring by echocardiogram; surgery if necessary
• The frequency of hypertension is not ↑ in adults.
• Treatment as in general population
• Standard treatment of cryptorchidism
• Provide developmentally appropriate sex education/contraception as needed.
• No treatment protocols for keloids but options incl steroid injection, laser, radiation, cryotherapy, & surgery.
• Pilomatrixomas can be surgically removed if symptomatic.
• 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 home nursing support
• 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
## 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
Rubinstein-Taybi Syndrome: Recommended Surveillance
Frequently during 1st yr of life & at regular checkups.
If growth differs from expected, assess for growth hormone deficiency.
Physical medicine, OT/PT assessment of mobility, self-help skills
Eval of gait
Bone density study if recurrent fractures
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Vaccinations per general population
If recurrent infections, baseline immune workup
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy; RSTS = Rubinstein-Taybi syndrome
• Frequently during 1st yr of life & at regular checkups.
• If growth differs from expected, assess for growth hormone deficiency.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Eval of gait
• Bone density study if recurrent fractures
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Vaccinations per general population
• If recurrent infections, baseline immune workup
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Preeclampsia was reported in 12/52 mothers whose fetus had
## Therapies Under Investigation
Search
## Genetic Counseling
Rubinstein-Taybi syndrome (RSTS) is inherited in an autosomal dominant manner.
Most individuals diagnosed with RSTS have the disorder as the result of a
Rarely, an individual diagnosed with RSTS has the disorder as the result of a
Because of variable clinical expression, there is a small chance that a parent with normal intelligence is heterozygous for a
Parental somatic and germline mosaicism has been reported [
Recommendations for the evaluation of parents of a proband include clinical examination for physical findings associated with RSTS and, if a molecular diagnosis has been established in the proband, 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 [
* 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 RSTS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing of the parents has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the
If the proband has a known
If the parents have not been tested for a causative pathogenic variant but are apparently asymptomatic, sibs are still presumed to be at increased risk for RSTS because of the possibility of a mild phenotype in a heterozygous parent or parental somatic and/or germline mosaicism. The empiric recurrence risk for sibs is less than 1%.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing 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 had a child with RSTS.
Once the RSTS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for RSTS 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 centers 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 RSTS have the disorder as the result of a
• Rarely, an individual diagnosed with RSTS has the disorder as the result of a
• Because of variable clinical expression, there is a small chance that a parent with normal intelligence is heterozygous for a
• Parental somatic and germline mosaicism has been reported [
• Because of variable clinical expression, there is a small chance that a parent with normal intelligence is heterozygous for a
• Parental somatic and germline mosaicism has been reported [
• Recommendations for the evaluation of parents of a proband include clinical examination for physical findings associated with RSTS and, if a molecular diagnosis has been established in the proband, 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 [
• * 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 [
• * 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 RSTS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing of the parents has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
• Because of variable clinical expression, there is a small chance that a parent with normal intelligence is heterozygous for a
• Parental somatic and germline mosaicism has been reported [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• * 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 affected and/or is known to have the
• If the proband has a known
• If the parents have not been tested for a causative pathogenic variant but are apparently asymptomatic, sibs are still presumed to be at increased risk for RSTS because of the possibility of a mild phenotype in a heterozygous parent or parental somatic and/or germline mosaicism. The empiric recurrence risk for sibs is less than 1%.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing 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 had a child with RSTS.
## Mode of Inheritance
Rubinstein-Taybi syndrome (RSTS) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with RSTS have the disorder as the result of a
Rarely, an individual diagnosed with RSTS has the disorder as the result of a
Because of variable clinical expression, there is a small chance that a parent with normal intelligence is heterozygous for a
Parental somatic and germline mosaicism has been reported [
Recommendations for the evaluation of parents of a proband include clinical examination for physical findings associated with RSTS and, if a molecular diagnosis has been established in the proband, 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 [
* 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 RSTS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing of the parents has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the
If the proband has a known
If the parents have not been tested for a causative pathogenic variant but are apparently asymptomatic, sibs are still presumed to be at increased risk for RSTS because of the possibility of a mild phenotype in a heterozygous parent or parental somatic and/or germline mosaicism. The empiric recurrence risk for sibs is less than 1%.
• Most individuals diagnosed with RSTS have the disorder as the result of a
• Rarely, an individual diagnosed with RSTS has the disorder as the result of a
• Because of variable clinical expression, there is a small chance that a parent with normal intelligence is heterozygous for a
• Parental somatic and germline mosaicism has been reported [
• Because of variable clinical expression, there is a small chance that a parent with normal intelligence is heterozygous for a
• Parental somatic and germline mosaicism has been reported [
• Recommendations for the evaluation of parents of a proband include clinical examination for physical findings associated with RSTS and, if a molecular diagnosis has been established in the proband, 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 [
• * 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 [
• * 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 RSTS may appear to be negative because of failure to recognize the disorder in affected family members. Therefore, an apparently negative family history cannot be confirmed unless a molecular diagnosis has been established in the proband and molecular genetic testing of the parents has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
• Because of variable clinical expression, there is a small chance that a parent with normal intelligence is heterozygous for a
• Parental somatic and germline mosaicism has been reported [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• * 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 affected and/or is known to have the
• If the proband has a known
• If the parents have not been tested for a causative pathogenic variant but are apparently asymptomatic, sibs are still presumed to be at increased risk for RSTS because of the possibility of a mild phenotype in a heterozygous parent or parental somatic and/or germline mosaicism. The empiric recurrence risk for sibs is less than 1%.
## 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 have had a child with RSTS.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing 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 had a child with RSTS.
## Prenatal Testing and Preimplantation Genetic Testing
Once the RSTS-related pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for RSTS 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 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
Rubinstein-Taybi Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Rubinstein-Taybi Syndrome (
## Chapter Notes
Dr Simpson is also interested in hearing from clinicians treating families affected by RSTS in whom no causative pathogenic variant has been identified through molecular genetic testing of the genes known to be involved in RSTS.
Contact Dr Simpson to inquire about review of
9 November 2023 (gm) Comprehensive update posted live
22 August 2019 (sw) Comprehensive update posted live
7 August 2014 (me) Comprehensive update posted live
16 April 2009 (me) Comprehensive update posted live
2 October 2006 (me) Comprehensive update posted live
22 July 2004 (me) Comprehensive update posted live
30 August 2002 (tk,me) Review posted live
5 April 2002 (cs) Original submission
• 9 November 2023 (gm) Comprehensive update posted live
• 22 August 2019 (sw) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 16 April 2009 (me) Comprehensive update posted live
• 2 October 2006 (me) Comprehensive update posted live
• 22 July 2004 (me) Comprehensive update posted live
• 30 August 2002 (tk,me) Review posted live
• 5 April 2002 (cs) Original submission
## Author Notes
Dr Simpson is also interested in hearing from clinicians treating families affected by RSTS in whom no causative pathogenic variant has been identified through molecular genetic testing of the genes known to be involved in RSTS.
Contact Dr Simpson to inquire about review of
## Revision History
9 November 2023 (gm) Comprehensive update posted live
22 August 2019 (sw) Comprehensive update posted live
7 August 2014 (me) Comprehensive update posted live
16 April 2009 (me) Comprehensive update posted live
2 October 2006 (me) Comprehensive update posted live
22 July 2004 (me) Comprehensive update posted live
30 August 2002 (tk,me) Review posted live
5 April 2002 (cs) Original submission
• 9 November 2023 (gm) Comprehensive update posted live
• 22 August 2019 (sw) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 16 April 2009 (me) Comprehensive update posted live
• 2 October 2006 (me) Comprehensive update posted live
• 22 July 2004 (me) Comprehensive update posted live
• 30 August 2002 (tk,me) Review posted live
• 5 April 2002 (cs) Original submission
## References
## Literature Cited
Typical facial appearance in individuals with RSTS. Note arched brows, downslanted palpebral fissures, low-hanging columella, and grimacing smile.
Broad terminal phalanges (A) and broad, radially deviated thumbs (B)
Broad, partially duplicated halluces
|
[] |
30/8/2002
|
9/11/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
rtps
|
rtps
|
[
"Rhabdoid Predisposition Syndrome",
"RTPS",
"Rhabdoid Predisposition Syndrome",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 4",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1",
"SMARCA4",
"SMARCB1",
"Rhabdoid Tumor Predisposition Syndrome (RTPS)"
] |
Rhabdoid Tumor Predisposition Syndrome
|
Karolina Nemes, Susanne Bens, Franck Bourdeaut, Pascal Johann, Uwe Kordes, Reiner Siebert, Michael C Frühwald
|
Summary Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk for the development of rhabdoid tumors – rare and highly aggressive malignant tumors occurring predominantly in infants and children younger than age three years. Malignant rhabdoid tumors can occur in almost any anatomic location. They often occur in the central nervous system (i.e., atypical teratoid/rhabdoid tumor]); more than 50% occur in the cerebellum. Other common locations include extracranial malignant rhabdoid tumors (e.g., rhabdoid tumors of the head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart), rhabdoid tumor of the kidney, and possibly small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT). More than 70% of individuals with RTPS present before age 12 months with synchronous tumors that exhibit aggressive clinical behavior. The diagnosis of RTPS is established in a proband with a rhabdoid tumor and/or a family history of rhabdoid tumor and/or multiple SMARCB1- or SMARCA4-deficient tumors (synchronous or metachronous), and a heterozygous disease-causing germline variant in RTPS is inherited in an autosomal dominant fashion. The vast majority of individuals with
|
## Diagnosis
Rhabdoid tumor predisposition syndrome (RTPS)
Congenital presentation (i.e., prenatal diagnosis or symptoms within the first 28 days of life)
Early-onset rhabdoid tumor (age <12 months)
Advanced stage of rhabdoid tumor at diagnosis (e.g., >M
Synchronous rhabdoid tumors (>1 primary rhabdoid tumor)
Family history of rhabdoid tumor, small-cell carcinoma of the ovary, hypercalcemic type, or other malignant entities such as cribriform neuroepithelial tumor, malignant peripheral nerve sheath tumor, myeloid sarcoma, epithelioid schwannoma, meningioma, benign myoepithelioma, chondrosarcoma, and/or ganglioglioma
Family history of RTPS
Germline molecular genetic testing for RTPS is recommended in any individual with:
A rhabdoid tumor (at any age), familial rhabdoid tumors, multifocal tumors, or congenital onset tumors;
A SMARCB1-deficient tumor with a family history of rhabdoid tumor OR family history of nonspecified cancer in early childhood (age <5 years);
A SMARCA4-deficient tumor with a family history of rhabdoid tumor OR family history of nonspecified cancer in early childhood (age <5 years).
Note: (1) It remains to be determined whether adult-onset rhabdoid tumors are caused by disease-causing germline variants in
There is currently no consensus regarding formal diagnostic criteria for RTPS.
The diagnosis of RTPS
A rhabdoid tumor and/or a family history of rhabdoid tumor and/or multiple SMARCB1- or SMARCA4-deficient tumors (synchronous or metachronous) AND
Identification of a disease-causing germline variant in
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Rhabdoid Tumor Predisposition 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.
In persons with RTPS confirmed by germline molecular testing, a germline
EU-RHAB ‒ Author, personal communication
In persons with RTPS confirmed by germline molecular testing, a germline
• Congenital presentation (i.e., prenatal diagnosis or symptoms within the first 28 days of life)
• Early-onset rhabdoid tumor (age <12 months)
• Advanced stage of rhabdoid tumor at diagnosis (e.g., >M
• Synchronous rhabdoid tumors (>1 primary rhabdoid tumor)
• Family history of rhabdoid tumor, small-cell carcinoma of the ovary, hypercalcemic type, or other malignant entities such as cribriform neuroepithelial tumor, malignant peripheral nerve sheath tumor, myeloid sarcoma, epithelioid schwannoma, meningioma, benign myoepithelioma, chondrosarcoma, and/or ganglioglioma
• Family history of RTPS
• A rhabdoid tumor (at any age), familial rhabdoid tumors, multifocal tumors, or congenital onset tumors;
• A SMARCB1-deficient tumor with a family history of rhabdoid tumor OR family history of nonspecified cancer in early childhood (age <5 years);
• A SMARCA4-deficient tumor with a family history of rhabdoid tumor OR family history of nonspecified cancer in early childhood (age <5 years).
• A rhabdoid tumor and/or a family history of rhabdoid tumor and/or multiple SMARCB1- or SMARCA4-deficient tumors (synchronous or metachronous) AND
• Identification of a disease-causing germline variant in
• For an introduction to multigene panels click
## Suggestive Findings
Rhabdoid tumor predisposition syndrome (RTPS)
Congenital presentation (i.e., prenatal diagnosis or symptoms within the first 28 days of life)
Early-onset rhabdoid tumor (age <12 months)
Advanced stage of rhabdoid tumor at diagnosis (e.g., >M
Synchronous rhabdoid tumors (>1 primary rhabdoid tumor)
Family history of rhabdoid tumor, small-cell carcinoma of the ovary, hypercalcemic type, or other malignant entities such as cribriform neuroepithelial tumor, malignant peripheral nerve sheath tumor, myeloid sarcoma, epithelioid schwannoma, meningioma, benign myoepithelioma, chondrosarcoma, and/or ganglioglioma
Family history of RTPS
Germline molecular genetic testing for RTPS is recommended in any individual with:
A rhabdoid tumor (at any age), familial rhabdoid tumors, multifocal tumors, or congenital onset tumors;
A SMARCB1-deficient tumor with a family history of rhabdoid tumor OR family history of nonspecified cancer in early childhood (age <5 years);
A SMARCA4-deficient tumor with a family history of rhabdoid tumor OR family history of nonspecified cancer in early childhood (age <5 years).
Note: (1) It remains to be determined whether adult-onset rhabdoid tumors are caused by disease-causing germline variants in
• Congenital presentation (i.e., prenatal diagnosis or symptoms within the first 28 days of life)
• Early-onset rhabdoid tumor (age <12 months)
• Advanced stage of rhabdoid tumor at diagnosis (e.g., >M
• Synchronous rhabdoid tumors (>1 primary rhabdoid tumor)
• Family history of rhabdoid tumor, small-cell carcinoma of the ovary, hypercalcemic type, or other malignant entities such as cribriform neuroepithelial tumor, malignant peripheral nerve sheath tumor, myeloid sarcoma, epithelioid schwannoma, meningioma, benign myoepithelioma, chondrosarcoma, and/or ganglioglioma
• Family history of RTPS
• A rhabdoid tumor (at any age), familial rhabdoid tumors, multifocal tumors, or congenital onset tumors;
• A SMARCB1-deficient tumor with a family history of rhabdoid tumor OR family history of nonspecified cancer in early childhood (age <5 years);
• A SMARCA4-deficient tumor with a family history of rhabdoid tumor OR family history of nonspecified cancer in early childhood (age <5 years).
## Establishing the Diagnosis
There is currently no consensus regarding formal diagnostic criteria for RTPS.
The diagnosis of RTPS
A rhabdoid tumor and/or a family history of rhabdoid tumor and/or multiple SMARCB1- or SMARCA4-deficient tumors (synchronous or metachronous) AND
Identification of a disease-causing germline variant in
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Rhabdoid Tumor Predisposition 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.
In persons with RTPS confirmed by germline molecular testing, a germline
EU-RHAB ‒ Author, personal communication
In persons with RTPS confirmed by germline molecular testing, a germline
• A rhabdoid tumor and/or a family history of rhabdoid tumor and/or multiple SMARCB1- or SMARCA4-deficient tumors (synchronous or metachronous) AND
• Identification of a disease-causing germline variant in
• For an introduction to multigene panels click
## Clinical Characteristics
Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk of developing rhabdoid tumors.
Rhabdoid tumors are rare and highly aggressive malignant tumors occurring predominantly in infants and children younger than age three years. The term rhabdoid is derived from the histologic resemblance of tumor cells to rhabdomyoblasts. Rhabdoid tumors are characterized by heaps of cells with an eccentric nucleus and prominent nucleoli, abundant cytoplasm with eosinophilic inclusion bodies, and distinct cellular membranes. Immunohistochemically, rhabdoid tumor cells are characterized by increased expression of vimentin (a nonspecific marker), epithelial membrane antigen, cytokeratins, and loss of SMARCB1 protein (a strong indicator for rhabdoid tumor) or, more rarely, of SMARCA4.
As morphologic rhabdoid features may not be present in all rhabdoid tumor biopsies because of inter- and intratumoral heterogeneity, any small blue round cell tumor in infants and young children should be evaluated for absence of nuclear SMARCB1 staining [
Primary rhabdoid tumor locations include the following:
Central nervous system: atypical teratoid/rhabdoid tumor (AT/RT); >50% are cerebellar.
Head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart: extracranial malignant rhabdoid tumor (eMRT)
Kidney: rhabdoid tumor of the kidney (RTK)
Ovary: small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT)
Rhabdoid tumors have been reported in nearly all anatomic locations [
More than 70% of individuals with RTPS present before age 12 months with synchronous tumors that exhibit aggressive clinical behavior, often in one of the following clinical settings:
Pre- or perinatally detected synchronous rhabdoid tumors [
Infantile-onset or congenital rhabdoid tumor, presenting at a median age of five and a half months (range: prenatal to 60 months) compared to individuals with sporadic rhabdoid tumors (median age: 11.5 to 29.5 months; range: 1 day to 228 months) [
Note: A bias toward increased molecular testing in younger individuals may confound the data.
Synchronous (multiple primary) rhabdoid tumors. Ninety-one percent (10/11) of individuals with synchronous tumors demonstrated disease-causing germline variants [
Family history of a rhabdoid tumor, epithelioid schwannoma, malignant peripheral nerve sheath tumor, myeloid sarcoma [
Family history of SCCOHT for
Note: No individual with SCCOHT published to date developed a malignant rhabdoid tumor (MRT) during infancy. Apart from SCCOHT, truncating germline disease-causing variants of
Clinically aggressive rhabdoid tumors. Tumor progression at the time of follow up was identified in 84.5% (76/90) of individuals with RTPS [EU-RHAB ‒ Author, personal communication]. Progression occurred while on chemotherapy in 48% (35/73) of individuals with RTPS [
Rhabdoid tumor and syndromic features suggestive of 22q11.2 distal deletion syndrome (OMIM
While these molecular groups are widely accepted in AT/RT, the molecular subgroups of eMRT are still evolving.
In a more recent integrative analysis of genomic, transcriptomic, and epigenomic profiles of 301 malignant rhabdoid tumors, five DNA methylation groups were identified based on anatomic site,
Group 1 – AT/RT-MYC-like (ATRT-MYC and a subgroup of eMRT)
Group 2 – AT/RT-TYR
Group 3 – RTK-like
Group 4 – Extrarenal MRT-like
Group 5 – AT/RT-SHH
Notably, subgroup 2 (identified by differential gene expression analyses) largely corresponded to group 3 (RTK-like), while there was no clear equivalent for subgroup 1.
Groups 1, 3, and 4 (AT/RT-MYC-like, RTK-like, and extrarenal MRT-like) overexpressed
Groups 2 and 5 (AT/RT-TYR and AT/RT-SHH) largely corresponded to the respective AT/RT subgroups and were characterized by an expression of melanosomal features (AT/RT-TYR) and a proneural gene expression profile (AT/RT-SHH).
These results suggest that eMRTs share molecular features with AT/RT-MYC. Another feature distinguishing AT/RT-TYR and AT/RT-SHH from most other pediatric brain tumors is genome-wide hypermethylation – a characteristic that is not present in eMRT subgroups 1 and 2 and AT/RT-MYC.
Information on the specific molecular characteristics of SMARCA4-deficient eMRT has been sparse until very recently. A recent study shed light on the specific transcriptomic and DNA methylation characteristics of these entities [
Note: Current data suggest the value of subgroup determination for diagnostic and therapeutic decision making. A study by
No genotype-phenotype correlations have been identified.
Among newly diagnosed individuals with rhabdoid tumors, 25%-35% will have a disease-causing germline variant in
The incidence of rhabdoid tumors may be estimated according to the following data:
The age-standardized annual incidence rate is between 5 (eMRT) and 8.1 per million (AT/RT) in children younger than age one year and decreases to between 0.6 and 2.2 per million at ages one to four years [
In the United States, annual incidence among children younger than age 15 years is 0.89 per million for AT/RT, 0.32 per million for eMRT, and 0.2 per million for RTK [
• Central nervous system: atypical teratoid/rhabdoid tumor (AT/RT); >50% are cerebellar.
• Head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart: extracranial malignant rhabdoid tumor (eMRT)
• Kidney: rhabdoid tumor of the kidney (RTK)
• Ovary: small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT)
• Pre- or perinatally detected synchronous rhabdoid tumors [
• Infantile-onset or congenital rhabdoid tumor, presenting at a median age of five and a half months (range: prenatal to 60 months) compared to individuals with sporadic rhabdoid tumors (median age: 11.5 to 29.5 months; range: 1 day to 228 months) [
• Note: A bias toward increased molecular testing in younger individuals may confound the data.
• Synchronous (multiple primary) rhabdoid tumors. Ninety-one percent (10/11) of individuals with synchronous tumors demonstrated disease-causing germline variants [
• Family history of a rhabdoid tumor, epithelioid schwannoma, malignant peripheral nerve sheath tumor, myeloid sarcoma [
• Family history of SCCOHT for
• Note: No individual with SCCOHT published to date developed a malignant rhabdoid tumor (MRT) during infancy. Apart from SCCOHT, truncating germline disease-causing variants of
• Clinically aggressive rhabdoid tumors. Tumor progression at the time of follow up was identified in 84.5% (76/90) of individuals with RTPS [EU-RHAB ‒ Author, personal communication]. Progression occurred while on chemotherapy in 48% (35/73) of individuals with RTPS [
• Rhabdoid tumor and syndromic features suggestive of 22q11.2 distal deletion syndrome (OMIM
• Group 1 – AT/RT-MYC-like (ATRT-MYC and a subgroup of eMRT)
• Group 2 – AT/RT-TYR
• Group 3 – RTK-like
• Group 4 – Extrarenal MRT-like
• Group 5 – AT/RT-SHH
• The age-standardized annual incidence rate is between 5 (eMRT) and 8.1 per million (AT/RT) in children younger than age one year and decreases to between 0.6 and 2.2 per million at ages one to four years [
• In the United States, annual incidence among children younger than age 15 years is 0.89 per million for AT/RT, 0.32 per million for eMRT, and 0.2 per million for RTK [
## Clinical Description
Rhabdoid tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk of developing rhabdoid tumors.
Rhabdoid tumors are rare and highly aggressive malignant tumors occurring predominantly in infants and children younger than age three years. The term rhabdoid is derived from the histologic resemblance of tumor cells to rhabdomyoblasts. Rhabdoid tumors are characterized by heaps of cells with an eccentric nucleus and prominent nucleoli, abundant cytoplasm with eosinophilic inclusion bodies, and distinct cellular membranes. Immunohistochemically, rhabdoid tumor cells are characterized by increased expression of vimentin (a nonspecific marker), epithelial membrane antigen, cytokeratins, and loss of SMARCB1 protein (a strong indicator for rhabdoid tumor) or, more rarely, of SMARCA4.
As morphologic rhabdoid features may not be present in all rhabdoid tumor biopsies because of inter- and intratumoral heterogeneity, any small blue round cell tumor in infants and young children should be evaluated for absence of nuclear SMARCB1 staining [
Primary rhabdoid tumor locations include the following:
Central nervous system: atypical teratoid/rhabdoid tumor (AT/RT); >50% are cerebellar.
Head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart: extracranial malignant rhabdoid tumor (eMRT)
Kidney: rhabdoid tumor of the kidney (RTK)
Ovary: small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT)
Rhabdoid tumors have been reported in nearly all anatomic locations [
More than 70% of individuals with RTPS present before age 12 months with synchronous tumors that exhibit aggressive clinical behavior, often in one of the following clinical settings:
Pre- or perinatally detected synchronous rhabdoid tumors [
Infantile-onset or congenital rhabdoid tumor, presenting at a median age of five and a half months (range: prenatal to 60 months) compared to individuals with sporadic rhabdoid tumors (median age: 11.5 to 29.5 months; range: 1 day to 228 months) [
Note: A bias toward increased molecular testing in younger individuals may confound the data.
Synchronous (multiple primary) rhabdoid tumors. Ninety-one percent (10/11) of individuals with synchronous tumors demonstrated disease-causing germline variants [
Family history of a rhabdoid tumor, epithelioid schwannoma, malignant peripheral nerve sheath tumor, myeloid sarcoma [
Family history of SCCOHT for
Note: No individual with SCCOHT published to date developed a malignant rhabdoid tumor (MRT) during infancy. Apart from SCCOHT, truncating germline disease-causing variants of
Clinically aggressive rhabdoid tumors. Tumor progression at the time of follow up was identified in 84.5% (76/90) of individuals with RTPS [EU-RHAB ‒ Author, personal communication]. Progression occurred while on chemotherapy in 48% (35/73) of individuals with RTPS [
Rhabdoid tumor and syndromic features suggestive of 22q11.2 distal deletion syndrome (OMIM
While these molecular groups are widely accepted in AT/RT, the molecular subgroups of eMRT are still evolving.
In a more recent integrative analysis of genomic, transcriptomic, and epigenomic profiles of 301 malignant rhabdoid tumors, five DNA methylation groups were identified based on anatomic site,
Group 1 – AT/RT-MYC-like (ATRT-MYC and a subgroup of eMRT)
Group 2 – AT/RT-TYR
Group 3 – RTK-like
Group 4 – Extrarenal MRT-like
Group 5 – AT/RT-SHH
Notably, subgroup 2 (identified by differential gene expression analyses) largely corresponded to group 3 (RTK-like), while there was no clear equivalent for subgroup 1.
Groups 1, 3, and 4 (AT/RT-MYC-like, RTK-like, and extrarenal MRT-like) overexpressed
Groups 2 and 5 (AT/RT-TYR and AT/RT-SHH) largely corresponded to the respective AT/RT subgroups and were characterized by an expression of melanosomal features (AT/RT-TYR) and a proneural gene expression profile (AT/RT-SHH).
These results suggest that eMRTs share molecular features with AT/RT-MYC. Another feature distinguishing AT/RT-TYR and AT/RT-SHH from most other pediatric brain tumors is genome-wide hypermethylation – a characteristic that is not present in eMRT subgroups 1 and 2 and AT/RT-MYC.
Information on the specific molecular characteristics of SMARCA4-deficient eMRT has been sparse until very recently. A recent study shed light on the specific transcriptomic and DNA methylation characteristics of these entities [
Note: Current data suggest the value of subgroup determination for diagnostic and therapeutic decision making. A study by
• Central nervous system: atypical teratoid/rhabdoid tumor (AT/RT); >50% are cerebellar.
• Head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart: extracranial malignant rhabdoid tumor (eMRT)
• Kidney: rhabdoid tumor of the kidney (RTK)
• Ovary: small-cell carcinoma of the ovary, hypercalcemic type (SCCOHT)
• Pre- or perinatally detected synchronous rhabdoid tumors [
• Infantile-onset or congenital rhabdoid tumor, presenting at a median age of five and a half months (range: prenatal to 60 months) compared to individuals with sporadic rhabdoid tumors (median age: 11.5 to 29.5 months; range: 1 day to 228 months) [
• Note: A bias toward increased molecular testing in younger individuals may confound the data.
• Synchronous (multiple primary) rhabdoid tumors. Ninety-one percent (10/11) of individuals with synchronous tumors demonstrated disease-causing germline variants [
• Family history of a rhabdoid tumor, epithelioid schwannoma, malignant peripheral nerve sheath tumor, myeloid sarcoma [
• Family history of SCCOHT for
• Note: No individual with SCCOHT published to date developed a malignant rhabdoid tumor (MRT) during infancy. Apart from SCCOHT, truncating germline disease-causing variants of
• Clinically aggressive rhabdoid tumors. Tumor progression at the time of follow up was identified in 84.5% (76/90) of individuals with RTPS [EU-RHAB ‒ Author, personal communication]. Progression occurred while on chemotherapy in 48% (35/73) of individuals with RTPS [
• Rhabdoid tumor and syndromic features suggestive of 22q11.2 distal deletion syndrome (OMIM
• Group 1 – AT/RT-MYC-like (ATRT-MYC and a subgroup of eMRT)
• Group 2 – AT/RT-TYR
• Group 3 – RTK-like
• Group 4 – Extrarenal MRT-like
• Group 5 – AT/RT-SHH
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
## Nomenclature
## Prevalence
Among newly diagnosed individuals with rhabdoid tumors, 25%-35% will have a disease-causing germline variant in
The incidence of rhabdoid tumors may be estimated according to the following data:
The age-standardized annual incidence rate is between 5 (eMRT) and 8.1 per million (AT/RT) in children younger than age one year and decreases to between 0.6 and 2.2 per million at ages one to four years [
In the United States, annual incidence among children younger than age 15 years is 0.89 per million for AT/RT, 0.32 per million for eMRT, and 0.2 per million for RTK [
• The age-standardized annual incidence rate is between 5 (eMRT) and 8.1 per million (AT/RT) in children younger than age one year and decreases to between 0.6 and 2.2 per million at ages one to four years [
• In the United States, annual incidence among children younger than age 15 years is 0.89 per million for AT/RT, 0.32 per million for eMRT, and 0.2 per million for RTK [
## Genetically Related (Allelic) Disorders
Other phenotypes caused by germline disease-causing variants in
Allelic Disorders
## Differential Diagnosis
Demonstration of loss of the SMARCB1 or SMARCA4 protein (in tumor tissue) as a result of inactivation or loss of one allele of
Hereditary Disorders in the Differential Diagnosis of Rhabdoid Tumor Predisposition Syndrome
AD = autosomal dominant;
## Management
To establish the extent of disease and needs of an individual diagnosed with rhabdoid tumor predisposition syndrome (RTPS), the following are recommended:
For all individuals (regardless of age), a whole-body MRI should be offered at diagnosis.
Individuals who have not yet developed a rhabdoid tumor should be referred to a pediatric oncologist or tumor surveillance program.
In those with a tumor, prior to planning therapy consider consulting a radiologist to assist in the selection and review of subsequent imaging, to evaluate the size and location of the primary tumor, and to evaluate for the presence of synchronous tumors and/or metastases (whole-body MRI).
For individuals with atypical teratoid/rhabdoid tumor (AT/RT), examine cerebrospinal fluid and determine classification according to Chang staging [
Refer to genetic counseling to inform affected individuals and their families about the nature, mode of inheritance, and implications of RTPS to facilitate medical and personal decision making.
Because of the rarity of RTPS, standards for management are evolving. Most individuals are treated using intensive multimodal therapeutic strategies combining surgery, radiotherapy, and chemotherapy according to institutional preference:
The Children's Oncology Group has employed a combination of surgery, two cycles of induction chemotherapy (cisplatin, cyclophosphamide, etoposide, vincristine, methotrexate), three cycles of high-dose chemotherapy (HDCT) with stem cell rescue (thiotepa, carboplatin) as consolidation therapy, and radiotherapy according to age and stage [
The Dana-Farber Consortium has tested combination therapy with surgery, radiotherapy, and chemotherapy (vincristine, dactinomycin, cyclophosphamide, cisplatin, doxorubicin, temozolomide and intrathecal methotrexate, cytarabine, and hydrocortisone) [
The
The Canadian Brain Tumour Consortium retrospectively evaluated children diagnosed with rhabdoid tumors between 1995 and 2007. Among 40 individuals, 22 received conventional chemotherapy and 18 received HDCT regimens; 15 received adjuvant radiation. Notably, six of 12 long-term survivors never received any radiotherapy [
Note: RTPS most commonly affects infants; therapy presents a complex challenge because of the vulnerability of infants. The use of aggressive multimodal treatment on the developing nervous system and other organ systems in a young individual may profoundly affect neurodevelopmental outcome and lead to significant short- and long-term side effects. Intensive induction chemotherapy may often achieve a good response, and individuals may proceed with radiotherapy or (tandem) HDCT followed by autologous stem cell support.
The intensive multimodal treatment strategies required for clinically aggressive tumors in children with RTPS lead to a higher rate of secondary complications. Therapies and interventions that may prevent secondary complications include consideration of risk-reducing treatment strategies (e.g., postponing or replacing radiotherapy with HDCT or proton beam therapy; targeted therapy used concomitantly with – or before – standard chemotherapy). It remains to be determined whether a subgroup of children may be cured by surgery and chemotherapy alone, thus avoiding the potential severe side effects of radiotherapy to the developing brain.
Prophylactic risk-reducing bilateral salpingo-oophorectomy may be discussed following the end of family planning in women with
Surveillance guidelines for individuals with RTPS have been provided by
Every six months, thorough clinical examination including neurologic examination;
Annual whole-body MRI;
Abdominal and pelvic ultrasound every six months in individuals with
Note: (1) Current data do not allow for a determination of how long surveillance should continue. (2) Recommendations are subject to continuous updates; the authors recommend close monitoring of the evolving literature.
Limit exposure to DNA-damaging agents including radiation (e.g., x-ray, CT, external beam radiotherapy), tobacco, UV light, and chemotherapy to minimize the lifetime risk of developing late-onset secondary cancers. Imaging tests utilizing radioactive compounds should be used only if absolutely necessary for essential health care. This recommendation is based on the increased risk of adverse effects in young developing children, not increased risk as a result of a
It is appropriate to clarify the genetic status of at-risk relatives of an affected individual by molecular genetic testing for the
Early detection of individuals who are heterozygous for an
Family members who have not inherited the disease-causing variant and their subsequent offspring have risks similar to the general population.
See
The following clinical trials are currently recruiting unless otherwise indicated.
Overview of Clinical Trials in Pediatric Malignant Rhabdoid Tumors Including Rhabdoid Tumor Predisposition Syndrome
Based on
Search
• For all individuals (regardless of age), a whole-body MRI should be offered at diagnosis.
• Individuals who have not yet developed a rhabdoid tumor should be referred to a pediatric oncologist or tumor surveillance program.
• In those with a tumor, prior to planning therapy consider consulting a radiologist to assist in the selection and review of subsequent imaging, to evaluate the size and location of the primary tumor, and to evaluate for the presence of synchronous tumors and/or metastases (whole-body MRI).
• For individuals with atypical teratoid/rhabdoid tumor (AT/RT), examine cerebrospinal fluid and determine classification according to Chang staging [
• Refer to genetic counseling to inform affected individuals and their families about the nature, mode of inheritance, and implications of RTPS to facilitate medical and personal decision making.
• The Children's Oncology Group has employed a combination of surgery, two cycles of induction chemotherapy (cisplatin, cyclophosphamide, etoposide, vincristine, methotrexate), three cycles of high-dose chemotherapy (HDCT) with stem cell rescue (thiotepa, carboplatin) as consolidation therapy, and radiotherapy according to age and stage [
• The Dana-Farber Consortium has tested combination therapy with surgery, radiotherapy, and chemotherapy (vincristine, dactinomycin, cyclophosphamide, cisplatin, doxorubicin, temozolomide and intrathecal methotrexate, cytarabine, and hydrocortisone) [
• The
• The Canadian Brain Tumour Consortium retrospectively evaluated children diagnosed with rhabdoid tumors between 1995 and 2007. Among 40 individuals, 22 received conventional chemotherapy and 18 received HDCT regimens; 15 received adjuvant radiation. Notably, six of 12 long-term survivors never received any radiotherapy [
• Every six months, thorough clinical examination including neurologic examination;
• Annual whole-body MRI;
• Abdominal and pelvic ultrasound every six months in individuals with
• Early detection of individuals who are heterozygous for an
• Family members who have not inherited the disease-causing variant and their subsequent offspring have risks similar to the general population.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with rhabdoid tumor predisposition syndrome (RTPS), the following are recommended:
For all individuals (regardless of age), a whole-body MRI should be offered at diagnosis.
Individuals who have not yet developed a rhabdoid tumor should be referred to a pediatric oncologist or tumor surveillance program.
In those with a tumor, prior to planning therapy consider consulting a radiologist to assist in the selection and review of subsequent imaging, to evaluate the size and location of the primary tumor, and to evaluate for the presence of synchronous tumors and/or metastases (whole-body MRI).
For individuals with atypical teratoid/rhabdoid tumor (AT/RT), examine cerebrospinal fluid and determine classification according to Chang staging [
Refer to genetic counseling to inform affected individuals and their families about the nature, mode of inheritance, and implications of RTPS to facilitate medical and personal decision making.
• For all individuals (regardless of age), a whole-body MRI should be offered at diagnosis.
• Individuals who have not yet developed a rhabdoid tumor should be referred to a pediatric oncologist or tumor surveillance program.
• In those with a tumor, prior to planning therapy consider consulting a radiologist to assist in the selection and review of subsequent imaging, to evaluate the size and location of the primary tumor, and to evaluate for the presence of synchronous tumors and/or metastases (whole-body MRI).
• For individuals with atypical teratoid/rhabdoid tumor (AT/RT), examine cerebrospinal fluid and determine classification according to Chang staging [
• Refer to genetic counseling to inform affected individuals and their families about the nature, mode of inheritance, and implications of RTPS to facilitate medical and personal decision making.
## Treatment of Manifestations
Because of the rarity of RTPS, standards for management are evolving. Most individuals are treated using intensive multimodal therapeutic strategies combining surgery, radiotherapy, and chemotherapy according to institutional preference:
The Children's Oncology Group has employed a combination of surgery, two cycles of induction chemotherapy (cisplatin, cyclophosphamide, etoposide, vincristine, methotrexate), three cycles of high-dose chemotherapy (HDCT) with stem cell rescue (thiotepa, carboplatin) as consolidation therapy, and radiotherapy according to age and stage [
The Dana-Farber Consortium has tested combination therapy with surgery, radiotherapy, and chemotherapy (vincristine, dactinomycin, cyclophosphamide, cisplatin, doxorubicin, temozolomide and intrathecal methotrexate, cytarabine, and hydrocortisone) [
The
The Canadian Brain Tumour Consortium retrospectively evaluated children diagnosed with rhabdoid tumors between 1995 and 2007. Among 40 individuals, 22 received conventional chemotherapy and 18 received HDCT regimens; 15 received adjuvant radiation. Notably, six of 12 long-term survivors never received any radiotherapy [
Note: RTPS most commonly affects infants; therapy presents a complex challenge because of the vulnerability of infants. The use of aggressive multimodal treatment on the developing nervous system and other organ systems in a young individual may profoundly affect neurodevelopmental outcome and lead to significant short- and long-term side effects. Intensive induction chemotherapy may often achieve a good response, and individuals may proceed with radiotherapy or (tandem) HDCT followed by autologous stem cell support.
The intensive multimodal treatment strategies required for clinically aggressive tumors in children with RTPS lead to a higher rate of secondary complications. Therapies and interventions that may prevent secondary complications include consideration of risk-reducing treatment strategies (e.g., postponing or replacing radiotherapy with HDCT or proton beam therapy; targeted therapy used concomitantly with – or before – standard chemotherapy). It remains to be determined whether a subgroup of children may be cured by surgery and chemotherapy alone, thus avoiding the potential severe side effects of radiotherapy to the developing brain.
• The Children's Oncology Group has employed a combination of surgery, two cycles of induction chemotherapy (cisplatin, cyclophosphamide, etoposide, vincristine, methotrexate), three cycles of high-dose chemotherapy (HDCT) with stem cell rescue (thiotepa, carboplatin) as consolidation therapy, and radiotherapy according to age and stage [
• The Dana-Farber Consortium has tested combination therapy with surgery, radiotherapy, and chemotherapy (vincristine, dactinomycin, cyclophosphamide, cisplatin, doxorubicin, temozolomide and intrathecal methotrexate, cytarabine, and hydrocortisone) [
• The
• The Canadian Brain Tumour Consortium retrospectively evaluated children diagnosed with rhabdoid tumors between 1995 and 2007. Among 40 individuals, 22 received conventional chemotherapy and 18 received HDCT regimens; 15 received adjuvant radiation. Notably, six of 12 long-term survivors never received any radiotherapy [
## Prevention of Primary Manifestations
Prophylactic risk-reducing bilateral salpingo-oophorectomy may be discussed following the end of family planning in women with
## Surveillance
Surveillance guidelines for individuals with RTPS have been provided by
Every six months, thorough clinical examination including neurologic examination;
Annual whole-body MRI;
Abdominal and pelvic ultrasound every six months in individuals with
Note: (1) Current data do not allow for a determination of how long surveillance should continue. (2) Recommendations are subject to continuous updates; the authors recommend close monitoring of the evolving literature.
• Every six months, thorough clinical examination including neurologic examination;
• Annual whole-body MRI;
• Abdominal and pelvic ultrasound every six months in individuals with
## Agents/Circumstances to Avoid
Limit exposure to DNA-damaging agents including radiation (e.g., x-ray, CT, external beam radiotherapy), tobacco, UV light, and chemotherapy to minimize the lifetime risk of developing late-onset secondary cancers. Imaging tests utilizing radioactive compounds should be used only if absolutely necessary for essential health care. This recommendation is based on the increased risk of adverse effects in young developing children, not increased risk as a result of a
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of at-risk relatives of an affected individual by molecular genetic testing for the
Early detection of individuals who are heterozygous for an
Family members who have not inherited the disease-causing variant and their subsequent offspring have risks similar to the general population.
See
• Early detection of individuals who are heterozygous for an
• Family members who have not inherited the disease-causing variant and their subsequent offspring have risks similar to the general population.
## Therapies Under Investigation
The following clinical trials are currently recruiting unless otherwise indicated.
Overview of Clinical Trials in Pediatric Malignant Rhabdoid Tumors Including Rhabdoid Tumor Predisposition Syndrome
Based on
Search
## Genetic Counseling
Rhabdoid tumor predisposition syndrome (RTPS) is inherited in an autosomal dominant manner.
The vast majority of individuals diagnosed with
Most reported individuals diagnosed with
If a 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 a phenotypically healthy parent is found to have a
If the
The proband has a
The proband inherited a disease-causing variant from a parent with germline (or somatic and germline) mosaicism. Parental germline mosaicism in
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a disease-causing variant that is present in the germ cells only.
The family history of most individuals with RTPS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (highly likely in
If a parent of the proband is affected and/or known to have the
The
Reduced
The types of RTPS-related tumors can vary among family members with the same disease-causing variant.
If the
If the parents have not been tested for the disease-causing variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for RTPS because of the possibility of reduced penetrance in a heterozygous parent (highly likely in
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.
Note: Rhabdoid tumors associated with RTPS may develop before birth; therefore, if 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 vast majority of individuals diagnosed with
• Most reported individuals diagnosed with
• If a 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 a phenotypically healthy parent is found to have a
• If the
• The proband has a
• The proband inherited a disease-causing variant from a parent with germline (or somatic and germline) mosaicism. Parental germline mosaicism in
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a disease-causing variant that is present in the germ cells only.
• The proband has a
• The proband inherited a disease-causing variant from a parent with germline (or somatic and germline) mosaicism. Parental germline mosaicism in
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a disease-causing variant that is present in the germ cells only.
• The family history of most individuals with RTPS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (highly likely in
• The proband has a
• The proband inherited a disease-causing variant from a parent with germline (or somatic and germline) mosaicism. Parental germline mosaicism in
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a disease-causing variant that is present in the germ cells only.
• If a parent of the proband is affected and/or known to have the
• The
• Reduced
• The types of RTPS-related tumors can vary among family members with the same disease-causing variant.
• The
• Reduced
• The types of RTPS-related tumors can vary among family members with the same disease-causing variant.
• If the
• If the parents have not been tested for the disease-causing variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for RTPS because of the possibility of reduced penetrance in a heterozygous parent (highly likely in
• The
• Reduced
• The types of RTPS-related tumors can vary among family members with the same disease-causing 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
Rhabdoid tumor predisposition syndrome (RTPS) is inherited in an autosomal dominant manner.
## Risk to Family Members
The vast majority of individuals diagnosed with
Most reported individuals diagnosed with
If a 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 a phenotypically healthy parent is found to have a
If the
The proband has a
The proband inherited a disease-causing variant from a parent with germline (or somatic and germline) mosaicism. Parental germline mosaicism in
Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a disease-causing variant that is present in the germ cells only.
The family history of most individuals with RTPS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (highly likely in
If a parent of the proband is affected and/or known to have the
The
Reduced
The types of RTPS-related tumors can vary among family members with the same disease-causing variant.
If the
If the parents have not been tested for the disease-causing variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for RTPS because of the possibility of reduced penetrance in a heterozygous parent (highly likely in
• The vast majority of individuals diagnosed with
• Most reported individuals diagnosed with
• If a 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 a phenotypically healthy parent is found to have a
• If the
• The proband has a
• The proband inherited a disease-causing variant from a parent with germline (or somatic and germline) mosaicism. Parental germline mosaicism in
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a disease-causing variant that is present in the germ cells only.
• The proband has a
• The proband inherited a disease-causing variant from a parent with germline (or somatic and germline) mosaicism. Parental germline mosaicism in
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a disease-causing variant that is present in the germ cells only.
• The family history of most individuals with RTPS may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (highly likely in
• The proband has a
• The proband inherited a disease-causing variant from a parent with germline (or somatic and germline) mosaicism. Parental germline mosaicism in
• Note: Testing of parental leukocyte DNA may not detect all instances of somatic mosaicism and will not detect a disease-causing variant that is present in the germ cells only.
• If a parent of the proband is affected and/or known to have the
• The
• Reduced
• The types of RTPS-related tumors can vary among family members with the same disease-causing variant.
• The
• Reduced
• The types of RTPS-related tumors can vary among family members with the same disease-causing variant.
• If the
• If the parents have not been tested for the disease-causing variant identified in the proband but are clinically unaffected, sibs are still presumed to be at increased risk for RTPS because of the possibility of reduced penetrance in a heterozygous parent (highly likely in
• The
• Reduced
• The types of RTPS-related tumors can vary among family members with the same disease-causing 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 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
Note: Rhabdoid tumors associated with RTPS may develop before birth; therefore, if 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
Stenglingstr. 2.
Augsburg 86156
Germany
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## Molecular Genetics
Rhabdoid Tumor Predisposition Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Rhabdoid Tumor Predisposition Syndrome (
Rhabdoid tumor predisposition syndrome (RTPS) is typically characterized by heterozygous germline disease-causing variants that predict inactivation of
SMARCA4 with its ATPase activity is the catalytic subunit and SMARCB1 is a core protein of the SWI/SNF chromatin remodeling complex. SWI/SNF interacts with various pathways (p16-Rb pathway, Wnt/β-catenin pathway, sonic hedgehog signal pathway, polycomb pathway, MYCC, Aurora A) and affects many essential biological functions in developing organs, including cell cycle and cell differentiation, gene expression, and DNA repair [
Sporadic rhabdoid tumors may occur as single tumors in the absence of any other findings of RTPS and harbor somatic (acquired)
## Molecular Pathogenesis
Rhabdoid tumor predisposition syndrome (RTPS) is typically characterized by heterozygous germline disease-causing variants that predict inactivation of
SMARCA4 with its ATPase activity is the catalytic subunit and SMARCB1 is a core protein of the SWI/SNF chromatin remodeling complex. SWI/SNF interacts with various pathways (p16-Rb pathway, Wnt/β-catenin pathway, sonic hedgehog signal pathway, polycomb pathway, MYCC, Aurora A) and affects many essential biological functions in developing organs, including cell cycle and cell differentiation, gene expression, and DNA repair [
## Cancer and Benign Tumors
Sporadic rhabdoid tumors may occur as single tumors in the absence of any other findings of RTPS and harbor somatic (acquired)
## Chapter Notes
MCF is supported by the "Deutsche Kinderkrebsstiftung" DKS 2020.10, "Deutsche Forschungsgemeinschaft" DFG FR 1516/4-1, and "Deutsche Krebshilfe" DKH 70113981. RS received grant support for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen and "Deutsche Krebhilfe" DKH 70114040. PDJ is supported by the Else-Kroener-Fresenius Stiftung.
We thank P Neumayer and S Breitmoser for expert assistance in data acquisition, management, and analysis.
Karolina Nemes, MD, PhD (2017-present)Susanne Bens, MD, PhD (2017-present)Franck Bourdeaut, MD, PhD (2017-present)Martin Hasselblatt, MD, Prof; University Hospital Münster (2017-2022)Marcel Kool, PhD; German Cancer Consortium (2017-2022)Pascal Johann, MD (2017-present)Uwe Kordes, MD (2017-present)Reinhard Schneppenheim, MD, PhD, Prof; University Medical Center Hamburg–Eppendorf (2017-2022)Reiner Siebert, MD, Prof (2017-present)Michael C Frühwald, MD, PhD, Prof (2017-present)
12 May 2022 (sw) Comprehensive update posted live
7 December 2017 (sw) Review posted live
8 March 2017 (mcf) Original submission
• 12 May 2022 (sw) Comprehensive update posted live
• 7 December 2017 (sw) Review posted live
• 8 March 2017 (mcf) Original submission
## Author Notes
## Acknowledgments
MCF is supported by the "Deutsche Kinderkrebsstiftung" DKS 2020.10, "Deutsche Forschungsgemeinschaft" DFG FR 1516/4-1, and "Deutsche Krebshilfe" DKH 70113981. RS received grant support for infrastructure by the KinderKrebsInitiative Buchholz/Holm-Seppensen and "Deutsche Krebhilfe" DKH 70114040. PDJ is supported by the Else-Kroener-Fresenius Stiftung.
We thank P Neumayer and S Breitmoser for expert assistance in data acquisition, management, and analysis.
## Author History
Karolina Nemes, MD, PhD (2017-present)Susanne Bens, MD, PhD (2017-present)Franck Bourdeaut, MD, PhD (2017-present)Martin Hasselblatt, MD, Prof; University Hospital Münster (2017-2022)Marcel Kool, PhD; German Cancer Consortium (2017-2022)Pascal Johann, MD (2017-present)Uwe Kordes, MD (2017-present)Reinhard Schneppenheim, MD, PhD, Prof; University Medical Center Hamburg–Eppendorf (2017-2022)Reiner Siebert, MD, Prof (2017-present)Michael C Frühwald, MD, PhD, Prof (2017-present)
## Revision History
12 May 2022 (sw) Comprehensive update posted live
7 December 2017 (sw) Review posted live
8 March 2017 (mcf) Original submission
• 12 May 2022 (sw) Comprehensive update posted live
• 7 December 2017 (sw) Review posted live
• 8 March 2017 (mcf) Original submission
## References
## Literature Cited
Overview of molecular features of the malignant rhabdoid tumor subgroups
Reprinted from
|
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"F Le Loarer, L Zhang, CD Fletcher, A Ribeiro, S Singer, A Italiano, A Neuville, A Houlier, F Chibon, JM Coindre, CR Antonescu. Consistent SMARCB1 homozygous deletions in epithelioid sarcoma and in a subset of myoepithelial carcinomas can be reliably detected by FISH in archival material.. Genes Chromosomes Cancer. 2014;53:475-86",
"D Li, RC Ahrens-Nicklas, J Baker, V Bhambhani, A Calhoun, JS Cohen, MA Deardorff, A Fernández-Jaén, B Kamien, M Jain, F Mckenzie, M Mintz, C Motter, K Niles, A Ritter, C Rogers, M Roifman, S Townshend, C Ward-Melver, SA Schrier Vergano. The variability of SMARCA4-related Coffin-Siris syndrome: Do nonsense candidate variants add to milder phenotypes?. Am J Med Genet A. 2020;182:2058-67",
"DI Lin, JM Allen, JL Hecht, JK Killian, NT Ngo, C Edgerly, EA Severson, SM Ali, RL Erlich, SH Ramkissoon, JA Vergilio, JS Ross, JA Elvin. SMARCA4 inactivation defines a subset of undifferentiated uterine sarcomas with rhabdoid and small cell features and germline mutation association.. Mod Pathol. 2019;32:1675-87",
"AS Margol, AR Judkins. Pathology and diagnosis of SMARCB1-deficient tumors.. Cancer Genet. 2014;207:358-64",
"JL Metts, SI Park, BP Soares, C Fong, JA Biegel, KC Goldsmith. Concurrent myeloid sarcoma, atypical teratoid/rhabdoid tumor, and hypereosinophilia in an infant with a germline SMARCB1 mutation.. Pediatr Blood Cancer. 2017:64",
"J Moes-Sosnowska, L Szafron, D Nowakowska, A Dansonka-Mieszkowska, A Budzilowska, B Konopka, J Plisiecka-Halasa, A Podgorska, IK Rzepecka, J Kupryjanczyk. Germline SMARCA4 mutations in patients with ovarian small cell carcinoma of hypercalcemic type.. Orphanet J Rare Dis. 2015;10:32",
"K Nakata, M Colombet, CA Stiller, K Pritchard-Jones, E Steliarova-Foucher. Incidence of childhood renal tumours: an international population-based study.. Int J Cancer. 2020;147:3313-27",
"S Negahban, N Ahmadi, A Oryan, HN Khojasteh, A Aledavood, H Soleimanpour, M Mohammadianpanah, I Oschlies, S Gesk, R Siebert, K Daneshbod, Y Daneshbod. Primary bilateral Burkitt lymphoma of the lactating breast: a case report and review of the literature.. Mol Diagn Ther. 2010;14:243-50",
"K Nemes, S Bens, D Kachanov, M Teleshova, P Hauser, T Simon, S Tippelt, W Woessmann, O Beck, C Flotho, L Grigull, PH Driever, PG Schlegel, C Khurana, K Hering, R Kolb, A Leipold, F Abbink, MJ Gil-Da-Costa, M Benesch, K Kerl, S Lowis, CH Marques, N Graf, K Nysom, C Vokuhl, P Melchior, T Kröncke, R Schneppenheim, U Kordes, J Gerss, R Siebert, R Furtwängler, MC Frühwald. Clinical and genetic risk factors define two risk groups of extracranial malignant rhabdoid tumours (eMRT/RTK).. Eur J Cancer. 2021;142:112-22",
"K Nemes, N Clément, D Kachanov, S Bens, M Hasselblatt, B Timmermann, R Schneppenheim, J Gerss, R Siebert, R Furtwängler, F Bourdeaut, MC Frühwald. The extraordinary challenge of treating patients with congenital rhabdoid tumors--a collaborative European effort.. Pediatr Blood Cancer. 2018;65",
"K Nemes, MC Frühwald. Emerging therapeutic targets for the treatment of malignant rhabdoid tumors.. Expert Opin Ther Targets. 2018;22:365-79",
"K Nemes, PD Johann, S Tüchert, P Melchior, C Vokuhl, R Siebert, R Furtwängler, MC Frühwald. Current and emerging therapeutic approaches for extracranial malignant rhabdoid tumors.. Cancer Manag Res. 2022;14:479-98",
"T Pejovic, WG McCluggage, AJ Krieg, F Xu, DM Lee, L Witkowski, WD Foulkes. The dilemma of early preventive oophorectomy in familial small cell carcinoma of the ovary of hypercalcemic type.. Gynecol Oncol Rep. 2019;28:47-49",
"RN Prasad, UG Gardner, A Yaney, DM Prevedello, DC Koboldt, DL Thomas, ER Mardis, JD Palmer. Germline BAP1 mutation in a family with multi-generational meningioma with rhabdoid features: a case series and literature review.. Front Oncol. 2021;11",
"AT Reddy, DR Strother, AR Judkins, PC Burger, IF Pollack, MD Krailo, AB Buxton, C Williams-Hughes, M Fouladi, A Mahajan, TE Merchant, B Ho, CM Mazewski, VA Lewis, A Gajjar, LG Vezina, TN Booth, KW Parsons, VL Poss, T Zhou, JA Biegel, A Huang. Efficacy of high-dose chemotherapy and three-dimensional conformal radiation for atypical teratoid/rhabdoid tumor: a report from the Children's Oncology Group Trial ACNS0333.. J Clin Oncol. 2020;38:1175-85",
"CV Schenone, A King, E Castro, P Ketwaroo, R Donepudi, M Sanz-Cortes. Prenatal detection of disseminated extrarenal malignant rhabdoid tumor with placental metastases.. Ultrasound Obstet Gynecol. 2021;57:1008-10",
"R Schneppenheim, MC Frühwald, S Gesk, M Hasselblatt, A Jeibmann, U Kordes, M Kreuz, I Leuschner, JI Martin Subero, T Obser, F Oyen, I Vater, R Siebert. Germline nonsense mutation and somatic inactivation of SMARCA4/BRG1 in a family with rhabdoid tumor predisposition syndrome.. Am J Hum Genet. 2010;86:279-84",
"D Schrey, F Carceller Lechón, G Malietzis, L Moreno, C Dufour, S Chi, L Lafay-Cousin, K von Hoff, T Athanasiou, LV Marshall, S Zacharoulis. Multimodal therapy in children and adolescents with newly diagnosed atypical teratoid rhabdoid tumor: individual pooled data analysis and review of the literature.. J Neurooncol. 2016;126:81-90",
"A Seeringer, K Bartelheim, K Kerl, M Hasselblatt, I Leuschner, S Rutkowski, B Timmermann, RD Kortmann, E Koscielniak, R Schneppenheim, M Warmuth-Metz, J Gerss, R Siebert, N Graf, J Boos, MC Frühwald. Feasibility of intensive multimodal therapy in infants affected by rhabdoid tumors - experience of the EU-RHAB registry.. Klin Padiatr. 2014a;226:143-8",
"A Seeringer, H Reinhard, M Hasselblatt, R Schneppenheim, R Siebert, K Bartelheim, I Leuschner, MC Frühwald. Synchronous congenital malignant rhabdoid tumor of the orbit and atypical teratoid/rhabdoid tumor--feasibility and efficacy of multimodal therapy in a long-term survivor.. Cancer Genet. 2014b;207:429-33",
"MJ Smith, AJ Wallace, NL Bowers, H Eaton, DG Evans. SMARCB1 mutations in schwannomatosis and genotype correlations with rhabdoid tumors.. Cancer Genet. 2014;207:373-8",
"ST Sredni, T Tomita. Rhabdoid tumor predisposition syndrome.. Pediatr Dev Pathol. 2015;18:49-58",
"A Teplick, M Kowalski, JA Biegel, KE Nichols. Educational paper: screening in cancer predisposition syndromes: guidelines for the general pediatrician.. Eur J Pediatr. 2011;170:285-94",
"J Torchia, B Golbourn, S Feng, KC Ho, P Sin-Chan, A Vasiljevic, JD Norman, P Guilhamon, L Garzia, NR Agamez, M Lu, TS Chan, D Picard, P de Antonellis, DA Khuong-Quang, AC Planello, C Zeller, D Barsyte-Lovejoy, L Lafay-Cousin, L Letourneau, M Bourgey, M Yu, DM Gendoo, M Dzamba, M Barszczyk, T Medina, AN Riemenschneider, AS Morrissy, YS Ra, V Ramaswamy, M Remke, CP Dunham, S Yip, HK Ng, JQ Lu, V Mehta, S Albrecht, J Pimentel, JA Chan, GR Somers, CC Faria, L Roque, M Fouladi, LM Hoffman, AS Moore, Y Wang, SA Choi, JR Hansford, D Catchpoole, DK Birks, NK Foreman, D Strother, A Klekner, L Bognár, M Garami, P Hauser, T Hortobágyi, B Wilson, J Hukin, AS Carret, TE Van Meter, EI Hwang, A Gajjar, SH Chiou, H Nakamura, H Toledano, I Fried, D Fults, T Wataya, C Fryer, DD Eisenstat, K Scheinemann, AJ Fleming, DL Johnston, J Michaud, S Zelcer, R Hammond, S Afzal, DA Ramsay, N Sirachainan, S Hongeng, N Larbcharoensub, RG Grundy, RR Lulla, JR Fangusaro, H Druker, U Bartels, R Grant, D Malkin, CJ McGlade, T Nicolaides, T Tihan, J Phillips, J Majewski, A Montpetit, G Bourque, GD Bader, AT Reddy, GY Gillespie, M Warmuth-Metz, S Rutkowski, U Tabori, M Lupien, M Brudno, U Schüller, T Pietsch, AR Judkins, CE Hawkins, E Bouffet, SK Kim, PB Dirks, MD Taylor, A Erdreich-Epstein, CH Arrowsmith, DD De Carvalho, JT Rutka, N Jabado, A Huang. Integrated (epi)-genomic analyses identify subgroup-specific therapeutic targets in CNS rhabdoid tumors.. Cancer Cell. 2016;30:891-908",
"J Torchia, D Picard, L Lafay-Cousin, CE Hawkins, SK Kim, L Letourneau, YS Ra, KC Ho, TS Chan, P Sin-Chan, CP Dunham, S Yip, HK Ng, JQ Lu, S Albrecht, J Pimentel, JA Chan, GR Somers, M Zielenska, CC Faria, L Roque, B Baskin, D Birks, N Foreman, D Strother, A Klekner, M Garami, P Hauser, T Hortobágyi, L Bognár, B Wilson, J Hukin, AS Carret, TE Van Meter, H Nakamura, H Toledano, I Fried, D Fults, T Wataya, C Fryer, DD Eisenstat, K Scheineman, D Johnston, J Michaud, S Zelcer, R Hammond, DA Ramsay, AJ Fleming, RR Lulla, JR Fangusaro, N Sirachainan, N Larbcharoensub, S Hongeng, MA Barakzai, A Montpetit, D Stephens, RG Grundy, U Schüller, T Nicolaides, T Tihan, J Phillips, MD Taylor, JT Rutka, P Dirks, GD Bader, M Warmuth-Metz, S Rutkowski, T Pietsch, AR Judkins, N Jabado, E Bouffet, A Huang. Molecular subgroups of atypical teratoid rhabdoid tumours in children: an integrated genomic and clinicopathological analysis.. Lancet Oncol. 2015;16:569-82",
"P van den Munckhof, I Christiaans, SB Kenter, F Baas, TJ Hulsebos. Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri.. Neurogenetics. 2012;13:1-7",
"MR Voisin, C Ovenden, DS Tsang, AA Gupta, A Huang, AF Gao, P Diamandis, JP Almeida, F Gentili. Atypical teratoid/rhabdoid sellar tumor in an adult with a familial history of a germline SMARCB1 mutation: case report and review of the literature.. World Neurosurg. 2019;127:336-45",
"L Witkowski, N Donini, R Byler-Dann, JA Knost, S Albrecht, A Berchuck, WG McCluggage, M Hasselblatt, WD Foulkes. The hereditary nature of small cell carcinoma of the ovary, hypercalcemic type: two new familial cases.. Fam Cancer. 2017;16:395-9",
"L Witkowski, C Goudie, P Ramos, T Boshari, JS Brunet, AN Karnezis, M Longy, JA Knost, E Saloustros, WG McCluggage, CJR Stewart, WPD Hendricks, H Cunliffe, DG Huntsman, P Pautier, DA Levine, JM Trent, A Berchuck, M Hasselblatt, WD Foulkes. The influence of clinical and genetic factors on patient outcome in small cell carcinoma of the ovary, hypercalcemic type.. Gynecol Oncol. 2016;141:454-60",
"L Witkowski, E Lalonde, J Zhang, S Albrecht, N Hamel, L Cavallone, ST May, JC Nicholson, N Coleman, MJ Murray, PF Tauber, DG Huntsman, S Schönberger, D Yandell, M Hasselblatt, MD Tischkowitz, J Majewski, WD Foulkes. Familial rhabdoid tumour \"avant la letter\"--from pathology review to exome sequencing and back again.. J Pathol. 2013;231:35-43",
"W Zaky, G Dhall, L Ji, K Haley, J Allen, M Atlas, S Bertolone, A Cornelius, S Gardner, R Patel, K Pradhan, V Shen, S Thompson, J Torkildson, R Sposto, JL Finlay. Intensive induction chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic progenitor cell rescue for young children newly-diagnosed with central nervous system atypical teratoid/rhabdoid tumors: the Head Start III experience.. Pediatr Blood Cancer. 2014;61:95-101"
] |
7/12/2017
|
12/5/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
rts
|
rts
|
[
"Anaphase-promoting complex subunit 1",
"ATP-dependent DNA helicase Q4",
"ANAPC1",
"RECQL4",
"Rothmund-Thomson Syndrome"
] |
Rothmund-Thomson Syndrome
|
Lisa L Wang, Sharon E Plon
|
Summary Rothmund-Thomson syndrome (RTS) is characterized by a rash that progresses to poikiloderma; sparse hair, eyelashes, and/or eyebrows; small size; skeletal and dental abnormalities; juvenile cataracts; and an increased risk for cancer, especially osteosarcoma. A variety of benign and malignant hematologic abnormalities have been reported in affected individuals. The rash of RTS typically develops between ages three and six months (occasionally as late as age two years) as erythema, swelling, and blistering on the face, subsequently spreading to the buttocks and extremities. The rash evolves over months to years into the chronic pattern of reticulated hypo- and hyperpigmentation, telangiectasias, and punctate atrophy (collectively known as poikiloderma) that persist throughout life. Hyperkeratotic lesions occur in approximately one third of individuals. Skeletal abnormalities can include radial ray defects, ulnar defects, absent or hypoplastic patella, and osteopenia. The diagnosis of RTS is established by clinical findings (in particular, the characteristic rash) and/or the identification of biallelic pathogenic variants in RTS 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, prenatal testing for pregnancies at increased risk, and preimplantation genetic testing are possible if the
|
## Diagnosis
Rothmund-Thomson syndrome (RTS)
Starts in infancy, usually between ages three and six months
Erythema on the cheeks and face
Spreads to involve the extensor surfaces of the extremities
Typically sparing of the trunk and abdomen; possible involvement of the buttocks
Gradually develops over a period of months to years
Reticulated hyper- and hypopigmentation, telangiectasias, and areas of punctate atrophy (i.e., poikiloderma)
Persists throughout life
If the rash is atypical (either in appearance, distribution, or pattern of onset and spread), a diagnosis of
Sparse scalp hair, eyelashes, and/or eyebrows
Small size, usually symmetric for height and weight
Gastrointestinal disturbance as young children, usually consisting of chronic vomiting and diarrhea, sometimes requiring feeding tubes
Dental abnormalities that include rudimentary or hypoplastic teeth, enamel defects, delayed tooth eruption
Nail abnormalities such as dysplastic or poorly formed nails
Hyperkeratosis, particularly of the soles of the feet
Cataracts, usually juvenile, bilateral
Skeletal abnormalities including radial ray defects, ulnar defects, absent or hypoplastic patella, osteopenia, abnormal trabeculation
Cancers including skin cancers (basal cell carcinoma and squamous cell carcinoma) and in particular osteosarcoma
The diagnosis of RTS
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 Rothmund-Thomson syndrome is broad, individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of Rothmund-Thomson syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
Note: As
If the individual presents with skeletal abnormalities or osteosarcoma, recommend starting with
For individuals with early-onset juvenile cataracts without skeletal defects or osteosarcoma, recommend starting with
Sequence analysis of either gene can detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no pathogenic variant is detected in either gene by the sequencing method used, gene-targeted deletion/duplication analysis may be considered; however, no exon or whole-gene deletions/duplications have thus far been identified as a cause of RTS.
When the diagnosis of Rothmund-Thomson syndrome is unclear because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Rothmund-Thomson Syndrome (RTS)
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 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 the Human Gene Mutation Database [
The most frequently detected pathogenic variant,
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Some pathogenic variants are in short introns of
In nearly 40% of individuals with the typical clinical findings of RTS, molecular genetic testing fails to identify a pathogenic variant in
• Starts in infancy, usually between ages three and six months
• Erythema on the cheeks and face
• Spreads to involve the extensor surfaces of the extremities
• Typically sparing of the trunk and abdomen; possible involvement of the buttocks
• Gradually develops over a period of months to years
• Reticulated hyper- and hypopigmentation, telangiectasias, and areas of punctate atrophy (i.e., poikiloderma)
• Persists throughout life
• Sparse scalp hair, eyelashes, and/or eyebrows
• Small size, usually symmetric for height and weight
• Gastrointestinal disturbance as young children, usually consisting of chronic vomiting and diarrhea, sometimes requiring feeding tubes
• Dental abnormalities that include rudimentary or hypoplastic teeth, enamel defects, delayed tooth eruption
• Nail abnormalities such as dysplastic or poorly formed nails
• Hyperkeratosis, particularly of the soles of the feet
• Cataracts, usually juvenile, bilateral
• Skeletal abnormalities including radial ray defects, ulnar defects, absent or hypoplastic patella, osteopenia, abnormal trabeculation
• Cancers including skin cancers (basal cell carcinoma and squamous cell carcinoma) and in particular osteosarcoma
• If the individual presents with skeletal abnormalities or osteosarcoma, recommend starting with
• For individuals with early-onset juvenile cataracts without skeletal defects or osteosarcoma, recommend starting with
## Suggestive Findings
Rothmund-Thomson syndrome (RTS)
Starts in infancy, usually between ages three and six months
Erythema on the cheeks and face
Spreads to involve the extensor surfaces of the extremities
Typically sparing of the trunk and abdomen; possible involvement of the buttocks
Gradually develops over a period of months to years
Reticulated hyper- and hypopigmentation, telangiectasias, and areas of punctate atrophy (i.e., poikiloderma)
Persists throughout life
If the rash is atypical (either in appearance, distribution, or pattern of onset and spread), a diagnosis of
Sparse scalp hair, eyelashes, and/or eyebrows
Small size, usually symmetric for height and weight
Gastrointestinal disturbance as young children, usually consisting of chronic vomiting and diarrhea, sometimes requiring feeding tubes
Dental abnormalities that include rudimentary or hypoplastic teeth, enamel defects, delayed tooth eruption
Nail abnormalities such as dysplastic or poorly formed nails
Hyperkeratosis, particularly of the soles of the feet
Cataracts, usually juvenile, bilateral
Skeletal abnormalities including radial ray defects, ulnar defects, absent or hypoplastic patella, osteopenia, abnormal trabeculation
Cancers including skin cancers (basal cell carcinoma and squamous cell carcinoma) and in particular osteosarcoma
• Starts in infancy, usually between ages three and six months
• Erythema on the cheeks and face
• Spreads to involve the extensor surfaces of the extremities
• Typically sparing of the trunk and abdomen; possible involvement of the buttocks
• Gradually develops over a period of months to years
• Reticulated hyper- and hypopigmentation, telangiectasias, and areas of punctate atrophy (i.e., poikiloderma)
• Persists throughout life
• Sparse scalp hair, eyelashes, and/or eyebrows
• Small size, usually symmetric for height and weight
• Gastrointestinal disturbance as young children, usually consisting of chronic vomiting and diarrhea, sometimes requiring feeding tubes
• Dental abnormalities that include rudimentary or hypoplastic teeth, enamel defects, delayed tooth eruption
• Nail abnormalities such as dysplastic or poorly formed nails
• Hyperkeratosis, particularly of the soles of the feet
• Cataracts, usually juvenile, bilateral
• Skeletal abnormalities including radial ray defects, ulnar defects, absent or hypoplastic patella, osteopenia, abnormal trabeculation
• Cancers including skin cancers (basal cell carcinoma and squamous cell carcinoma) and in particular osteosarcoma
## Establishing the Diagnosis
The diagnosis of RTS
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 Rothmund-Thomson syndrome is broad, individuals with the distinctive findings described in
When the phenotypic findings suggest the diagnosis of Rothmund-Thomson syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
Note: As
If the individual presents with skeletal abnormalities or osteosarcoma, recommend starting with
For individuals with early-onset juvenile cataracts without skeletal defects or osteosarcoma, recommend starting with
Sequence analysis of either gene can detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no pathogenic variant is detected in either gene by the sequencing method used, gene-targeted deletion/duplication analysis may be considered; however, no exon or whole-gene deletions/duplications have thus far been identified as a cause of RTS.
When the diagnosis of Rothmund-Thomson syndrome is unclear because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Rothmund-Thomson Syndrome (RTS)
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 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 the Human Gene Mutation Database [
The most frequently detected pathogenic variant,
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Some pathogenic variants are in short introns of
In nearly 40% of individuals with the typical clinical findings of RTS, molecular genetic testing fails to identify a pathogenic variant in
• If the individual presents with skeletal abnormalities or osteosarcoma, recommend starting with
• For individuals with early-onset juvenile cataracts without skeletal defects or osteosarcoma, recommend starting with
## Option 1
When the phenotypic findings suggest the diagnosis of Rothmund-Thomson syndrome, molecular genetic testing approaches can include use of a
For an introduction to multigene panels click
Note: As
If the individual presents with skeletal abnormalities or osteosarcoma, recommend starting with
For individuals with early-onset juvenile cataracts without skeletal defects or osteosarcoma, recommend starting with
Sequence analysis of either gene can detect small intragenic deletions/insertions and missense, nonsense, and splice site variants. Note: Depending on the sequencing method used, single-exon, multiexon, or whole-gene deletions/duplications may not be detected. If only one or no pathogenic variant is detected in either gene by the sequencing method used, gene-targeted deletion/duplication analysis may be considered; however, no exon or whole-gene deletions/duplications have thus far been identified as a cause of RTS.
• If the individual presents with skeletal abnormalities or osteosarcoma, recommend starting with
• For individuals with early-onset juvenile cataracts without skeletal defects or osteosarcoma, recommend starting with
## Option 2
When the diagnosis of Rothmund-Thomson syndrome is unclear because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Rothmund-Thomson Syndrome (RTS)
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 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 the Human Gene Mutation Database [
The most frequently detected pathogenic variant,
No data on detection rate of gene-targeted deletion/duplication analysis are available.
Some pathogenic variants are in short introns of
In nearly 40% of individuals with the typical clinical findings of RTS, molecular genetic testing fails to identify a pathogenic variant in
## Clinical Characteristics
Rothmund-Thomson syndrome (RTS) is a genetic disorder associated with a characteristic skin rash in combination with certain other findings detailed in this section. One subset of affected individuals defined by the lack of
Hyperkeratotic lesions occur in approximately one third of individuals.
Uncommon but reported findings [
Calcinosis, the formation of calcium deposits in the skin, usually at the site of an injury
Note: Calcinosis cutis differs from osteoma cutis, which is true bone formation.
Porokeratosis, a sign of disordered keratinization. This has been reported in one person with RTS, and thus may or may not be a related finding.
In a study of metabolic bone disease in 29 individuals with a clinical diagnosis of RTS, a significant proportion were found to have decreased bone mineral density as well as history of fractures [
Immunologic function appears to be intact. However, there are several isolated reports of individuals with RTS who have concomitant immune dysfunction. These include an individual who had humoral immune deficiency associated with granulomatous skin lesions [
Most individuals with RTS appear to have normal intelligence.
Osteosarcoma and skeletal defects are more often found in individuals with RTS associated with
No genotype-phenotype correlations have been identified.
"Poikiloderma congenitale," the name given by M Sidney Thomson to the disorder he described in 1923, has been used in the literature to describe RTS in the past.
RTS is a rare disorder. Since its original description by Auguste Rothmund in Austria in 1868, fewer than 500 individuals have been described in the English-language literature.
RTS has been described in all ethnicities. No population appears to be at higher or lower risk for the disorder. However, specific pathogenic variants may exist within certain ethnic groups.
The population prevalence and carrier frequency of RTS are unknown [
• Calcinosis, the formation of calcium deposits in the skin, usually at the site of an injury
• Note: Calcinosis cutis differs from osteoma cutis, which is true bone formation.
• Porokeratosis, a sign of disordered keratinization. This has been reported in one person with RTS, and thus may or may not be a related finding.
## Clinical Description
Rothmund-Thomson syndrome (RTS) is a genetic disorder associated with a characteristic skin rash in combination with certain other findings detailed in this section. One subset of affected individuals defined by the lack of
Hyperkeratotic lesions occur in approximately one third of individuals.
Uncommon but reported findings [
Calcinosis, the formation of calcium deposits in the skin, usually at the site of an injury
Note: Calcinosis cutis differs from osteoma cutis, which is true bone formation.
Porokeratosis, a sign of disordered keratinization. This has been reported in one person with RTS, and thus may or may not be a related finding.
In a study of metabolic bone disease in 29 individuals with a clinical diagnosis of RTS, a significant proportion were found to have decreased bone mineral density as well as history of fractures [
Immunologic function appears to be intact. However, there are several isolated reports of individuals with RTS who have concomitant immune dysfunction. These include an individual who had humoral immune deficiency associated with granulomatous skin lesions [
Most individuals with RTS appear to have normal intelligence.
• Calcinosis, the formation of calcium deposits in the skin, usually at the site of an injury
• Note: Calcinosis cutis differs from osteoma cutis, which is true bone formation.
• Porokeratosis, a sign of disordered keratinization. This has been reported in one person with RTS, and thus may or may not be a related finding.
## Phenotype Correlations by Gene
Osteosarcoma and skeletal defects are more often found in individuals with RTS associated with
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
"Poikiloderma congenitale," the name given by M Sidney Thomson to the disorder he described in 1923, has been used in the literature to describe RTS in the past.
## Prevalence
RTS is a rare disorder. Since its original description by Auguste Rothmund in Austria in 1868, fewer than 500 individuals have been described in the English-language literature.
RTS has been described in all ethnicities. No population appears to be at higher or lower risk for the disorder. However, specific pathogenic variants may exist within certain ethnic groups.
The population prevalence and carrier frequency of RTS are unknown [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Other phenotypes associated with germline pathogenic variants in
RAPADILINO (
The Finn-specific
• RAPADILINO (
• The Finn-specific
## Differential Diagnosis
The differential diagnosis of Rothmund-Thomson syndrome (RTS) includes the disorders summarized in
Disorders That Can Exhibit Features of Poikiloderma to Consider in the Differential Diagnosis of Rothmund-Thomson Syndrome (RTS)
Rash characterized by an erythematous, sun-sensitive lesion of the face; not true poikiloderma
Loss of lower eyelashes & blister & fissure formation of lower lip common
Café au lait macules or paired hypopigmented & hyperpigmented macules in some
Most common cause of death: cancer (at younger-than-usual ages)
Severe pre- & postnatal growth deficiency w/↓ subcutaneous fat
Recurrent infections (otitis media & pneumonia)
Chronic pulmonary disease
Diabetes mellitus
Initial findings (usually in 3rd decade): loss & graying of hair, alopecia, scleroderma-like skin changes
Skin ulcers (4th decade)
Cancer predisposition
Premature appearance of features assoc w/normal aging
Normal development until end of 1st decade
1st symptom: no growth spurt during early teen years
Initial signs: (3rd decade) hoarseness followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, & osteoporosis in 4th decade
↑ risk of malignancy, particularly leukemia & lymphoma
Unusual sensitivity to ionizing radiation
Progressive cerebellar ataxia beginning ages 1-4 yrs
Oculomotor apraxia
Frequent infections
Choreoathetosis
Telangiectasias of the conjunctivae
Immunodeficiency
Abnormal skin pigmentation
↑ risk of malignancy: 10%-30% incidence of hematologic malignancies (primarily acute myeloid leukemia); 25%-30% incidence of nonhematologic malignancies (solid tumors, particularly of head & neck, skin, GI tract, & genital tract)
Bone marrow failure in 1st decade; 90% estimated cumulative incidence of bone marrow failure by age 40-50 yrs
Physical abnormalities: short stature; malformations of thumbs, forearms, skeletal system, eye, kidneys & urinary tract, ear, heart, GI system, oral cavity, & CNS; hearing loss; hypogonadism; DD
Sun sensitivity (sunburn w/blistering; persistent erythema on minimal sun exposure in ~60%; severe, marked freckle-like pigmentation of face before age 2 yrs)
Greatly ↑ risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma)
Xerosis (dry skin)
Poikiloderma
Loss of lashes
Median age of onset of non-melanoma skin cancer: <10 yrs
Neurologic manifestations in ~25%
Photophobia
Keratitis
Atrophy of skin of eyelids
Acral bullae at birth & after minor trauma
Diffuse poikiloderma w/striate & reticulate atrophy
Widespread eczematoid dermatitis
Keratotic papules of hands, feet, elbows, knees
Marked photosensitivity
Esophageal & urethral strictures
Webbing of fingers & toes
No ↑ risk for cataract or malignancy
Lacy reticular pigmentation of neck & upper chest
Nail dystrophy
↑ risk of leukemia & skin cancers
Bone marrow failure
Oral leukoplakia w/variable onset
Not assoc w/radial ray defects or cataracts
Rash
Less common finding: acute myeloid leukemia
Onset of rash differs from that seen in RTS: more eczematous, starting peripherally & spreading centrally
Rash affecting the trunk
Not assoc w/radial ray abnormalities
Clinically significant neutropenia w/recurrent sinopulmonary infection
Less common finding: bone marrow failure
Paronychias common
Poikiloderma (typically beginning in 1st 6 mos & mainly facial)
Chronic erythematous & scaly skin lesions on extremities (distinct from chronic poikiloderma of extremities seen in RTS)
Sclerosis of digits
Mild palmoplantar keratoderma
Scalp hair, eyelashes, &/or eyebrows typically sparse
Nail dysplasia in some
Hypohidrosis w/heat intolerance
Mild lymphedema of extremities
Muscle contractures usually seen in childhood; can be present by age 2 yrs
In most: progressive weakness of proximal & distal muscles of all 4 limbs
In some adults: progressive interstitial pulmonary fibrosis that can be life threatening w/in 3-4 yrs after respiratory symptoms appear
AD = autosomal dominant; AR = autosomal recessive; CNS = central nervous system; DD = developmental delay; GI = gastrointestinal; MOI = mode of inheritance; XL = X-linked
A greatly increased frequency of sister chromatid exchanges (SCEs) in cells exposed to bromodeoxyuridine (BrdU) is diagnostic. Bloom syndrome is the only disorder in which such evidence of hyper-recombination is known to occur.
See
• Rash characterized by an erythematous, sun-sensitive lesion of the face; not true poikiloderma
• Loss of lower eyelashes & blister & fissure formation of lower lip common
• Café au lait macules or paired hypopigmented & hyperpigmented macules in some
• Most common cause of death: cancer (at younger-than-usual ages)
• Severe pre- & postnatal growth deficiency w/↓ subcutaneous fat
• Recurrent infections (otitis media & pneumonia)
• Chronic pulmonary disease
• Diabetes mellitus
• Initial findings (usually in 3rd decade): loss & graying of hair, alopecia, scleroderma-like skin changes
• Skin ulcers (4th decade)
• Cancer predisposition
• Premature appearance of features assoc w/normal aging
• Normal development until end of 1st decade
• 1st symptom: no growth spurt during early teen years
• Initial signs: (3rd decade) hoarseness followed by bilateral ocular cataracts, type 2 diabetes mellitus, hypogonadism, & osteoporosis in 4th decade
• ↑ risk of malignancy, particularly leukemia & lymphoma
• Unusual sensitivity to ionizing radiation
• Progressive cerebellar ataxia beginning ages 1-4 yrs
• Oculomotor apraxia
• Frequent infections
• Choreoathetosis
• Telangiectasias of the conjunctivae
• Immunodeficiency
• Abnormal skin pigmentation
• ↑ risk of malignancy: 10%-30% incidence of hematologic malignancies (primarily acute myeloid leukemia); 25%-30% incidence of nonhematologic malignancies (solid tumors, particularly of head & neck, skin, GI tract, & genital tract)
• Bone marrow failure in 1st decade; 90% estimated cumulative incidence of bone marrow failure by age 40-50 yrs
• Physical abnormalities: short stature; malformations of thumbs, forearms, skeletal system, eye, kidneys & urinary tract, ear, heart, GI system, oral cavity, & CNS; hearing loss; hypogonadism; DD
• Sun sensitivity (sunburn w/blistering; persistent erythema on minimal sun exposure in ~60%; severe, marked freckle-like pigmentation of face before age 2 yrs)
• Greatly ↑ risk of cutaneous neoplasms (basal cell carcinoma, squamous cell carcinoma, melanoma)
• Xerosis (dry skin)
• Poikiloderma
• Loss of lashes
• Median age of onset of non-melanoma skin cancer: <10 yrs
• Neurologic manifestations in ~25%
• Photophobia
• Keratitis
• Atrophy of skin of eyelids
• Acral bullae at birth & after minor trauma
• Diffuse poikiloderma w/striate & reticulate atrophy
• Widespread eczematoid dermatitis
• Keratotic papules of hands, feet, elbows, knees
• Marked photosensitivity
• Esophageal & urethral strictures
• Webbing of fingers & toes
• No ↑ risk for cataract or malignancy
• Lacy reticular pigmentation of neck & upper chest
• Nail dystrophy
• ↑ risk of leukemia & skin cancers
• Bone marrow failure
• Oral leukoplakia w/variable onset
• Not assoc w/radial ray defects or cataracts
• Rash
• Less common finding: acute myeloid leukemia
• Onset of rash differs from that seen in RTS: more eczematous, starting peripherally & spreading centrally
• Rash affecting the trunk
• Not assoc w/radial ray abnormalities
• Clinically significant neutropenia w/recurrent sinopulmonary infection
• Less common finding: bone marrow failure
• Paronychias common
• Poikiloderma (typically beginning in 1st 6 mos & mainly facial)
• Chronic erythematous & scaly skin lesions on extremities (distinct from chronic poikiloderma of extremities seen in RTS)
• Sclerosis of digits
• Mild palmoplantar keratoderma
• Scalp hair, eyelashes, &/or eyebrows typically sparse
• Nail dysplasia in some
• Hypohidrosis w/heat intolerance
• Mild lymphedema of extremities
• Muscle contractures usually seen in childhood; can be present by age 2 yrs
• In most: progressive weakness of proximal & distal muscles of all 4 limbs
• In some adults: progressive interstitial pulmonary fibrosis that can be life threatening w/in 3-4 yrs after respiratory symptoms appear
## Management
To establish the extent of disease and needs in an individual diagnosed with Rothmund-Thomson syndrome (RTS), the evaluations in
Recommended Evaluations Following Initial Diagnosis in Individuals with Rothmund-Thomson Syndrome (RTS)
CBC = complete blood count; DXA = dual-energy x-ray absorptiometry
Treatment of Manifestations in Individuals with Rothmund-Thomson Syndrome (RTS)
Recommended Surveillance for Individuals with Rothmund-Thomson Syndrome (RTS)
Surveillance screening for osteosarcoma is not routinely recommended for individuals with RTS [
Exposure to heat or sunlight may exacerbate the rash in some individuals.
Avoidance of excessive sun exposure decreases the risk for skin cancer.
Given the theoretic potential for tumorigenesis, growth hormone (GH) therapy is not recommended for individuals with normal GH levels. For individuals with documented GH deficiency, standard treatment with growth hormone is appropriate.
See
Search
Given the theoretic potential for tumorigenesis, growth hormone (GH) therapy is not recommended for individuals with normal GH levels. For individuals with documented GH deficiency, routine treatment with growth hormone is appropriate.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Rothmund-Thomson syndrome (RTS), the evaluations in
Recommended Evaluations Following Initial Diagnosis in Individuals with Rothmund-Thomson Syndrome (RTS)
CBC = complete blood count; DXA = dual-energy x-ray absorptiometry
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Rothmund-Thomson Syndrome (RTS)
## Surveillance
Recommended Surveillance for Individuals with Rothmund-Thomson Syndrome (RTS)
Surveillance screening for osteosarcoma is not routinely recommended for individuals with RTS [
## Agents/Circumstances to Avoid
Exposure to heat or sunlight may exacerbate the rash in some individuals.
Avoidance of excessive sun exposure decreases the risk for skin cancer.
Given the theoretic potential for tumorigenesis, growth hormone (GH) therapy is not recommended for individuals with normal GH levels. For individuals with documented GH deficiency, standard treatment with growth hormone is appropriate.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Other
Given the theoretic potential for tumorigenesis, growth hormone (GH) therapy is not recommended for individuals with normal GH levels. For individuals with documented GH deficiency, routine treatment with growth hormone is appropriate.
## Genetic Counseling
Rothmund-Thomson syndrome (RTS) is inherited in an autosomal recessive manner.
The parents of a proband with confirmed biallelic pathogenic variants in
Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an
Heterozygotes (carriers) are apparently asymptomatic, although this issue has not been carefully studied.
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 apparently asymptomatic, although this issue has not been carefully studied.
The offspring of an individual with RTS are obligate heterozygotes (carriers) for a pathogenic variant in
The carrier frequency for RTS is unknown; however, given the rarity of the disorder, the likelihood that an affected individual will have children with a carrier is very low. Exceptions include areas in which a founder variant in
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 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 a proband with confirmed biallelic pathogenic variants in
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an
• Heterozygotes (carriers) are apparently asymptomatic, although this issue has not been carefully studied.
• 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 apparently asymptomatic, although this issue has not been carefully studied.
• The offspring of an individual with RTS are obligate heterozygotes (carriers) for a pathogenic variant in
• The carrier frequency for RTS is unknown; however, given the rarity of the disorder, the likelihood that an affected individual will have children with a carrier is very low. Exceptions include areas in which a founder variant in
• 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
Rothmund-Thomson syndrome (RTS) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of a proband with confirmed biallelic pathogenic variants in
Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an
Heterozygotes (carriers) are apparently asymptomatic, although this issue has not been carefully studied.
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 apparently asymptomatic, although this issue has not been carefully studied.
The offspring of an individual with RTS are obligate heterozygotes (carriers) for a pathogenic variant in
The carrier frequency for RTS is unknown; however, given the rarity of the disorder, the likelihood that an affected individual will have children with a carrier is very low. Exceptions include areas in which a founder variant in
• The parents of a proband with confirmed biallelic pathogenic variants in
• Molecular genetic testing is recommended for the parents of a proband to confirm that each parent is heterozygous for an
• Heterozygotes (carriers) are apparently asymptomatic, although this issue has not been carefully studied.
• 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 apparently asymptomatic, although this issue has not been carefully studied.
• The offspring of an individual with RTS are obligate heterozygotes (carriers) for a pathogenic variant in
• The carrier frequency for RTS is unknown; however, given the rarity of the disorder, the likelihood that an affected individual will have children with a carrier is very low. Exceptions include areas in which a founder variant in
## 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 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
RTS Foundation
4307 Woodward Court
Chantilly VA 20151
•
•
•
• RTS Foundation
• 4307 Woodward Court
• Chantilly VA 20151
•
## Molecular Genetics
Rothmund-Thomson Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Rothmund-Thomson Syndrome (
Rothmund-Thomson syndrome (RTS) is caused by pathogenic variants in
Pathogenic variants in
Rothmund-Thomson Syndrome: Gene-Specific Laboratory Considerations
Genes are listed in alphabetic order.
Rothmund-Thomson Syndrome: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes are listed in alphabetic order.
## Molecular Pathogenesis
Rothmund-Thomson syndrome (RTS) is caused by pathogenic variants in
Pathogenic variants in
Rothmund-Thomson Syndrome: Gene-Specific Laboratory Considerations
Genes are listed in alphabetic order.
Rothmund-Thomson Syndrome: Notable Pathogenic Variants by Gene
Variants listed in the table have been provided by the authors.
Genes are listed in alphabetic order.
## References
## Literature Cited
## Chapter Notes
Dr Wang is a pediatric oncologist at Texas Children's Cancer Center with particular interest in treating children with solid tumors, including osteosarcoma.
Dr Wang's
Dr Plon is a board-certified geneticist with expertise in cancer genetics and the control of genomic stability. She directs the Baylor Cancer Genetics Clinic at Texas Children's Hospital/Baylor College of Medicine and is actively involved in genetic evaluation and counseling for families at increased risk for cancer.
Dr Plon's
4 June 2020 (ha) Revision: added
3 January 2019 (ha) Comprehensive update posted live
11 August 2016 (bp) Revision: POIKTMP added to
3 December 2015 (me) Comprehensive update posted live
6 June 2013 (me) Comprehensive update posted live
7 April 2009 (me) Comprehensive update posted live
2 October 2006 (cd) Revision: deletion/duplication analysis clinically available
26 September 2006 (me) Comprehensive update posted live
5 January 2005 (sp) Revision:
9 June 2004 (me) Comprehensive update posted live
19 April 2004 (cd) Revision: clinical testing availability
31 May 2002 (me) Comprehensive update posted live
6 October 1999 (me) Review posted live
1 July 1999 (sp) Original submission
• 4 June 2020 (ha) Revision: added
• 3 January 2019 (ha) Comprehensive update posted live
• 11 August 2016 (bp) Revision: POIKTMP added to
• 3 December 2015 (me) Comprehensive update posted live
• 6 June 2013 (me) Comprehensive update posted live
• 7 April 2009 (me) Comprehensive update posted live
• 2 October 2006 (cd) Revision: deletion/duplication analysis clinically available
• 26 September 2006 (me) Comprehensive update posted live
• 5 January 2005 (sp) Revision:
• 9 June 2004 (me) Comprehensive update posted live
• 19 April 2004 (cd) Revision: clinical testing availability
• 31 May 2002 (me) Comprehensive update posted live
• 6 October 1999 (me) Review posted live
• 1 July 1999 (sp) Original submission
## Author Notes
Dr Wang is a pediatric oncologist at Texas Children's Cancer Center with particular interest in treating children with solid tumors, including osteosarcoma.
Dr Wang's
Dr Plon is a board-certified geneticist with expertise in cancer genetics and the control of genomic stability. She directs the Baylor Cancer Genetics Clinic at Texas Children's Hospital/Baylor College of Medicine and is actively involved in genetic evaluation and counseling for families at increased risk for cancer.
Dr Plon's
## Revision History
4 June 2020 (ha) Revision: added
3 January 2019 (ha) Comprehensive update posted live
11 August 2016 (bp) Revision: POIKTMP added to
3 December 2015 (me) Comprehensive update posted live
6 June 2013 (me) Comprehensive update posted live
7 April 2009 (me) Comprehensive update posted live
2 October 2006 (cd) Revision: deletion/duplication analysis clinically available
26 September 2006 (me) Comprehensive update posted live
5 January 2005 (sp) Revision:
9 June 2004 (me) Comprehensive update posted live
19 April 2004 (cd) Revision: clinical testing availability
31 May 2002 (me) Comprehensive update posted live
6 October 1999 (me) Review posted live
1 July 1999 (sp) Original submission
• 4 June 2020 (ha) Revision: added
• 3 January 2019 (ha) Comprehensive update posted live
• 11 August 2016 (bp) Revision: POIKTMP added to
• 3 December 2015 (me) Comprehensive update posted live
• 6 June 2013 (me) Comprehensive update posted live
• 7 April 2009 (me) Comprehensive update posted live
• 2 October 2006 (cd) Revision: deletion/duplication analysis clinically available
• 26 September 2006 (me) Comprehensive update posted live
• 5 January 2005 (sp) Revision:
• 9 June 2004 (me) Comprehensive update posted live
• 19 April 2004 (cd) Revision: clinical testing availability
• 31 May 2002 (me) Comprehensive update posted live
• 6 October 1999 (me) Review posted live
• 1 July 1999 (sp) Original submission
|
[
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"LL Wang, ML Levy, RA Lewis, MM Chintagumpala, D Lev, M Rogers, SE Plon. Clinical manifestations in a cohort of 41 Rothmund-Thomson syndrome patients.. Am J Med Genet 2001;102:11-7",
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] |
6/10/1999
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3/1/2019
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4/6/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
runx1
|
runx1
|
[
"Familial Platelet Disorder / Acute Myeloid Leukemia (FPD/AML)",
"RUNX1 Familial Platelet Disorder (FPD)",
"Familial Platelet Disorder / Acute Myeloid Leukemia (FPD/AML)",
"RUNX1 Familial Platelet Disorder (FPD)",
"Runt-related transcription factor 1",
"RUNX1",
"RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies"
] |
Natalie Deuitch, Elizabeth Broadbridge, Lea Cunningham, Paul Liu
|
Summary The diagnosis of
|
## Diagnosis
Abnormal bruising or bleeding (90%)
Bruising without known trauma
Excessive bleeding following surgery or trauma
Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions
Obstetric and gynecologic manifestations may include menorrhagia, miscarriage, and bleeding before or after childbirth.
20%-25% of individuals require platelet transfusions or medications to assist primary hemostasis such as antifibrinolytics (e.g., tranexamic acid, aminocaproic acid).
Hematologic malignancy (up to 50%)
Eczema (up to 50% of families)
History of hematologic malignancy (50%) and/or abnormal bleeding or bruising consistent with autosomal dominant inheritance (e.g., affected males and females in multiple consecutive generations)
Note: Absence of a known family history does not preclude the diagnosis.
Mild-to-moderate thrombocytopenia (50-150 x 10
Platelets are typically normal in size; however, individuals with both smaller and larger than normal mean platelet volume have been reported.
Qualitative platelet defect
Prolonged bleeding time (not clinically performed in the current era)
Abnormal platelet aggregation studies are seen in most individuals with absent or decreased response to arachidonic acid and collagen. Platelets from these individuals also exhibit absent or decreased second wave response to adenosine diphosphate and epinephrine, indicating decreased platelet degranulation.
Platelet storage pool disorder seen on electron microscopy in about half of individuals (decrease or absence of alpha-granules or dense granules)
Baseline morphologic abnormalities may include:
Hypo- or normocellular marrow for age (Marrow may become hypercellular or more hypocellular in individuals with hematologic malignancy or bone marrow failure.)
Atypical (but not frankly dysplastic) megakaryocytes (small in size with scant cytoplasm, and hypo-lobated nuclei with asynchronous nuclear cytoplasmic maturation)
Eosinophilia
Pathologists who are not familiar with
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
Given that the
For an introduction to comprehensive genomic testing click
Note: (1) Testing for a germline pathogenic variant should not be performed on blood or bone marrow during active hematologic malignancy.
Molecular Genetic Testing Used in
See
See
Individuals with contiguous gene deletions of various sizes that include
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
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.
• Abnormal bruising or bleeding (90%)
• Bruising without known trauma
• Excessive bleeding following surgery or trauma
• Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions
• Obstetric and gynecologic manifestations may include menorrhagia, miscarriage, and bleeding before or after childbirth.
• 20%-25% of individuals require platelet transfusions or medications to assist primary hemostasis such as antifibrinolytics (e.g., tranexamic acid, aminocaproic acid).
• Bruising without known trauma
• Excessive bleeding following surgery or trauma
• Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions
• Obstetric and gynecologic manifestations may include menorrhagia, miscarriage, and bleeding before or after childbirth.
• 20%-25% of individuals require platelet transfusions or medications to assist primary hemostasis such as antifibrinolytics (e.g., tranexamic acid, aminocaproic acid).
• Hematologic malignancy (up to 50%)
• Eczema (up to 50% of families)
• Bruising without known trauma
• Excessive bleeding following surgery or trauma
• Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions
• Obstetric and gynecologic manifestations may include menorrhagia, miscarriage, and bleeding before or after childbirth.
• 20%-25% of individuals require platelet transfusions or medications to assist primary hemostasis such as antifibrinolytics (e.g., tranexamic acid, aminocaproic acid).
• History of hematologic malignancy (50%) and/or abnormal bleeding or bruising consistent with autosomal dominant inheritance (e.g., affected males and females in multiple consecutive generations)
• Note: Absence of a known family history does not preclude the diagnosis.
• Mild-to-moderate thrombocytopenia (50-150 x 10
• Platelets are typically normal in size; however, individuals with both smaller and larger than normal mean platelet volume have been reported.
• Qualitative platelet defect
• Prolonged bleeding time (not clinically performed in the current era)
• Abnormal platelet aggregation studies are seen in most individuals with absent or decreased response to arachidonic acid and collagen. Platelets from these individuals also exhibit absent or decreased second wave response to adenosine diphosphate and epinephrine, indicating decreased platelet degranulation.
• Platelet storage pool disorder seen on electron microscopy in about half of individuals (decrease or absence of alpha-granules or dense granules)
• Prolonged bleeding time (not clinically performed in the current era)
• Abnormal platelet aggregation studies are seen in most individuals with absent or decreased response to arachidonic acid and collagen. Platelets from these individuals also exhibit absent or decreased second wave response to adenosine diphosphate and epinephrine, indicating decreased platelet degranulation.
• Platelet storage pool disorder seen on electron microscopy in about half of individuals (decrease or absence of alpha-granules or dense granules)
• Prolonged bleeding time (not clinically performed in the current era)
• Abnormal platelet aggregation studies are seen in most individuals with absent or decreased response to arachidonic acid and collagen. Platelets from these individuals also exhibit absent or decreased second wave response to adenosine diphosphate and epinephrine, indicating decreased platelet degranulation.
• Platelet storage pool disorder seen on electron microscopy in about half of individuals (decrease or absence of alpha-granules or dense granules)
• Baseline morphologic abnormalities may include:
• Hypo- or normocellular marrow for age (Marrow may become hypercellular or more hypocellular in individuals with hematologic malignancy or bone marrow failure.)
• Atypical (but not frankly dysplastic) megakaryocytes (small in size with scant cytoplasm, and hypo-lobated nuclei with asynchronous nuclear cytoplasmic maturation)
• Eosinophilia
• Hypo- or normocellular marrow for age (Marrow may become hypercellular or more hypocellular in individuals with hematologic malignancy or bone marrow failure.)
• Atypical (but not frankly dysplastic) megakaryocytes (small in size with scant cytoplasm, and hypo-lobated nuclei with asynchronous nuclear cytoplasmic maturation)
• Eosinophilia
• Pathologists who are not familiar with
• Hypo- or normocellular marrow for age (Marrow may become hypercellular or more hypocellular in individuals with hematologic malignancy or bone marrow failure.)
• Atypical (but not frankly dysplastic) megakaryocytes (small in size with scant cytoplasm, and hypo-lobated nuclei with asynchronous nuclear cytoplasmic maturation)
• Eosinophilia
## Suggestive Findings
Abnormal bruising or bleeding (90%)
Bruising without known trauma
Excessive bleeding following surgery or trauma
Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions
Obstetric and gynecologic manifestations may include menorrhagia, miscarriage, and bleeding before or after childbirth.
20%-25% of individuals require platelet transfusions or medications to assist primary hemostasis such as antifibrinolytics (e.g., tranexamic acid, aminocaproic acid).
Hematologic malignancy (up to 50%)
Eczema (up to 50% of families)
History of hematologic malignancy (50%) and/or abnormal bleeding or bruising consistent with autosomal dominant inheritance (e.g., affected males and females in multiple consecutive generations)
Note: Absence of a known family history does not preclude the diagnosis.
Mild-to-moderate thrombocytopenia (50-150 x 10
Platelets are typically normal in size; however, individuals with both smaller and larger than normal mean platelet volume have been reported.
Qualitative platelet defect
Prolonged bleeding time (not clinically performed in the current era)
Abnormal platelet aggregation studies are seen in most individuals with absent or decreased response to arachidonic acid and collagen. Platelets from these individuals also exhibit absent or decreased second wave response to adenosine diphosphate and epinephrine, indicating decreased platelet degranulation.
Platelet storage pool disorder seen on electron microscopy in about half of individuals (decrease or absence of alpha-granules or dense granules)
Baseline morphologic abnormalities may include:
Hypo- or normocellular marrow for age (Marrow may become hypercellular or more hypocellular in individuals with hematologic malignancy or bone marrow failure.)
Atypical (but not frankly dysplastic) megakaryocytes (small in size with scant cytoplasm, and hypo-lobated nuclei with asynchronous nuclear cytoplasmic maturation)
Eosinophilia
Pathologists who are not familiar with
• Abnormal bruising or bleeding (90%)
• Bruising without known trauma
• Excessive bleeding following surgery or trauma
• Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions
• Obstetric and gynecologic manifestations may include menorrhagia, miscarriage, and bleeding before or after childbirth.
• 20%-25% of individuals require platelet transfusions or medications to assist primary hemostasis such as antifibrinolytics (e.g., tranexamic acid, aminocaproic acid).
• Bruising without known trauma
• Excessive bleeding following surgery or trauma
• Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions
• Obstetric and gynecologic manifestations may include menorrhagia, miscarriage, and bleeding before or after childbirth.
• 20%-25% of individuals require platelet transfusions or medications to assist primary hemostasis such as antifibrinolytics (e.g., tranexamic acid, aminocaproic acid).
• Hematologic malignancy (up to 50%)
• Eczema (up to 50% of families)
• Bruising without known trauma
• Excessive bleeding following surgery or trauma
• Bleeding from the gums after brushing or flossing teeth or prolonged bleeding following dental cleaning or dental extractions
• Obstetric and gynecologic manifestations may include menorrhagia, miscarriage, and bleeding before or after childbirth.
• 20%-25% of individuals require platelet transfusions or medications to assist primary hemostasis such as antifibrinolytics (e.g., tranexamic acid, aminocaproic acid).
• History of hematologic malignancy (50%) and/or abnormal bleeding or bruising consistent with autosomal dominant inheritance (e.g., affected males and females in multiple consecutive generations)
• Note: Absence of a known family history does not preclude the diagnosis.
• Mild-to-moderate thrombocytopenia (50-150 x 10
• Platelets are typically normal in size; however, individuals with both smaller and larger than normal mean platelet volume have been reported.
• Qualitative platelet defect
• Prolonged bleeding time (not clinically performed in the current era)
• Abnormal platelet aggregation studies are seen in most individuals with absent or decreased response to arachidonic acid and collagen. Platelets from these individuals also exhibit absent or decreased second wave response to adenosine diphosphate and epinephrine, indicating decreased platelet degranulation.
• Platelet storage pool disorder seen on electron microscopy in about half of individuals (decrease or absence of alpha-granules or dense granules)
• Prolonged bleeding time (not clinically performed in the current era)
• Abnormal platelet aggregation studies are seen in most individuals with absent or decreased response to arachidonic acid and collagen. Platelets from these individuals also exhibit absent or decreased second wave response to adenosine diphosphate and epinephrine, indicating decreased platelet degranulation.
• Platelet storage pool disorder seen on electron microscopy in about half of individuals (decrease or absence of alpha-granules or dense granules)
• Prolonged bleeding time (not clinically performed in the current era)
• Abnormal platelet aggregation studies are seen in most individuals with absent or decreased response to arachidonic acid and collagen. Platelets from these individuals also exhibit absent or decreased second wave response to adenosine diphosphate and epinephrine, indicating decreased platelet degranulation.
• Platelet storage pool disorder seen on electron microscopy in about half of individuals (decrease or absence of alpha-granules or dense granules)
• Baseline morphologic abnormalities may include:
• Hypo- or normocellular marrow for age (Marrow may become hypercellular or more hypocellular in individuals with hematologic malignancy or bone marrow failure.)
• Atypical (but not frankly dysplastic) megakaryocytes (small in size with scant cytoplasm, and hypo-lobated nuclei with asynchronous nuclear cytoplasmic maturation)
• Eosinophilia
• Hypo- or normocellular marrow for age (Marrow may become hypercellular or more hypocellular in individuals with hematologic malignancy or bone marrow failure.)
• Atypical (but not frankly dysplastic) megakaryocytes (small in size with scant cytoplasm, and hypo-lobated nuclei with asynchronous nuclear cytoplasmic maturation)
• Eosinophilia
• Pathologists who are not familiar with
• Hypo- or normocellular marrow for age (Marrow may become hypercellular or more hypocellular in individuals with hematologic malignancy or bone marrow failure.)
• Atypical (but not frankly dysplastic) megakaryocytes (small in size with scant cytoplasm, and hypo-lobated nuclei with asynchronous nuclear cytoplasmic maturation)
• Eosinophilia
## 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
Given that the
For an introduction to comprehensive genomic testing click
Note: (1) Testing for a germline pathogenic variant should not be performed on blood or bone marrow during active hematologic malignancy.
Molecular Genetic Testing Used in
See
See
Individuals with contiguous gene deletions of various sizes that include
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
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
Given that the
For an introduction to comprehensive genomic testing click
Note: (1) Testing for a germline pathogenic variant should not be performed on blood or bone marrow during active hematologic malignancy.
Molecular Genetic Testing Used in
See
See
Individuals with contiguous gene deletions of various sizes that include
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
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, more than 130 individuals have been identified with a germline pathogenic variant in
No consistent clinically relevant genotype-phenotype correlations have been identified.
The penetrance of germline
More than 130 individuals with
## Clinical Description
To date, more than 130 individuals have been identified with a germline pathogenic variant in
## Genotype-Phenotype Correlations
No consistent clinically relevant genotype-phenotype correlations have been identified.
## Penetrance
The penetrance of germline
## Nomenclature
## Prevalence
More than 130 individuals with
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
A nonrecurrent 21q22 contiguous gene deletion syndrome that includes
Sporadic hematopoietic neoplasms (e.g., acute myelogenous leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia), clonal cytopenias of uncertain significance [
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
AD = autosomal dominant; AML = acute myeloid leukemia; DiffDx = differential diagnosis; MDS = myelodysplastic syndrome; MOI = mode of inheritance;
Immune thrombocytopenia
Secondary thrombocytopenia
Medication-related (e.g., NSAIDs, antiplatelet agents, statins, furosemide, heparin, ranitidine, linezolid) increased risk of bruising and prolonged bleeding
Leukemia
• Immune thrombocytopenia
• Secondary thrombocytopenia
• Medication-related (e.g., NSAIDs, antiplatelet agents, statins, furosemide, heparin, ranitidine, linezolid) increased risk of bruising and prolonged bleeding
• Leukemia
## 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
CBC = complete blood count; MOI = mode of inheritance;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse, or hematologist with expertise in these disorders
Treatment of Manifestations in Individuals with
FPDMM is not thought to be curable w/chemotherapy alone; HSCT is almost always required.
Test for familial
Providing a medical letter for school explaining easy bruising at baseline, as referrals for social services for concern of child abuse can occur;
Use of a medical alert bracelet for thrombocytopenia, platelet dysfunction, or hematologic malignancy as indicated.
FPDMM = familial platelet disorder with associated myeloid malignancies; HSCT = hematopoietic stem cell transplant
Recurrence of leukemia was reported after a donor sib was found to have the familial
Guidelines on the type of testing or frequency of surveillance have not been published.
Recommended Surveillance for Individuals with
If constitutional symptoms &/or abnormalities on CBC are identified
Consider annually (although there is no consensus on this recommendation).
CBC = complete blood count
Avoid the following:
Medications that affect platelet function, such as NSAIDs and antiplatelet agents
Activities with a high risk of trauma, such as high-risk contact sports
Factors such as smoking, chemical exposure, unnecessary radiation, and obesity may increase the risk of developing hematologic malignancy.
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance for malignancy and more targeted medical management.
See
Platelet counts and bleeding complications should be monitored during pregnancy. Qualitative and quantitative platelet disorders can lead to severe bleeding before, during, or after delivery. While thrombocytopenia itself (particularly if mild) in the absence of aggregation and storage pool disorders is unlikely to affect pregnancy, low platelet counts (<50 x 10
See
The NIH
Search
• FPDMM is not thought to be curable w/chemotherapy alone; HSCT is almost always required.
• Test for familial
• Providing a medical letter for school explaining easy bruising at baseline, as referrals for social services for concern of child abuse can occur;
• Use of a medical alert bracelet for thrombocytopenia, platelet dysfunction, or hematologic malignancy as indicated.
• If constitutional symptoms &/or abnormalities on CBC are identified
• Consider annually (although there is no consensus on this recommendation).
• Medications that affect platelet function, such as NSAIDs and antiplatelet agents
• Activities with a high risk of trauma, such as high-risk 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
CBC = complete blood count; MOI = mode of inheritance;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse, or hematologist with expertise in these disorders
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
FPDMM is not thought to be curable w/chemotherapy alone; HSCT is almost always required.
Test for familial
Providing a medical letter for school explaining easy bruising at baseline, as referrals for social services for concern of child abuse can occur;
Use of a medical alert bracelet for thrombocytopenia, platelet dysfunction, or hematologic malignancy as indicated.
FPDMM = familial platelet disorder with associated myeloid malignancies; HSCT = hematopoietic stem cell transplant
Recurrence of leukemia was reported after a donor sib was found to have the familial
• FPDMM is not thought to be curable w/chemotherapy alone; HSCT is almost always required.
• Test for familial
• Providing a medical letter for school explaining easy bruising at baseline, as referrals for social services for concern of child abuse can occur;
• Use of a medical alert bracelet for thrombocytopenia, platelet dysfunction, or hematologic malignancy as indicated.
## Surveillance
Guidelines on the type of testing or frequency of surveillance have not been published.
Recommended Surveillance for Individuals with
If constitutional symptoms &/or abnormalities on CBC are identified
Consider annually (although there is no consensus on this recommendation).
CBC = complete blood count
• If constitutional symptoms &/or abnormalities on CBC are identified
• Consider annually (although there is no consensus on this recommendation).
## Agents/Circumstances to Avoid
Avoid the following:
Medications that affect platelet function, such as NSAIDs and antiplatelet agents
Activities with a high risk of trauma, such as high-risk contact sports
Factors such as smoking, chemical exposure, unnecessary radiation, and obesity may increase the risk of developing hematologic malignancy.
• Medications that affect platelet function, such as NSAIDs and antiplatelet agents
• Activities with a high risk of trauma, such as high-risk contact sports
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from surveillance for malignancy and more targeted medical management.
See
## Pregnancy Management
Platelet counts and bleeding complications should be monitored during pregnancy. Qualitative and quantitative platelet disorders can lead to severe bleeding before, during, or after delivery. While thrombocytopenia itself (particularly if mild) in the absence of aggregation and storage pool disorders is unlikely to affect pregnancy, low platelet counts (<50 x 10
See
## Therapies Under Investigation
The NIH
Search
## Genetic Counseling
Most individuals diagnosed with
Some individuals diagnosed with
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 assess their genetic status and to allow reliable recurrence risk counseling. Note: Because somatically acquired loss of heterozygosity may result in a false negative molecular result when testing leukocyte DNA, use of DNA derived from non-hematopoietic tissues (e.g., skin fibroblasts, hair roots) should be considered if feasible (see
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband may have a
The proband may have inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The frequency of
The proband may have inherited a
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.
Sibs who inherit a
Significant clinical variability is observed within families [
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.
• Most individuals diagnosed with
• Some individuals diagnosed with
• 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 assess their genetic status and to allow reliable recurrence risk counseling. Note: Because somatically acquired loss of heterozygosity may result in a false negative molecular result when testing leukocyte DNA, use of DNA derived from non-hematopoietic tissues (e.g., skin fibroblasts, hair roots) should be considered if feasible (see
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband may have a
• The proband may have inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The frequency of
• The proband may have inherited a
• The proband may have a
• The proband may have inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The frequency of
• The proband may have inherited a
• The family history of some individuals diagnosed with
• The proband may have a
• The proband may have inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The frequency of
• The proband may have inherited 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 sibs of inheriting the pathogenic variant is 50%.
• Sibs who inherit a
• Significant clinical variability is observed within families [
• Sibs who inherit a
• Significant clinical variability is observed within families [
• If the
• If the parents have not been tested for the
• Sibs who inherit a
• Significant clinical variability is observed within families [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Most individuals diagnosed with
Some individuals diagnosed with
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 assess their genetic status and to allow reliable recurrence risk counseling. Note: Because somatically acquired loss of heterozygosity may result in a false negative molecular result when testing leukocyte DNA, use of DNA derived from non-hematopoietic tissues (e.g., skin fibroblasts, hair roots) should be considered if feasible (see
If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
The proband may have a
The proband may have inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The frequency of
The proband may have inherited a
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the pathogenic variant identified in the proband, the risk to sibs of inheriting the pathogenic variant is 50%.
Sibs who inherit a
Significant clinical variability is observed within families [
If the
If the parents have not been tested for the
• Most individuals diagnosed with
• Some individuals diagnosed with
• 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 assess their genetic status and to allow reliable recurrence risk counseling. Note: Because somatically acquired loss of heterozygosity may result in a false negative molecular result when testing leukocyte DNA, use of DNA derived from non-hematopoietic tissues (e.g., skin fibroblasts, hair roots) should be considered if feasible (see
• If the pathogenic variant identified in the proband is not identified in either parent, the following possibilities should be considered:
• The proband may have a
• The proband may have inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The frequency of
• The proband may have inherited a
• The proband may have a
• The proband may have inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The frequency of
• The proband may have inherited a
• The family history of some individuals diagnosed with
• The proband may have a
• The proband may have inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism. The frequency of
• The proband may have inherited 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 sibs of inheriting the pathogenic variant is 50%.
• Sibs who inherit a
• Significant clinical variability is observed within families [
• Sibs who inherit a
• Significant clinical variability is observed within families [
• If the
• If the parents have not been tested for the
• Sibs who inherit a
• Significant clinical variability is observed within families [
## 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
111 Presidential Boulevard
Suite 203
Bala Cynwyd PA 19004
4330 East West Highway
Suite 230
Bethesda MD 20814
•
•
•
• 111 Presidential Boulevard
• Suite 203
• Bala Cynwyd PA 19004
•
•
• 4330 East West Highway
• Suite 230
• Bethesda MD 20814
•
•
•
•
•
## Molecular Genetics
RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for RUNX1 Familial Platelet Disorder with Associated Myeloid Malignancies (
The majority of
Malignant transformation in individuals with
Sporadic hematopoietic neoplasms (e.g., acute myelogenous leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia) and sporadic solid tumors (most notably, breast cancer) may occur as single tumors in the absence of any other findings of
## Molecular Pathogenesis
The majority of
Malignant transformation in individuals with
## Cancer and Benign Tumors
Sporadic hematopoietic neoplasms (e.g., acute myelogenous leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia) and sporadic solid tumors (most notably, breast cancer) may occur as single tumors in the absence of any other findings of
## Chapter Notes
Natalie Deuitch and Paul Liu are actively involved in clinical research regarding individuals with
Natalie Deuitch is a genetic counselor at the National Human Genome Research Institute (NHGRI). She works with patients enrolled in the germline
Liesl Broadridge is a genetic counseling student at the Johns Hopkins University/NHGRI combined program. She previously studied
Dr Lea Cunningham is a hematologist/oncologist and Director of the NIH Pediatric Bone Marrow Transplantation Fellowship Program.
Dr Paul Liu is Principle Investigator of the
We would like to thank the
11 January 2023 (nd) Revision: added NIH
6 May 2021 (ma) Revision: added Braddock-Carey syndrome to
4 March 2021 (sw) Review posted live
5 October 2020 (nd) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 11 January 2023 (nd) Revision: added NIH
• 6 May 2021 (ma) Revision: added Braddock-Carey syndrome to
• 4 March 2021 (sw) Review posted live
• 5 October 2020 (nd) Original submission
## Author Notes
Natalie Deuitch and Paul Liu are actively involved in clinical research regarding individuals with
Natalie Deuitch is a genetic counselor at the National Human Genome Research Institute (NHGRI). She works with patients enrolled in the germline
Liesl Broadridge is a genetic counseling student at the Johns Hopkins University/NHGRI combined program. She previously studied
Dr Lea Cunningham is a hematologist/oncologist and Director of the NIH Pediatric Bone Marrow Transplantation Fellowship Program.
Dr Paul Liu is Principle Investigator of the
## Acknowledgments
We would like to thank the
## Revision History
11 January 2023 (nd) Revision: added NIH
6 May 2021 (ma) Revision: added Braddock-Carey syndrome to
4 March 2021 (sw) Review posted live
5 October 2020 (nd) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 11 January 2023 (nd) Revision: added NIH
• 6 May 2021 (ma) Revision: added Braddock-Carey syndrome to
• 4 March 2021 (sw) Review posted live
• 5 October 2020 (nd) Original submission
## References
## Literature Cited
|
[] |
4/3/2021
|
11/1/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
rvcl
|
rvcl
|
[
"Cerebroretinal Vasculopathy (CRV)",
"Hereditary Endotheliopathy, Retinopathy, Nephropathy, and Stroke (HERNS)",
"Hereditary Systemic Angiopathy (HSA)",
"Hereditary Vascular Retinopathy (HVR)",
"Retinal Vasculopathy with Cerebral Leukodystrophy (RVCL)",
"RVCL-S",
"RVCL-S",
"Retinal Vasculopathy with Cerebral Leukodystrophy (RVCL)",
"Cerebroretinal Vasculopathy (CRV)",
"Hereditary Vascular Retinopathy (HVR)",
"Hereditary Systemic Angiopathy (HAS)",
"Hereditary Endotheliopathy, Retinopathy, Nephropathy, and Stroke (HERNS)",
"Three prime repair exonuclease 1",
"TREX1",
"Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations"
] |
Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
|
Irene de Boer, Nadine Pelzer, Gisela Terwindt
|
Summary The diagnosis of RVCL-S is established in a proband with suggestive findings and a heterozygous pathogenic variant in RVCL-S is inherited in an autosomal dominant manner. Most individuals diagnosed with RVCL-S have an affected parent. However, disease onset and severity vary considerably even within the same family. The offspring of an individual with RVCL-S are at a 50% risk of inheriting the
|
## Diagnosis
There are no consensus clinical diagnostic criteria for retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S).
RVCL-S
Vascular retinopathy typically manifesting as decreased visual acuity and/or visual field defects
Focal and/or global brain dysfunction and brain MRI abnormalities
Focal neurologic signs can include but are not limited to hemiparesis, facial weakness, aphasia, and hemianopsia.
Global brain dysfunction may manifest as progressive cognitive impairment.
Brain MRI abnormalities are restricted to the white matter (see Clinical Characteristics,
Family history of middle-age onset of disease manifestations consistent with an autosomal dominant inheritance pattern
Note: Absence of a known family history of similarly affected individuals does not preclude the diagnosis.
Calcifications on brain CT scan, typically not present in healthy controls
Nonspecific MRI white matter lesions that occur more frequently than expected given the age of the individual
Microvascular liver disease, manifested by modest elevations of alkaline phosphatase and gamma-glutamyltransferase
Microvascular kidney disease, typically manifested by a mild-to-moderate increase in serum creatinine or by proteinuria
Anemia consistent with blood loss and/or chronic disease (typically normocytic and normochromic)
Microscopic gastrointestinal bleeding
Hypertension
Migraine with or without aura
Raynaud phenomenon (typically mild)
Subclinical hypothyroidism
The diagnosis of RVCL-S
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Note: At the Leiden University Medical Center, a panel of genes is used to screen for pathogenic variants that cause cerebral angiopathies and adult-onset leukoencephalopathies. New pathogenic variants that cause these disorders continue to be discovered; click
Molecular Genetic Testing Used in Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
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
The identification of a heterozygous pathogenic variant in
To date, all pathogenic 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.
• Vascular retinopathy typically manifesting as decreased visual acuity and/or visual field defects
• Focal and/or global brain dysfunction and brain MRI abnormalities
• Focal neurologic signs can include but are not limited to hemiparesis, facial weakness, aphasia, and hemianopsia.
• Global brain dysfunction may manifest as progressive cognitive impairment.
• Brain MRI abnormalities are restricted to the white matter (see Clinical Characteristics,
• Focal neurologic signs can include but are not limited to hemiparesis, facial weakness, aphasia, and hemianopsia.
• Global brain dysfunction may manifest as progressive cognitive impairment.
• Brain MRI abnormalities are restricted to the white matter (see Clinical Characteristics,
• Family history of middle-age onset of disease manifestations consistent with an autosomal dominant inheritance pattern
• Note: Absence of a known family history of similarly affected individuals does not preclude the diagnosis.
• Focal neurologic signs can include but are not limited to hemiparesis, facial weakness, aphasia, and hemianopsia.
• Global brain dysfunction may manifest as progressive cognitive impairment.
• Brain MRI abnormalities are restricted to the white matter (see Clinical Characteristics,
• Calcifications on brain CT scan, typically not present in healthy controls
• Nonspecific MRI white matter lesions that occur more frequently than expected given the age of the individual
• Microvascular liver disease, manifested by modest elevations of alkaline phosphatase and gamma-glutamyltransferase
• Microvascular kidney disease, typically manifested by a mild-to-moderate increase in serum creatinine or by proteinuria
• Anemia consistent with blood loss and/or chronic disease (typically normocytic and normochromic)
• Microscopic gastrointestinal bleeding
• Hypertension
• Migraine with or without aura
• Raynaud phenomenon (typically mild)
• Subclinical hypothyroidism
• For an introduction to multigene panels click
• Note: At the Leiden University Medical Center, a panel of genes is used to screen for pathogenic variants that cause cerebral angiopathies and adult-onset leukoencephalopathies. New pathogenic variants that cause these disorders continue to be discovered; click
## Suggestive Findings
RVCL-S
Vascular retinopathy typically manifesting as decreased visual acuity and/or visual field defects
Focal and/or global brain dysfunction and brain MRI abnormalities
Focal neurologic signs can include but are not limited to hemiparesis, facial weakness, aphasia, and hemianopsia.
Global brain dysfunction may manifest as progressive cognitive impairment.
Brain MRI abnormalities are restricted to the white matter (see Clinical Characteristics,
Family history of middle-age onset of disease manifestations consistent with an autosomal dominant inheritance pattern
Note: Absence of a known family history of similarly affected individuals does not preclude the diagnosis.
Calcifications on brain CT scan, typically not present in healthy controls
Nonspecific MRI white matter lesions that occur more frequently than expected given the age of the individual
Microvascular liver disease, manifested by modest elevations of alkaline phosphatase and gamma-glutamyltransferase
Microvascular kidney disease, typically manifested by a mild-to-moderate increase in serum creatinine or by proteinuria
Anemia consistent with blood loss and/or chronic disease (typically normocytic and normochromic)
Microscopic gastrointestinal bleeding
Hypertension
Migraine with or without aura
Raynaud phenomenon (typically mild)
Subclinical hypothyroidism
• Vascular retinopathy typically manifesting as decreased visual acuity and/or visual field defects
• Focal and/or global brain dysfunction and brain MRI abnormalities
• Focal neurologic signs can include but are not limited to hemiparesis, facial weakness, aphasia, and hemianopsia.
• Global brain dysfunction may manifest as progressive cognitive impairment.
• Brain MRI abnormalities are restricted to the white matter (see Clinical Characteristics,
• Focal neurologic signs can include but are not limited to hemiparesis, facial weakness, aphasia, and hemianopsia.
• Global brain dysfunction may manifest as progressive cognitive impairment.
• Brain MRI abnormalities are restricted to the white matter (see Clinical Characteristics,
• Family history of middle-age onset of disease manifestations consistent with an autosomal dominant inheritance pattern
• Note: Absence of a known family history of similarly affected individuals does not preclude the diagnosis.
• Focal neurologic signs can include but are not limited to hemiparesis, facial weakness, aphasia, and hemianopsia.
• Global brain dysfunction may manifest as progressive cognitive impairment.
• Brain MRI abnormalities are restricted to the white matter (see Clinical Characteristics,
• Calcifications on brain CT scan, typically not present in healthy controls
• Nonspecific MRI white matter lesions that occur more frequently than expected given the age of the individual
• Microvascular liver disease, manifested by modest elevations of alkaline phosphatase and gamma-glutamyltransferase
• Microvascular kidney disease, typically manifested by a mild-to-moderate increase in serum creatinine or by proteinuria
• Anemia consistent with blood loss and/or chronic disease (typically normocytic and normochromic)
• Microscopic gastrointestinal bleeding
• Hypertension
• Migraine with or without aura
• Raynaud phenomenon (typically mild)
• Subclinical hypothyroidism
## Establishing the Diagnosis
The diagnosis of RVCL-S
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Note: At the Leiden University Medical Center, a panel of genes is used to screen for pathogenic variants that cause cerebral angiopathies and adult-onset leukoencephalopathies. New pathogenic variants that cause these disorders continue to be discovered; click
Molecular Genetic Testing Used in Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations
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
The identification of a heterozygous pathogenic variant in
To date, all pathogenic 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
• Note: At the Leiden University Medical Center, a panel of genes is used to screen for pathogenic variants that cause cerebral angiopathies and adult-onset leukoencephalopathies. New pathogenic variants that cause these disorders continue to be discovered; click
## Clinical Characteristics
Clinical information about RVCL-S is summarized from the following reports of individuals with molecularly confirmed RVCL-S:
RVCL-S is a small-vessel disease that systemically affects various highly vascularized organs. Affected individuals develop retinal vasculopathy and neurologic symptoms, in addition to other systemic manifestations including impaired liver and renal function.
Clinical presentation is variable; onset is often between ages 35 and 50 years, with a mean age at clinical diagnosis of 42.9 years (SD ±8.3, range 25-61 years). Life expectancy is decreased; the average age of death is 53.1 years (SD ±9.6, range 32-72). Cause of death is frequently pneumonia or sepsis in the setting of general debilitation. For clinical course see
Symptoms caused by retinal vasculopathy are the most common presenting finding in individuals with RVCL-S but can also develop later in the disease course.
Affected individuals often notice decreased visual acuity and/or visual field defects. A gradual worsening often occurs and affected individuals can become legally blind.
All individuals with a heterozygous pathogenic variant in
The retinopathy is characterized in the early stages by telangiectasias, microaneurysms, and cotton wool spots.
In later stages perifoveal capillary obliterations and neovascularizations appear.
Macular edema and neovascular glaucoma may develop as a complication of vascular retinopathy.
Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
Often lead to displacement of adjacent structures and sulci effacement;
Can increase in size, remain stable, or diminish;
Are associated with calcifications on CT scan.
Renal disease has been demonstrated in 22/44 affected individuals. It is typically characterized by a mild-to-moderate increase in serum creatinine and mild proteinuria but may be severe (stage IV kidney disease) and fatal in some families. While the progression of the renal disease of RVCL-S requires further study, in most cases the renal manifestations are progressive; however, there is tremendous variability in the rate of renal decline.
Liver disease was present in 28/40 affected individuals and usually manifests as mildly elevated levels of alkaline phosphatase and gamma-glutamyltransferase (GGT).
Subclinical hypothyroidism was found to be part of the disease course in a recent cross-sectional study. Of the 19 affected individuals older than age 40 years, seven had subclinical hypothyroidism.
Psychiatric manifestations were present in 26/62 affected individuals and may include depression, psychosis, anxiety, and other psychiatric problems.
Additional findings may include the following:
Hypertension (present in 30/52 individuals)
Mild-to-moderate anemia that is typically normocytic and normochromic
Microscopic gastrointestinal bleeding resulting in anemia (present in 25/34 affected individuals)
Raynaud phenomenon, which is typically mild (present in approximately 31/73 individuals with a heterozygous pathogenic variant in
Avascular necrosis of the femoral head (2 individuals)
(Hypertensive) cardiomyopathy (3 individuals)
Macular skin rash and punctate skin lesions (3 individuals)
Histologic abnormalities have been demonstrated in all organs involved in RVCL-S, including the following.
Scattered microinfarcts
Thickened hyalinized retinal arterial walls
Focal areas of disruption of the ganglion cell layer and inner nuclear layer
Multiple – often confluent – foci of ischemic necrosis of white matter
Vasculopathy: vessel wall thickening and luminal stenosis; telangiectasias
A modest chronic inflammatory cell infiltrate in some individuals
Focal calcifications and reactive astrocytosis
Myelin loss
Renal arteriolosclerosis
Focal or diffuse glomerulosclerosis
Nodular regenerative hyperplasia
Micro- and macrovesicular steatosis
Periportal inflammation
Bridging and portal fibrosis
To date, all pathogenic variants have been frameshift variants in the region of
To date no genotype-phenotype correlations have been observed.
Penetrance of RVCL-S is age dependent; however, it is thought that all individuals with a heterozygous pathogenic
Previous descriptions of families with cerebroretinal vasculopathy (CRV); hereditary vascular retinopathy (HRV); hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS); hereditary systemic angiopathy (HSA); and retinal vasculopathy with cerebral leukodystrophy (RVCL) represent early reports of RVCL-S.
Currently, fewer than 25 families with RVCL-S are known. However, RVCL-S is most likely underdiagnosed because physicians are generally unfamiliar with the disorder. For example, in the Netherlands alone three unrelated families have been identified because of increased awareness of this condition. The widespread availability of exome and genome sequencing techniques likely also contribute to increased recognition of RVCL-S.
• Symptoms caused by retinal vasculopathy are the most common presenting finding in individuals with RVCL-S but can also develop later in the disease course.
• Affected individuals often notice decreased visual acuity and/or visual field defects. A gradual worsening often occurs and affected individuals can become legally blind.
• All individuals with a heterozygous pathogenic variant in
• The retinopathy is characterized in the early stages by telangiectasias, microaneurysms, and cotton wool spots.
• In later stages perifoveal capillary obliterations and neovascularizations appear.
• Macular edema and neovascular glaucoma may develop as a complication of vascular retinopathy.
• Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
• Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
• Often lead to displacement of adjacent structures and sulci effacement;
• Can increase in size, remain stable, or diminish;
• Are associated with calcifications on CT scan.
• Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
• Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
• Often lead to displacement of adjacent structures and sulci effacement;
• Can increase in size, remain stable, or diminish;
• Are associated with calcifications on CT scan.
• Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
• Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
• Often lead to displacement of adjacent structures and sulci effacement;
• Can increase in size, remain stable, or diminish;
• Are associated with calcifications on CT scan.
• Hypertension (present in 30/52 individuals)
• Mild-to-moderate anemia that is typically normocytic and normochromic
• Microscopic gastrointestinal bleeding resulting in anemia (present in 25/34 affected individuals)
• Raynaud phenomenon, which is typically mild (present in approximately 31/73 individuals with a heterozygous pathogenic variant in
• Avascular necrosis of the femoral head (2 individuals)
• (Hypertensive) cardiomyopathy (3 individuals)
• Macular skin rash and punctate skin lesions (3 individuals)
• Scattered microinfarcts
• Thickened hyalinized retinal arterial walls
• Focal areas of disruption of the ganglion cell layer and inner nuclear layer
• Multiple – often confluent – foci of ischemic necrosis of white matter
• Vasculopathy: vessel wall thickening and luminal stenosis; telangiectasias
• A modest chronic inflammatory cell infiltrate in some individuals
• Focal calcifications and reactive astrocytosis
• Myelin loss
• Renal arteriolosclerosis
• Focal or diffuse glomerulosclerosis
• Nodular regenerative hyperplasia
• Micro- and macrovesicular steatosis
• Periportal inflammation
• Bridging and portal fibrosis
## Clinical Description
Clinical information about RVCL-S is summarized from the following reports of individuals with molecularly confirmed RVCL-S:
RVCL-S is a small-vessel disease that systemically affects various highly vascularized organs. Affected individuals develop retinal vasculopathy and neurologic symptoms, in addition to other systemic manifestations including impaired liver and renal function.
Clinical presentation is variable; onset is often between ages 35 and 50 years, with a mean age at clinical diagnosis of 42.9 years (SD ±8.3, range 25-61 years). Life expectancy is decreased; the average age of death is 53.1 years (SD ±9.6, range 32-72). Cause of death is frequently pneumonia or sepsis in the setting of general debilitation. For clinical course see
Symptoms caused by retinal vasculopathy are the most common presenting finding in individuals with RVCL-S but can also develop later in the disease course.
Affected individuals often notice decreased visual acuity and/or visual field defects. A gradual worsening often occurs and affected individuals can become legally blind.
All individuals with a heterozygous pathogenic variant in
The retinopathy is characterized in the early stages by telangiectasias, microaneurysms, and cotton wool spots.
In later stages perifoveal capillary obliterations and neovascularizations appear.
Macular edema and neovascular glaucoma may develop as a complication of vascular retinopathy.
Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
Often lead to displacement of adjacent structures and sulci effacement;
Can increase in size, remain stable, or diminish;
Are associated with calcifications on CT scan.
Renal disease has been demonstrated in 22/44 affected individuals. It is typically characterized by a mild-to-moderate increase in serum creatinine and mild proteinuria but may be severe (stage IV kidney disease) and fatal in some families. While the progression of the renal disease of RVCL-S requires further study, in most cases the renal manifestations are progressive; however, there is tremendous variability in the rate of renal decline.
Liver disease was present in 28/40 affected individuals and usually manifests as mildly elevated levels of alkaline phosphatase and gamma-glutamyltransferase (GGT).
Subclinical hypothyroidism was found to be part of the disease course in a recent cross-sectional study. Of the 19 affected individuals older than age 40 years, seven had subclinical hypothyroidism.
Psychiatric manifestations were present in 26/62 affected individuals and may include depression, psychosis, anxiety, and other psychiatric problems.
Additional findings may include the following:
Hypertension (present in 30/52 individuals)
Mild-to-moderate anemia that is typically normocytic and normochromic
Microscopic gastrointestinal bleeding resulting in anemia (present in 25/34 affected individuals)
Raynaud phenomenon, which is typically mild (present in approximately 31/73 individuals with a heterozygous pathogenic variant in
Avascular necrosis of the femoral head (2 individuals)
(Hypertensive) cardiomyopathy (3 individuals)
Macular skin rash and punctate skin lesions (3 individuals)
Histologic abnormalities have been demonstrated in all organs involved in RVCL-S, including the following.
Scattered microinfarcts
Thickened hyalinized retinal arterial walls
Focal areas of disruption of the ganglion cell layer and inner nuclear layer
Multiple – often confluent – foci of ischemic necrosis of white matter
Vasculopathy: vessel wall thickening and luminal stenosis; telangiectasias
A modest chronic inflammatory cell infiltrate in some individuals
Focal calcifications and reactive astrocytosis
Myelin loss
Renal arteriolosclerosis
Focal or diffuse glomerulosclerosis
Nodular regenerative hyperplasia
Micro- and macrovesicular steatosis
Periportal inflammation
Bridging and portal fibrosis
• Symptoms caused by retinal vasculopathy are the most common presenting finding in individuals with RVCL-S but can also develop later in the disease course.
• Affected individuals often notice decreased visual acuity and/or visual field defects. A gradual worsening often occurs and affected individuals can become legally blind.
• All individuals with a heterozygous pathogenic variant in
• The retinopathy is characterized in the early stages by telangiectasias, microaneurysms, and cotton wool spots.
• In later stages perifoveal capillary obliterations and neovascularizations appear.
• Macular edema and neovascular glaucoma may develop as a complication of vascular retinopathy.
• Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
• Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
• Often lead to displacement of adjacent structures and sulci effacement;
• Can increase in size, remain stable, or diminish;
• Are associated with calcifications on CT scan.
• Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
• Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
• Often lead to displacement of adjacent structures and sulci effacement;
• Can increase in size, remain stable, or diminish;
• Are associated with calcifications on CT scan.
• Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
• Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
• Often lead to displacement of adjacent structures and sulci effacement;
• Can increase in size, remain stable, or diminish;
• Are associated with calcifications on CT scan.
• Hypertension (present in 30/52 individuals)
• Mild-to-moderate anemia that is typically normocytic and normochromic
• Microscopic gastrointestinal bleeding resulting in anemia (present in 25/34 affected individuals)
• Raynaud phenomenon, which is typically mild (present in approximately 31/73 individuals with a heterozygous pathogenic variant in
• Avascular necrosis of the femoral head (2 individuals)
• (Hypertensive) cardiomyopathy (3 individuals)
• Macular skin rash and punctate skin lesions (3 individuals)
• Scattered microinfarcts
• Thickened hyalinized retinal arterial walls
• Focal areas of disruption of the ganglion cell layer and inner nuclear layer
• Multiple – often confluent – foci of ischemic necrosis of white matter
• Vasculopathy: vessel wall thickening and luminal stenosis; telangiectasias
• A modest chronic inflammatory cell infiltrate in some individuals
• Focal calcifications and reactive astrocytosis
• Myelin loss
• Renal arteriolosclerosis
• Focal or diffuse glomerulosclerosis
• Nodular regenerative hyperplasia
• Micro- and macrovesicular steatosis
• Periportal inflammation
• Bridging and portal fibrosis
## Ophthalmologic Features
Symptoms caused by retinal vasculopathy are the most common presenting finding in individuals with RVCL-S but can also develop later in the disease course.
Affected individuals often notice decreased visual acuity and/or visual field defects. A gradual worsening often occurs and affected individuals can become legally blind.
All individuals with a heterozygous pathogenic variant in
The retinopathy is characterized in the early stages by telangiectasias, microaneurysms, and cotton wool spots.
In later stages perifoveal capillary obliterations and neovascularizations appear.
Macular edema and neovascular glaucoma may develop as a complication of vascular retinopathy.
• Symptoms caused by retinal vasculopathy are the most common presenting finding in individuals with RVCL-S but can also develop later in the disease course.
• Affected individuals often notice decreased visual acuity and/or visual field defects. A gradual worsening often occurs and affected individuals can become legally blind.
• All individuals with a heterozygous pathogenic variant in
• The retinopathy is characterized in the early stages by telangiectasias, microaneurysms, and cotton wool spots.
• In later stages perifoveal capillary obliterations and neovascularizations appear.
• Macular edema and neovascular glaucoma may develop as a complication of vascular retinopathy.
## Neurologic Features
Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
Often lead to displacement of adjacent structures and sulci effacement;
Can increase in size, remain stable, or diminish;
Are associated with calcifications on CT scan.
• Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
• Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
• Often lead to displacement of adjacent structures and sulci effacement;
• Can increase in size, remain stable, or diminish;
• Are associated with calcifications on CT scan.
• Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
• Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
• Often lead to displacement of adjacent structures and sulci effacement;
• Can increase in size, remain stable, or diminish;
• Are associated with calcifications on CT scan.
• Have been reported in 36/51 individuals with a heterozygous pathogenic variant in
• Are most frequently localized in the frontoparietal lobe but are occasionally found in other regions;
• Often lead to displacement of adjacent structures and sulci effacement;
• Can increase in size, remain stable, or diminish;
• Are associated with calcifications on CT scan.
## Renal Disease
Renal disease has been demonstrated in 22/44 affected individuals. It is typically characterized by a mild-to-moderate increase in serum creatinine and mild proteinuria but may be severe (stage IV kidney disease) and fatal in some families. While the progression of the renal disease of RVCL-S requires further study, in most cases the renal manifestations are progressive; however, there is tremendous variability in the rate of renal decline.
## Liver Disease
Liver disease was present in 28/40 affected individuals and usually manifests as mildly elevated levels of alkaline phosphatase and gamma-glutamyltransferase (GGT).
## Hypothyroidism
Subclinical hypothyroidism was found to be part of the disease course in a recent cross-sectional study. Of the 19 affected individuals older than age 40 years, seven had subclinical hypothyroidism.
## Psychiatric Symptoms
Psychiatric manifestations were present in 26/62 affected individuals and may include depression, psychosis, anxiety, and other psychiatric problems.
## Other
Additional findings may include the following:
Hypertension (present in 30/52 individuals)
Mild-to-moderate anemia that is typically normocytic and normochromic
Microscopic gastrointestinal bleeding resulting in anemia (present in 25/34 affected individuals)
Raynaud phenomenon, which is typically mild (present in approximately 31/73 individuals with a heterozygous pathogenic variant in
Avascular necrosis of the femoral head (2 individuals)
(Hypertensive) cardiomyopathy (3 individuals)
Macular skin rash and punctate skin lesions (3 individuals)
• Hypertension (present in 30/52 individuals)
• Mild-to-moderate anemia that is typically normocytic and normochromic
• Microscopic gastrointestinal bleeding resulting in anemia (present in 25/34 affected individuals)
• Raynaud phenomenon, which is typically mild (present in approximately 31/73 individuals with a heterozygous pathogenic variant in
• Avascular necrosis of the femoral head (2 individuals)
• (Hypertensive) cardiomyopathy (3 individuals)
• Macular skin rash and punctate skin lesions (3 individuals)
## Pathology
Histologic abnormalities have been demonstrated in all organs involved in RVCL-S, including the following.
Scattered microinfarcts
Thickened hyalinized retinal arterial walls
Focal areas of disruption of the ganglion cell layer and inner nuclear layer
Multiple – often confluent – foci of ischemic necrosis of white matter
Vasculopathy: vessel wall thickening and luminal stenosis; telangiectasias
A modest chronic inflammatory cell infiltrate in some individuals
Focal calcifications and reactive astrocytosis
Myelin loss
Renal arteriolosclerosis
Focal or diffuse glomerulosclerosis
Nodular regenerative hyperplasia
Micro- and macrovesicular steatosis
Periportal inflammation
Bridging and portal fibrosis
• Scattered microinfarcts
• Thickened hyalinized retinal arterial walls
• Focal areas of disruption of the ganglion cell layer and inner nuclear layer
• Multiple – often confluent – foci of ischemic necrosis of white matter
• Vasculopathy: vessel wall thickening and luminal stenosis; telangiectasias
• A modest chronic inflammatory cell infiltrate in some individuals
• Focal calcifications and reactive astrocytosis
• Myelin loss
• Renal arteriolosclerosis
• Focal or diffuse glomerulosclerosis
• Nodular regenerative hyperplasia
• Micro- and macrovesicular steatosis
• Periportal inflammation
• Bridging and portal fibrosis
## Genotype-Phenotype Correlations
To date, all pathogenic variants have been frameshift variants in the region of
To date no genotype-phenotype correlations have been observed.
## Penetrance
Penetrance of RVCL-S is age dependent; however, it is thought that all individuals with a heterozygous pathogenic
## Nomenclature
Previous descriptions of families with cerebroretinal vasculopathy (CRV); hereditary vascular retinopathy (HRV); hereditary endotheliopathy, retinopathy, nephropathy, and stroke (HERNS); hereditary systemic angiopathy (HSA); and retinal vasculopathy with cerebral leukodystrophy (RVCL) represent early reports of RVCL-S.
## Prevalence
Currently, fewer than 25 families with RVCL-S are known. However, RVCL-S is most likely underdiagnosed because physicians are generally unfamiliar with the disorder. For example, in the Netherlands alone three unrelated families have been identified because of increased awareness of this condition. The widespread availability of exome and genome sequencing techniques likely also contribute to increased recognition of RVCL-S.
## Genetically Related (Allelic) Disorders
Allelic Disorders
See hyperlinked
Pathogenic variants typically affect one of three exonuclease domains of
In addition, two individuals with
## Differential Diagnosis
Due to the systemic nature of retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S), the differential diagnosis is quite broad. Following are differential diagnoses specifically for the characteristic
Focal and/or global brain dysfunction and MRI brain abnormalities (intracerebral mass lesions and white matter abnormalities) seen in RVCL-S can be similar to intracranial neoplasm, multiple sclerosis, multi-infarct dementia, and central nervous system vasculitis. In these disorders other organs are usually not affected. Moreover, these conditions do not typically follow an autosomal dominant inheritance pattern.
In sarcoidosis and systemic lupus erythematosus (SLE) (see
With sarcoidosis, however, there is frequent involvement of the lungs and skin. No lesions in the lungs have been described in individuals with RVCL-S and skin lesions are not frequently reported [
Vascular retinopathy can occur as a long-term complication of diabetes mellitus and hypertension:
As the vascular retinopathy in RVCL-S is usually observed at a relatively young age (retinopathy has been found in the third decade of life) it is unlikely to be a complication of hypertension or diabetes mellitus, even in those with RVCL-S who have co-occurrence of hypertension or diabetes.
Vascular retinopathy can also be caused by systemic lupus erythematosus, sarcoidosis, and ophthalmologic infections (which are outside of the scope of this
In Susac syndrome, vascular retinopathy and encephalopathy are part of the symptomatology, as is hearing loss, but hearing loss is very rare in RVCL-S. The pattern of white matter lesions seen on MRI may also help to distinguish the two conditions.
Inherited Disorders to Consider in the Differential Diagnosis of RVCL-S
Focal neurologic symptoms
Progressive cognitive decline
Migraine
Mood disturbances
Apathy
White matter lesions on brain imaging
Positive family history
Clinical involvement limited to the brain
The pattern of white matter lesions on brain imaging differs from that in RVCL-S.
Ischemic stroke
Progressive cognitive decline
Extended white matter lesions on brain imaging
Hypertension
Stepwise deterioration in brain functions
Progressive cognitive decline
Extended white matter lesions on brain imaging
Positive family history
Spasticity in lower extremities, spondylosis deformans & alopecia
AR inheritance
Focal neurologic complaints
Nephropathy
Positive family history
Angiokeratomas, hypohidrosis, & corneal opacity
Onset usually in childhood or adolescence
XL inheritance; heterozygous females can be asymptomatic w/normal life span.
Focal neurologic symptoms w/mass lesions on brain imaging
Seizures
Migraine
Positive family history
Café au lait macules, neurofibroma, plexiform neurofibroma, freckling in axillary or inguinal regions, optic glioma, Lisch noduli, & distinctive osseous lesions
Pattern of lesions on brain imaging differs from that seen in RVCL-S.
Nephropathy
Anemia
Retinopathy
Mood disorders
Cognitive complaints
Seizures
Liver disease
Often no genetic pathogenic variant found
Features of vasculitis can occur, specifically cutaneous abnormalities, oral or nasal ulcers, alopecia, & arthritis.
Often associated w/↑ ANAs, anti-dsDNA; anti-Smith antibodies &/or antiphospholipid antibodies (anticardiolipin immunoglobin or lupus anticoagulant)
Multisystem disorder involving brain, kidney, & eye
Focal neurologic symptoms
Seizures
Mass lesions on brain imaging
Positive family history
Formation of hamartomas & skin& lung lesions
Many patients are diagnosed as children, but it is not uncommon for adults to be diagnosed.
AD = autosomal dominant; ANAs = antinuclear antibodies; AR = autosomal recessive; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL = cathepsin A–related arteriopathy with strokes and leukoencephalopathy; CARASIL = cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; dsDNA = double-stranded DNA; MOI = mode of inheritance; XL = X-linked
Most frequently, no genetic cause is identified.
• In sarcoidosis and systemic lupus erythematosus (SLE) (see
• With sarcoidosis, however, there is frequent involvement of the lungs and skin. No lesions in the lungs have been described in individuals with RVCL-S and skin lesions are not frequently reported [
• As the vascular retinopathy in RVCL-S is usually observed at a relatively young age (retinopathy has been found in the third decade of life) it is unlikely to be a complication of hypertension or diabetes mellitus, even in those with RVCL-S who have co-occurrence of hypertension or diabetes.
• Vascular retinopathy can also be caused by systemic lupus erythematosus, sarcoidosis, and ophthalmologic infections (which are outside of the scope of this
• In Susac syndrome, vascular retinopathy and encephalopathy are part of the symptomatology, as is hearing loss, but hearing loss is very rare in RVCL-S. The pattern of white matter lesions seen on MRI may also help to distinguish the two conditions.
• Focal neurologic symptoms
• Progressive cognitive decline
• Migraine
• Mood disturbances
• Apathy
• White matter lesions on brain imaging
• Positive family history
• Clinical involvement limited to the brain
• The pattern of white matter lesions on brain imaging differs from that in RVCL-S.
• Ischemic stroke
• Progressive cognitive decline
• Extended white matter lesions on brain imaging
• Hypertension
• Stepwise deterioration in brain functions
• Progressive cognitive decline
• Extended white matter lesions on brain imaging
• Positive family history
• Spasticity in lower extremities, spondylosis deformans & alopecia
• AR inheritance
• Focal neurologic complaints
• Nephropathy
• Positive family history
• Angiokeratomas, hypohidrosis, & corneal opacity
• Onset usually in childhood or adolescence
• XL inheritance; heterozygous females can be asymptomatic w/normal life span.
• Focal neurologic symptoms w/mass lesions on brain imaging
• Seizures
• Migraine
• Positive family history
• Café au lait macules, neurofibroma, plexiform neurofibroma, freckling in axillary or inguinal regions, optic glioma, Lisch noduli, & distinctive osseous lesions
• Pattern of lesions on brain imaging differs from that seen in RVCL-S.
• Nephropathy
• Anemia
• Retinopathy
• Mood disorders
• Cognitive complaints
• Seizures
• Liver disease
• Often no genetic pathogenic variant found
• Features of vasculitis can occur, specifically cutaneous abnormalities, oral or nasal ulcers, alopecia, & arthritis.
• Often associated w/↑ ANAs, anti-dsDNA; anti-Smith antibodies &/or antiphospholipid antibodies (anticardiolipin immunoglobin or lupus anticoagulant)
• Multisystem disorder involving brain, kidney, & eye
• Focal neurologic symptoms
• Seizures
• Mass lesions on brain imaging
• Positive family history
• Formation of hamartomas & skin& lung lesions
• Many patients are diagnosed as children, but it is not uncommon for adults to be diagnosed.
## Focal and/or Global Brain Dysfunction / MRI Brain Abnormalities
Focal and/or global brain dysfunction and MRI brain abnormalities (intracerebral mass lesions and white matter abnormalities) seen in RVCL-S can be similar to intracranial neoplasm, multiple sclerosis, multi-infarct dementia, and central nervous system vasculitis. In these disorders other organs are usually not affected. Moreover, these conditions do not typically follow an autosomal dominant inheritance pattern.
In sarcoidosis and systemic lupus erythematosus (SLE) (see
With sarcoidosis, however, there is frequent involvement of the lungs and skin. No lesions in the lungs have been described in individuals with RVCL-S and skin lesions are not frequently reported [
• In sarcoidosis and systemic lupus erythematosus (SLE) (see
• With sarcoidosis, however, there is frequent involvement of the lungs and skin. No lesions in the lungs have been described in individuals with RVCL-S and skin lesions are not frequently reported [
## Vascular Retinopathy
Vascular retinopathy can occur as a long-term complication of diabetes mellitus and hypertension:
As the vascular retinopathy in RVCL-S is usually observed at a relatively young age (retinopathy has been found in the third decade of life) it is unlikely to be a complication of hypertension or diabetes mellitus, even in those with RVCL-S who have co-occurrence of hypertension or diabetes.
Vascular retinopathy can also be caused by systemic lupus erythematosus, sarcoidosis, and ophthalmologic infections (which are outside of the scope of this
In Susac syndrome, vascular retinopathy and encephalopathy are part of the symptomatology, as is hearing loss, but hearing loss is very rare in RVCL-S. The pattern of white matter lesions seen on MRI may also help to distinguish the two conditions.
Inherited Disorders to Consider in the Differential Diagnosis of RVCL-S
Focal neurologic symptoms
Progressive cognitive decline
Migraine
Mood disturbances
Apathy
White matter lesions on brain imaging
Positive family history
Clinical involvement limited to the brain
The pattern of white matter lesions on brain imaging differs from that in RVCL-S.
Ischemic stroke
Progressive cognitive decline
Extended white matter lesions on brain imaging
Hypertension
Stepwise deterioration in brain functions
Progressive cognitive decline
Extended white matter lesions on brain imaging
Positive family history
Spasticity in lower extremities, spondylosis deformans & alopecia
AR inheritance
Focal neurologic complaints
Nephropathy
Positive family history
Angiokeratomas, hypohidrosis, & corneal opacity
Onset usually in childhood or adolescence
XL inheritance; heterozygous females can be asymptomatic w/normal life span.
Focal neurologic symptoms w/mass lesions on brain imaging
Seizures
Migraine
Positive family history
Café au lait macules, neurofibroma, plexiform neurofibroma, freckling in axillary or inguinal regions, optic glioma, Lisch noduli, & distinctive osseous lesions
Pattern of lesions on brain imaging differs from that seen in RVCL-S.
Nephropathy
Anemia
Retinopathy
Mood disorders
Cognitive complaints
Seizures
Liver disease
Often no genetic pathogenic variant found
Features of vasculitis can occur, specifically cutaneous abnormalities, oral or nasal ulcers, alopecia, & arthritis.
Often associated w/↑ ANAs, anti-dsDNA; anti-Smith antibodies &/or antiphospholipid antibodies (anticardiolipin immunoglobin or lupus anticoagulant)
Multisystem disorder involving brain, kidney, & eye
Focal neurologic symptoms
Seizures
Mass lesions on brain imaging
Positive family history
Formation of hamartomas & skin& lung lesions
Many patients are diagnosed as children, but it is not uncommon for adults to be diagnosed.
AD = autosomal dominant; ANAs = antinuclear antibodies; AR = autosomal recessive; CADASIL = cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy; CARASAL = cathepsin A–related arteriopathy with strokes and leukoencephalopathy; CARASIL = cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy; dsDNA = double-stranded DNA; MOI = mode of inheritance; XL = X-linked
Most frequently, no genetic cause is identified.
• As the vascular retinopathy in RVCL-S is usually observed at a relatively young age (retinopathy has been found in the third decade of life) it is unlikely to be a complication of hypertension or diabetes mellitus, even in those with RVCL-S who have co-occurrence of hypertension or diabetes.
• Vascular retinopathy can also be caused by systemic lupus erythematosus, sarcoidosis, and ophthalmologic infections (which are outside of the scope of this
• In Susac syndrome, vascular retinopathy and encephalopathy are part of the symptomatology, as is hearing loss, but hearing loss is very rare in RVCL-S. The pattern of white matter lesions seen on MRI may also help to distinguish the two conditions.
• Focal neurologic symptoms
• Progressive cognitive decline
• Migraine
• Mood disturbances
• Apathy
• White matter lesions on brain imaging
• Positive family history
• Clinical involvement limited to the brain
• The pattern of white matter lesions on brain imaging differs from that in RVCL-S.
• Ischemic stroke
• Progressive cognitive decline
• Extended white matter lesions on brain imaging
• Hypertension
• Stepwise deterioration in brain functions
• Progressive cognitive decline
• Extended white matter lesions on brain imaging
• Positive family history
• Spasticity in lower extremities, spondylosis deformans & alopecia
• AR inheritance
• Focal neurologic complaints
• Nephropathy
• Positive family history
• Angiokeratomas, hypohidrosis, & corneal opacity
• Onset usually in childhood or adolescence
• XL inheritance; heterozygous females can be asymptomatic w/normal life span.
• Focal neurologic symptoms w/mass lesions on brain imaging
• Seizures
• Migraine
• Positive family history
• Café au lait macules, neurofibroma, plexiform neurofibroma, freckling in axillary or inguinal regions, optic glioma, Lisch noduli, & distinctive osseous lesions
• Pattern of lesions on brain imaging differs from that seen in RVCL-S.
• Nephropathy
• Anemia
• Retinopathy
• Mood disorders
• Cognitive complaints
• Seizures
• Liver disease
• Often no genetic pathogenic variant found
• Features of vasculitis can occur, specifically cutaneous abnormalities, oral or nasal ulcers, alopecia, & arthritis.
• Often associated w/↑ ANAs, anti-dsDNA; anti-Smith antibodies &/or antiphospholipid antibodies (anticardiolipin immunoglobin or lupus anticoagulant)
• Multisystem disorder involving brain, kidney, & eye
• Focal neurologic symptoms
• Seizures
• Mass lesions on brain imaging
• Positive family history
• Formation of hamartomas & skin& lung lesions
• Many patients are diagnosed as children, but it is not uncommon for adults to be diagnosed.
## Management
To establish the extent of disease and needs of an individual diagnosed with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with RVCL-S
Liver enzymes
Consideration of serum lactate dehydrogenase levels, coagulation studies, & bilirubin concentration
Serum creatinine, BUN, and urinalysis (to include creatinine and protein content)
Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, gamma-glutamyltransferase (GGT)
TSH and free T4
Findings may include depression, psychosis, anxiety, or other psychiatric diagnoses.
It is crucial that unnecessary diagnostic tests not be undertaken. Biopsies of the brain, kidney, or liver are not required in individuals with RVCL-S and do not appear to provide additional prognostic or treatment information.
Treatment of Manifestations in Individuals with Retinal Vasculopathy with RVCL-S
When not properly monitored, affected individuals are frequently given incorrect diagnoses and often receive advice to stop drinking alcohol or stop their medication, while this is not required.
Intravenous methylprednisolone followed by an oral corticosteroid treatment
There are currently no consensus guidelines for monitoring individuals with RVCL-S. However, close monitoring is recommended. The frequency of monitoring depends on the manifestations and rate of disease progression (see
Recommended Surveillance for Individuals with RVCL-S
Serum creatinine, BUN, and urinalysis (to include creatinine and protein content)
Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, gamma-glutamyltransferase (GGT)
Although there is no evidence, the authors would advise against intravenous tissue-type plasminogen activator (IV tPA) for acute ischemic stroke. There is to date no proof that the neurologic manifestations are caused by occluded large blood vessels (RVCL-S is a small vessel disease), and the risk of complications of such treatment (e.g., a secondary hemorrhage) is assumed to be higher in affected individuals.
It is appropriate to evaluate the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the
See
Currently, a pilot study for treating RVCL-S with aclarubicin has been started. For details, see
Search
• Liver enzymes
• Consideration of serum lactate dehydrogenase levels, coagulation studies, & bilirubin concentration
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with RVCL-S
Liver enzymes
Consideration of serum lactate dehydrogenase levels, coagulation studies, & bilirubin concentration
Serum creatinine, BUN, and urinalysis (to include creatinine and protein content)
Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, gamma-glutamyltransferase (GGT)
TSH and free T4
Findings may include depression, psychosis, anxiety, or other psychiatric diagnoses.
It is crucial that unnecessary diagnostic tests not be undertaken. Biopsies of the brain, kidney, or liver are not required in individuals with RVCL-S and do not appear to provide additional prognostic or treatment information.
• Liver enzymes
• Consideration of serum lactate dehydrogenase levels, coagulation studies, & bilirubin concentration
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Retinal Vasculopathy with RVCL-S
When not properly monitored, affected individuals are frequently given incorrect diagnoses and often receive advice to stop drinking alcohol or stop their medication, while this is not required.
Intravenous methylprednisolone followed by an oral corticosteroid treatment
## Surveillance
There are currently no consensus guidelines for monitoring individuals with RVCL-S. However, close monitoring is recommended. The frequency of monitoring depends on the manifestations and rate of disease progression (see
Recommended Surveillance for Individuals with RVCL-S
Serum creatinine, BUN, and urinalysis (to include creatinine and protein content)
Aspartate transaminase (AST), alanine transaminase (ALT), alkaline phosphatase, gamma-glutamyltransferase (GGT)
## Agents/Circumstances to Avoid
Although there is no evidence, the authors would advise against intravenous tissue-type plasminogen activator (IV tPA) for acute ischemic stroke. There is to date no proof that the neurologic manifestations are caused by occluded large blood vessels (RVCL-S is a small vessel disease), and the risk of complications of such treatment (e.g., a secondary hemorrhage) is assumed to be higher in affected individuals.
## Evaluation of Relatives at Risk
It is appropriate to evaluate the genetic status of apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the
See
## Therapies Under Investigation
Currently, a pilot study for treating RVCL-S with aclarubicin has been started. For details, see
Search
## Genetic Counseling
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is inherited in an autosomal dominant manner.
Most individuals diagnosed with RVCL-S have an affected parent. However, there is large variability within families in disease onset and severity.
Some individuals diagnosed with RVCL-S have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
The family history of some individuals diagnosed with RVCL-S may appear to be negative because of failure to recognize the disorder in family members (RVLC-S can be misdiagnosed as multiple sclerosis, multi-infarct / frontal lobe dementia, or other organ dysfunction), 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 molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to be heterozygous for the
If the proband has a known
The absence of clinical 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 or late onset in a heterozygous parent or the theoretic possibility of parental germline 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 or at risk.
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.
• Most individuals diagnosed with RVCL-S have an affected parent. However, there is large variability within families in disease onset and severity.
• Some individuals diagnosed with RVCL-S have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• The family history of some individuals diagnosed with RVCL-S may appear to be negative because of failure to recognize the disorder in family members (RVLC-S can be misdiagnosed as multiple sclerosis, multi-infarct / frontal lobe dementia, or other organ dysfunction), 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 molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to be heterozygous for the
• If the proband has a known
• The absence of clinical 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 or late onset in a heterozygous parent or the theoretic 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 or at risk.
## Mode of Inheritance
Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations (RVCL-S) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with RVCL-S have an affected parent. However, there is large variability within families in disease onset and severity.
Some individuals diagnosed with RVCL-S have the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
The family history of some individuals diagnosed with RVCL-S may appear to be negative because of failure to recognize the disorder in family members (RVLC-S can be misdiagnosed as multiple sclerosis, multi-infarct / frontal lobe dementia, or other organ dysfunction), 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 molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to be heterozygous for the
If the proband has a known
The absence of clinical 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 or late onset in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Most individuals diagnosed with RVCL-S have an affected parent. However, there is large variability within families in disease onset and severity.
• Some individuals diagnosed with RVCL-S have the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• The family history of some individuals diagnosed with RVCL-S may appear to be negative because of failure to recognize the disorder in family members (RVLC-S can be misdiagnosed as multiple sclerosis, multi-infarct / frontal lobe dementia, or other organ dysfunction), 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 molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to be heterozygous for the
• If the proband has a known
• The absence of clinical 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 or late onset in a heterozygous parent or the theoretic possibility of parental 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
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
Netherlands
Ireland
•
• Netherlands
•
•
•
•
•
•
• Ireland
•
•
•
## Molecular Genetics
Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Retinal Vasculopathy with Cerebral Leukoencephalopathy and Systemic Manifestations (
## References
## Literature Cited
## Chapter Notes
The Leiden University Medical Center has expertise in the diagnosis and treatment of RVCL-S and other cerebral hereditary angiopathies (CHA). As part of a consortium we were involved in finding the locus and gene –
19 September 2019 (ma) Review posted live
15 November 2017 (gt) Original submission
• 19 September 2019 (ma) Review posted live
• 15 November 2017 (gt) Original submission
## Author Notes
The Leiden University Medical Center has expertise in the diagnosis and treatment of RVCL-S and other cerebral hereditary angiopathies (CHA). As part of a consortium we were involved in finding the locus and gene –
## Revision History
19 September 2019 (ma) Review posted live
15 November 2017 (gt) Original submission
• 19 September 2019 (ma) Review posted live
• 15 November 2017 (gt) Original submission
Clinical course of RVCL-S
Adapted from
|
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"AH Stam, PH Kothari, A Shaikh, A Gschwendter, JC Jen, S Hodgkinson, TA Hardy, M Hayes, PA Kempster, KE Kotschet, IM Bajema, SG van Duinen, ML Maat-Schieman, PT de Jong, MD de Smet, D de Wolff-Rouendaal, G Dijkman, N Pelzer, GR Kolar, RE Schmidt, J Lacey, D Joseph, DR Fintak, MG Grand, EM Brunt, H Liapis, RA Hajj-Ali, MC Kruit, MA van Buchem, M Dichgans, RR Frants, AM van den Maagdenberg, J Haan, RW Baloh, JP Atkinson, GM Terwindt, MD Ferrari. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations.. Brain. 2016;139:2909-22",
"CW Storimans, MJ Van Schooneveld, JA Oosterhuis, PJ Bos. A new autosomal dominant vascular retinopathy syndrome.. Eur J Ophthalmol. 1991;1:73-8",
"GM Terwindt, J Haan, RA Ophoff, SM Groenen, CW Storimans, JB Lanser, RA Roos, EM Bleeker-Wagemakers, RR Frants, MD Ferrari. Clinical and genetic analysis of a large Dutch family with autosomal dominant vascular retinopathy, migraine and Raynaud's phenomenon.. Brain. 1998;121:303-16",
"I Vodopivec, DH Oakley, CA Perugino, N Venna, ET Hedley-Whyte, JH. A Stone. 44-year-old man with eye, kidney, and brain dysfunction.. Ann Neurol. 2016;79:507-19",
"DT Winkler, P Lyrer, A Probst, D Devys, T Haufschild, S Haller, N Willi, MJ Mihatsch, AJ Steck, M Tolnay. Hereditary systemic angiopathy (HSA) with cerebral calcifications, retinopathy, progressive nephropathy, and hepatopathy.. J Neurol. 2008;255:77-88"
] |
19/9/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
rws
|
rws
|
[
"Calmodulin",
"Calmodulin-3",
"Caveolin-3",
"Inward rectifier potassium channel 2",
"Potassium voltage-gated channel subfamily E member 1",
"Potassium voltage-gated channel subfamily E member 2",
"Potassium voltage-gated channel subfamily KQT member 1",
"Sodium channel protein type 5 subunit alpha",
"Triadin",
"Voltage-dependent L-type calcium channel subunit alpha-1C",
"Voltage-gated inwardly rectifying potassium channel KCNH2",
"CACNA1C",
"CALM1",
"CALM2",
"CALM3",
"CAV3",
"KCNE1",
"KCNE2",
"KCNH2",
"KCNJ2",
"KCNQ1",
"SCN5A",
"TRDN",
"Long QT Syndrome",
"Overview"
] |
Long QT Syndrome Overview
|
Alexander J Groffen, Hennie Bikker, Imke Christiaans
|
Summary The purpose of this overview is to: Briefly describe the Review the Review the Provide an Review Inform
|
## Clinical Characteristics of Long QT Syndrome
Long QT syndrome (LQTS) is characterized by QT prolongation and T wave abnormalities on EKG. LQTS predisposes individuals to a significant risk of life-threatening arrhythmic events, especially in young individuals. Molecular genetic testing identifies a genetic cause in ~80% of affected individuals, most often in genes associated with autosomal dominant LQTS. Subsequent cascade genetic testing allows for identification of at-risk relatives who can benefit from tailored therapeutic management strategies to reduce morbidity and mortality.
The initial scoring system for a clinical diagnosis of LQTS was updated by
Long QT Syndrome: Scoring System for Clinical Diagnosis
Adapted from
LQTS = long QT syndrome; QTc = corrected QT
In the absence of medications or disorders known to affect these electrocardiographic features
QTc is calculated by the Bazett formula, where QTc = QT/√RR.
Mutually exclusive
Resting heart rate <2nd centile for age
The same family member cannot be used for both criteria.
T wave abnormalities include T wave alternans, notched T wave, broad-based and flattened T waves (see
Cardiac events (i.e., syncope, cardiac arrest, or sudden cardiac death) may occur from infancy through middle age but are most common from the preteen years through the 20s, with the risk generally diminishing throughout that time period. The usual age range of events differs somewhat for each genotype. Cardiac events are uncommon after age 40 years; when present, they are often triggered by administration of a QT-prolonging drug or hypokalemia. Cardiac events in individuals older than age 40 years are more likely associated with
Pathogenic variants in
Long QT Syndrome: Phenotype Correlations by Gene
SCD = sudden cardiac death
Average values from 807, 879, and 237 individuals with
Cumulative probability of a cardiac event (syncope, aborted cardiac arrest, or sudden death) at age 50 years in a cohort of individuals with
Percentage of individuals with one or more syncopal events [
Percentage of individuals with one or more aborted cardiac arrest(s) [
Although incidence of syncopal events is highest in those with
The risk of sudden cardiac death is dependent on history of syncope, proband status (i.e., being the first in the family in whom the genetic cause for LQTS has been identified), QTc interval, treatment, age, and sex. The age and sex dependency differs between the three main molecular causes of LQTS. Overall, boys are at relatively high risk before onset of adolescence, and girls after the onset of adolescence (age 13 to 14 years) [
Cumulative Probability of Cardiac Events by Age
Cardiac events include syncope, aborted cardiac arrest, and sudden cardiac death.
Studies from the LQTS Registry including individuals with clinical manifestations, 14%-20% probands and family members with a pathogenic variant (most individuals were on treatment; 52%-60% with beta-blockers) [
LQTS exhibits reduced penetrance for EKG changes and symptoms. Approximately 25% of individuals with an identified molecular cause of LQTS have a normal QTc (<440 ms) on baseline EKG. The percentage of individuals with a normal QTc was higher in those with
Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia.
LQTS associated with biallelic pathogenic variants (in genes associated with autosomal dominant LQTS) or heterozygosity for pathogenic variants in two different genes (i.e., digenic pathogenic variants) is generally associated with a more severe phenotype with longer QTc interval and a higher incidence of cardiac events [
The designation "acquired long QT syndrome" may be used to distinguish QT interval prolongation associated with non-heritable causes and conditions from heritable predisposition to QTc prolongation. Of note, gene-environment interactions occur, and drug exposures and conditions associated with acquired LQTS may also be cardiac event triggers in individuals with a genetic predisposition to QT prolongation.
The prevalence of LQTS has been estimated at 1:2,500 [
## Cardiac Features
T wave abnormalities include T wave alternans, notched T wave, broad-based and flattened T waves (see
Cardiac events (i.e., syncope, cardiac arrest, or sudden cardiac death) may occur from infancy through middle age but are most common from the preteen years through the 20s, with the risk generally diminishing throughout that time period. The usual age range of events differs somewhat for each genotype. Cardiac events are uncommon after age 40 years; when present, they are often triggered by administration of a QT-prolonging drug or hypokalemia. Cardiac events in individuals older than age 40 years are more likely associated with
Pathogenic variants in
Long QT Syndrome: Phenotype Correlations by Gene
SCD = sudden cardiac death
Average values from 807, 879, and 237 individuals with
Cumulative probability of a cardiac event (syncope, aborted cardiac arrest, or sudden death) at age 50 years in a cohort of individuals with
Percentage of individuals with one or more syncopal events [
Percentage of individuals with one or more aborted cardiac arrest(s) [
Although incidence of syncopal events is highest in those with
The risk of sudden cardiac death is dependent on history of syncope, proband status (i.e., being the first in the family in whom the genetic cause for LQTS has been identified), QTc interval, treatment, age, and sex. The age and sex dependency differs between the three main molecular causes of LQTS. Overall, boys are at relatively high risk before onset of adolescence, and girls after the onset of adolescence (age 13 to 14 years) [
Cumulative Probability of Cardiac Events by Age
Cardiac events include syncope, aborted cardiac arrest, and sudden cardiac death.
Studies from the LQTS Registry including individuals with clinical manifestations, 14%-20% probands and family members with a pathogenic variant (most individuals were on treatment; 52%-60% with beta-blockers) [
LQTS exhibits reduced penetrance for EKG changes and symptoms. Approximately 25% of individuals with an identified molecular cause of LQTS have a normal QTc (<440 ms) on baseline EKG. The percentage of individuals with a normal QTc was higher in those with
## Non-Cardiac Features
Some types of LQTS are associated with a phenotype extending beyond cardiac arrhythmia.
## Biallelic Pathogenic Variants / Digenic Inheritance
LQTS associated with biallelic pathogenic variants (in genes associated with autosomal dominant LQTS) or heterozygosity for pathogenic variants in two different genes (i.e., digenic pathogenic variants) is generally associated with a more severe phenotype with longer QTc interval and a higher incidence of cardiac events [
## Nomenclature
The designation "acquired long QT syndrome" may be used to distinguish QT interval prolongation associated with non-heritable causes and conditions from heritable predisposition to QTc prolongation. Of note, gene-environment interactions occur, and drug exposures and conditions associated with acquired LQTS may also be cardiac event triggers in individuals with a genetic predisposition to QT prolongation.
## Prevalence
The prevalence of LQTS has been estimated at 1:2,500 [
## Genetic Causes of Long QT Syndrome
Using the ClinGen Gene Curation Framework, the
Long QT Syndrome: Genetic Causes
Based on
CPVT = catecholaminergic polymorphic ventricular tachycardia; GoF = gain-of-function; LQTS = long QT syndrome
Genes are organized first by frequency of causation of LQTS, then strength of ClinGen classification, and then alphabetically.
Up to 25% of individuals with LQTS do not have a detectable pathogenic variant in one of the genes in
Gene validity classifications indicate the evidence level for association with the indicated phenotypes. Some genes have different classifications when associated with different phenotypes. Although
During a ClinGen evaluation of gene-disease validity by an expert panel for muscular dystrophies and myopathies, the panel decided to lump all indicated OMIM disease entities as "caveolinopathy" because they found no significant difference in phenotype, inheritance pattern, or molecular mechanism. See
See
Biallelic variants in
There is limited evidence for LQTS caused by
## Differential Diagnosis of Long QT Syndrome
Drug-induced QT prolongation (See drugs at
Hypokalemia
Certain neurologic conditions including subarachnoid bleed
Structural heart disease
Sudden infant death syndrome (SIDS), commonly defined as unexpected sudden death within the first year of life. Death during the first year of life in families with long QT syndrome (LQTS) appears to be rare, yet infants with SIDS have been shown to have pathogenic variants in one of the genes listed in
Vasovagal (neurally mediated) syncope, orthostatic hypotension
Seizures. Absence of aura, incontinence, and postictal findings help differentiate LQTS-associated syncope from seizures.
Familial ventricular fibrillation
Subtle cardiomyopathies (
Calcium release deficiency syndrome [
Anomalous coronary artery
• Drug-induced QT prolongation (See drugs at
• Hypokalemia
• Certain neurologic conditions including subarachnoid bleed
• Structural heart disease
• Sudden infant death syndrome (SIDS), commonly defined as unexpected sudden death within the first year of life. Death during the first year of life in families with long QT syndrome (LQTS) appears to be rare, yet infants with SIDS have been shown to have pathogenic variants in one of the genes listed in
• Vasovagal (neurally mediated) syncope, orthostatic hypotension
• Seizures. Absence of aura, incontinence, and postictal findings help differentiate LQTS-associated syncope from seizures.
• Familial ventricular fibrillation
• Subtle cardiomyopathies (
•
• Calcium release deficiency syndrome [
•
• Anomalous coronary artery
## Evaluation Strategies to Identify the Genetic Cause of Long QT Syndrome in a Proband
Establishing a specific genetic cause of long QT syndrome (LQTS):
Can aid in discussions of prognosis (which are beyond the scope of this
Usually involves a medical history, physical examination, family history, and genomic/genetic testing.
Depending on the sequencing method used and copy number variant detection tools, exon or whole-gene deletions/duplications may not be detected. Exon or multiexon deletions or duplications in
Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
• Can aid in discussions of prognosis (which are beyond the scope of this
• Usually involves a medical history, physical examination, family history, and genomic/genetic testing.
• Depending on the sequencing method used and copy number variant detection tools, exon or whole-gene deletions/duplications may not be detected. Exon or multiexon deletions or duplications in
• Note: (1) The genes included in the panel and the diagnostic sensitivity of the testing used for each gene vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this
## Management
To establish the extent of disease and needs in an individual diagnosed with long QT syndrome (LQTS), the main focus in the management of individuals with LQTS is to identify the subset of individuals at high risk for cardiac events. For this risk stratification the following evaluations are recommended if not performed as part of the evaluation that led to the diagnosis:
To aid in risk stratification, an
Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of LQTS in order to facilitate medical and personal decision making.
All symptomatic persons should be treated [
Avoid inadequate beta-blocker dosing by regular adjustments in growing children, with evaluation of the efficacy of dose by assessment of the exercise EKG or ambulatory EKG;
Administer beta-blockers daily, and have strategies in place in case of missed doses;
Use long-acting agents (e.g., nadolol) to increase adherence and avoid use of short-acting metoprolol [
Administer QT-prolonging drugs (see
Note: Most affected individuals live normal lives. Education of affected adults and the parents of affected children, especially about beta-blocker adherence, is an important aspect of management.
Assess for asthma, orthostatic hypotension, depression, and diabetes mellitus, because these disorders may be exacerbated by treatment with beta-blockers.
Electrolyte imbalances may lengthen the QTc interval; identification and correction of electrolyte abnormalities is important. These imbalances can occur as a result of diarrhea, vomiting, metabolic conditions, and unbalanced diets used for weight loss.
Although the incidence of arrhythmias during elective interventions such as surgery, endoscopies, childbirth, or dental work is low, it is prudent to monitor the EKG during such interventions and to alert the appropriate medical personnel in case intervention is needed.
Lifestyle modifications are advised based on genotype (see
Beta-blocker dose should be regularly assessed for efficacy and adverse effects; doses should be altered as needed. Dose adjustment including efficacy testing is especially important in growing children.
Individuals with an ICD should have regular, periodic evaluations of the ICD for inappropriate shocks and pocket or lead complications.
Drugs that cause further prolongation of the QT interval or provoke torsade de pointes should be avoided for all individuals with LQTS. See
Epinephrine given as part of local anesthetics can trigger arrhythmias and is best avoided.
Lifestyle modifications are advised based on genotype:
Individuals with
Individuals with
Individuals at high risk for cardiac events or with exercise-induced symptoms (as in
The postpartum period is associated with increased risk for a cardiac event, especially in individuals with
See
A current study is evaluating the drug ranolazine in individuals with
For individuals with
Search
• To aid in risk stratification, an
• Avoid inadequate beta-blocker dosing by regular adjustments in growing children, with evaluation of the efficacy of dose by assessment of the exercise EKG or ambulatory EKG;
• Administer beta-blockers daily, and have strategies in place in case of missed doses;
• Use long-acting agents (e.g., nadolol) to increase adherence and avoid use of short-acting metoprolol [
• Administer QT-prolonging drugs (see
• Individuals with
• Individuals with
• Individuals at high risk for cardiac events or with exercise-induced symptoms (as in
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with long QT syndrome (LQTS), the main focus in the management of individuals with LQTS is to identify the subset of individuals at high risk for cardiac events. For this risk stratification the following evaluations are recommended if not performed as part of the evaluation that led to the diagnosis:
To aid in risk stratification, an
Consultation with a clinical geneticist, certified genetic counselor, certified genetic nurse, or genetics advanced practice provider (nurse practitioner or physician assistant) is recommended to inform affected individuals and their families about the nature, mode of inheritance, and implications of LQTS in order to facilitate medical and personal decision making.
• To aid in risk stratification, an
## Treatment of Manifestations
All symptomatic persons should be treated [
Avoid inadequate beta-blocker dosing by regular adjustments in growing children, with evaluation of the efficacy of dose by assessment of the exercise EKG or ambulatory EKG;
Administer beta-blockers daily, and have strategies in place in case of missed doses;
Use long-acting agents (e.g., nadolol) to increase adherence and avoid use of short-acting metoprolol [
Administer QT-prolonging drugs (see
Note: Most affected individuals live normal lives. Education of affected adults and the parents of affected children, especially about beta-blocker adherence, is an important aspect of management.
Assess for asthma, orthostatic hypotension, depression, and diabetes mellitus, because these disorders may be exacerbated by treatment with beta-blockers.
Electrolyte imbalances may lengthen the QTc interval; identification and correction of electrolyte abnormalities is important. These imbalances can occur as a result of diarrhea, vomiting, metabolic conditions, and unbalanced diets used for weight loss.
Although the incidence of arrhythmias during elective interventions such as surgery, endoscopies, childbirth, or dental work is low, it is prudent to monitor the EKG during such interventions and to alert the appropriate medical personnel in case intervention is needed.
Lifestyle modifications are advised based on genotype (see
• Avoid inadequate beta-blocker dosing by regular adjustments in growing children, with evaluation of the efficacy of dose by assessment of the exercise EKG or ambulatory EKG;
• Administer beta-blockers daily, and have strategies in place in case of missed doses;
• Use long-acting agents (e.g., nadolol) to increase adherence and avoid use of short-acting metoprolol [
• Administer QT-prolonging drugs (see
## Targeted Therapy
All symptomatic persons should be treated [
Avoid inadequate beta-blocker dosing by regular adjustments in growing children, with evaluation of the efficacy of dose by assessment of the exercise EKG or ambulatory EKG;
Administer beta-blockers daily, and have strategies in place in case of missed doses;
Use long-acting agents (e.g., nadolol) to increase adherence and avoid use of short-acting metoprolol [
Administer QT-prolonging drugs (see
Note: Most affected individuals live normal lives. Education of affected adults and the parents of affected children, especially about beta-blocker adherence, is an important aspect of management.
• Avoid inadequate beta-blocker dosing by regular adjustments in growing children, with evaluation of the efficacy of dose by assessment of the exercise EKG or ambulatory EKG;
• Administer beta-blockers daily, and have strategies in place in case of missed doses;
• Use long-acting agents (e.g., nadolol) to increase adherence and avoid use of short-acting metoprolol [
• Administer QT-prolonging drugs (see
##
##
All symptomatic persons should be treated [
Avoid inadequate beta-blocker dosing by regular adjustments in growing children, with evaluation of the efficacy of dose by assessment of the exercise EKG or ambulatory EKG;
Administer beta-blockers daily, and have strategies in place in case of missed doses;
Use long-acting agents (e.g., nadolol) to increase adherence and avoid use of short-acting metoprolol [
Administer QT-prolonging drugs (see
Note: Most affected individuals live normal lives. Education of affected adults and the parents of affected children, especially about beta-blocker adherence, is an important aspect of management.
• Avoid inadequate beta-blocker dosing by regular adjustments in growing children, with evaluation of the efficacy of dose by assessment of the exercise EKG or ambulatory EKG;
• Administer beta-blockers daily, and have strategies in place in case of missed doses;
• Use long-acting agents (e.g., nadolol) to increase adherence and avoid use of short-acting metoprolol [
• Administer QT-prolonging drugs (see
## Supportive Care
Assess for asthma, orthostatic hypotension, depression, and diabetes mellitus, because these disorders may be exacerbated by treatment with beta-blockers.
Electrolyte imbalances may lengthen the QTc interval; identification and correction of electrolyte abnormalities is important. These imbalances can occur as a result of diarrhea, vomiting, metabolic conditions, and unbalanced diets used for weight loss.
Although the incidence of arrhythmias during elective interventions such as surgery, endoscopies, childbirth, or dental work is low, it is prudent to monitor the EKG during such interventions and to alert the appropriate medical personnel in case intervention is needed.
Lifestyle modifications are advised based on genotype (see
## Surveillance
Beta-blocker dose should be regularly assessed for efficacy and adverse effects; doses should be altered as needed. Dose adjustment including efficacy testing is especially important in growing children.
Individuals with an ICD should have regular, periodic evaluations of the ICD for inappropriate shocks and pocket or lead complications.
## Agents/Circumstances to Avoid
Drugs that cause further prolongation of the QT interval or provoke torsade de pointes should be avoided for all individuals with LQTS. See
Epinephrine given as part of local anesthetics can trigger arrhythmias and is best avoided.
Lifestyle modifications are advised based on genotype:
Individuals with
Individuals with
Individuals at high risk for cardiac events or with exercise-induced symptoms (as in
• Individuals with
• Individuals with
• Individuals at high risk for cardiac events or with exercise-induced symptoms (as in
## Pregnancy Management
The postpartum period is associated with increased risk for a cardiac event, especially in individuals with
See
## Therapies Under Investigation
A current study is evaluating the drug ranolazine in individuals with
For individuals with
Search
## Genetic Risk Assessment and Evaluations of At-Risk Relatives for Early Detection and Treatment of Long QT Syndrome
Long QT syndrome (LQTS) without extracardiac features is typically inherited in an autosomal dominant manner.
Long QT Syndrome: Mode of Inheritance
AD = autosomal dominant; AR = autosomal recessive; CPVT = catecholaminergic polymorphic ventricular tachycardia; GoF = gain-of-function; LQTS = long QT syndrome
Genes are ordered alphabetically
LQTS associated with biallelic pathogenic variants (in genes associated with autosomal dominant LQTS) or heterozygosity for pathogenic variants in two different genes (i.e., digenic pathogenic variants) has also been reported (see
A basic view of autosomal dominant LQTS genetic risk assessment is presented in this section; issues that may be specific to a given family or genetic cause of LQTS are not comprehensively addressed. If a proband has a specific syndrome (e.g.,
The majority of individuals diagnosed with LQTS inherited a pathogenic variant from a parent. Due to reduced penetrance and variable expressivity, a parent who is heterozygous for an LQTS-related pathogenic variant may or may not have LQTS-related EKG changes and symptoms.
A proband with LQTS may have the disorder as the result of a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and facilitate the use of morbidity- and mortality-reducing interventions for parents found to be heterozygous for an LQTS-related pathogenic variant.
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 incidence of germline mosaicism is very low: 0.1% [
The family history of some individuals diagnosed with LQTS 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 does not exclude the possibility of an inherited pathogenic variant and molecular genetic testing is indicated.
Note: Biallelic and digenic pathogenic variants have been described. If an individual with LQTS has biallelic or digenic pathogenic variants, the possibility that both parents have pathogenic variants should be considered.
If a parent of the proband is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because LQTS exhibits reduced penetrance, sibs who inherit a pathogenic variant may or may not have symptomatic LQTS. Considerable phenotypic variability within families has also been reported [
If the proband has a known LQTS-related pathogenic variant that 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 do not have signs of LQTS on cardiac evaluation but their genetic status is unknown, the risk to sibs of inheriting an LQTS-related pathogenic variant is estimated to be 50% because a heterozygous parent may be clinically unaffected due to reduced penetrance of LQTS-related EKG changes and symptoms. The likelihood that the proband has LQTS as the result of a pathogenic variant inherited from a heterozygous asymptomatic parent is far greater than the likelihood that the proband has LQTS as the result of a
Predictive genetic testing can be used to identify relatives who are heterozygous for a familial LQTS-related pathogenic variant and at risk for LQTS-related manifestations but cannot be used to predict disease course (i.e., whether LQTS-related EKG changes and symptoms will occur and, if so, the age of onset and severity).
Note: Because LQTS exhibits reduced penetrance for EKG changes and symptoms, the absence of LQTS-related findings on EKG evaluation cannot be used to assess genetic status (i.e., an individual who is heterozygous for an LQTS-related pathogenic variant may have a normal QTc on baseline EKG).
• The majority of individuals diagnosed with LQTS inherited a pathogenic variant from a parent. Due to reduced penetrance and variable expressivity, a parent who is heterozygous for an LQTS-related pathogenic variant may or may not have LQTS-related EKG changes and symptoms.
• A proband with LQTS may have the disorder as the result of a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and facilitate the use of morbidity- and mortality-reducing interventions for parents found to be heterozygous for an LQTS-related pathogenic variant.
• 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 incidence of germline mosaicism is very low: 0.1% [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (the incidence of germline mosaicism is very low: 0.1% [
• The family history of some individuals diagnosed with LQTS 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 does not exclude the possibility of an inherited pathogenic variant and molecular genetic testing is indicated.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (the incidence of germline mosaicism is very low: 0.1% [
• If a parent of the proband is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because LQTS exhibits reduced penetrance, sibs who inherit a pathogenic variant may or may not have symptomatic LQTS. Considerable phenotypic variability within families has also been reported [
• If the proband has a known LQTS-related pathogenic variant that 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 do not have signs of LQTS on cardiac evaluation but their genetic status is unknown, the risk to sibs of inheriting an LQTS-related pathogenic variant is estimated to be 50% because a heterozygous parent may be clinically unaffected due to reduced penetrance of LQTS-related EKG changes and symptoms. The likelihood that the proband has LQTS as the result of a pathogenic variant inherited from a heterozygous asymptomatic parent is far greater than the likelihood that the proband has LQTS as the result of a
## Genetic Risk Assessment
Long QT syndrome (LQTS) without extracardiac features is typically inherited in an autosomal dominant manner.
Long QT Syndrome: Mode of Inheritance
AD = autosomal dominant; AR = autosomal recessive; CPVT = catecholaminergic polymorphic ventricular tachycardia; GoF = gain-of-function; LQTS = long QT syndrome
Genes are ordered alphabetically
LQTS associated with biallelic pathogenic variants (in genes associated with autosomal dominant LQTS) or heterozygosity for pathogenic variants in two different genes (i.e., digenic pathogenic variants) has also been reported (see
## Risk to Family Members (Autosomal Dominant Inheritance)
A basic view of autosomal dominant LQTS genetic risk assessment is presented in this section; issues that may be specific to a given family or genetic cause of LQTS are not comprehensively addressed. If a proband has a specific syndrome (e.g.,
The majority of individuals diagnosed with LQTS inherited a pathogenic variant from a parent. Due to reduced penetrance and variable expressivity, a parent who is heterozygous for an LQTS-related pathogenic variant may or may not have LQTS-related EKG changes and symptoms.
A proband with LQTS may have the disorder as the result of a
If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and facilitate the use of morbidity- and mortality-reducing interventions for parents found to be heterozygous for an LQTS-related pathogenic variant.
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 incidence of germline mosaicism is very low: 0.1% [
The family history of some individuals diagnosed with LQTS 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 does not exclude the possibility of an inherited pathogenic variant and molecular genetic testing is indicated.
Note: Biallelic and digenic pathogenic variants have been described. If an individual with LQTS has biallelic or digenic pathogenic variants, the possibility that both parents have pathogenic variants should be considered.
If a parent of the proband is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because LQTS exhibits reduced penetrance, sibs who inherit a pathogenic variant may or may not have symptomatic LQTS. Considerable phenotypic variability within families has also been reported [
If the proband has a known LQTS-related pathogenic variant that 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 do not have signs of LQTS on cardiac evaluation but their genetic status is unknown, the risk to sibs of inheriting an LQTS-related pathogenic variant is estimated to be 50% because a heterozygous parent may be clinically unaffected due to reduced penetrance of LQTS-related EKG changes and symptoms. The likelihood that the proband has LQTS as the result of a pathogenic variant inherited from a heterozygous asymptomatic parent is far greater than the likelihood that the proband has LQTS as the result of a
• The majority of individuals diagnosed with LQTS inherited a pathogenic variant from a parent. Due to reduced penetrance and variable expressivity, a parent who is heterozygous for an LQTS-related pathogenic variant may or may not have LQTS-related EKG changes and symptoms.
• A proband with LQTS may have the disorder as the result of a
• If a molecular diagnosis has been established in the proband, molecular genetic testing is recommended for the parents of the proband to evaluate their genetic status, inform recurrence risk assessment, and facilitate the use of morbidity- and mortality-reducing interventions for parents found to be heterozygous for an LQTS-related pathogenic variant.
• 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 incidence of germline mosaicism is very low: 0.1% [
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (the incidence of germline mosaicism is very low: 0.1% [
• The family history of some individuals diagnosed with LQTS 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 does not exclude the possibility of an inherited pathogenic variant and molecular genetic testing is indicated.
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism (the incidence of germline mosaicism is very low: 0.1% [
• If a parent of the proband is heterozygous for the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. Because LQTS exhibits reduced penetrance, sibs who inherit a pathogenic variant may or may not have symptomatic LQTS. Considerable phenotypic variability within families has also been reported [
• If the proband has a known LQTS-related pathogenic variant that 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 do not have signs of LQTS on cardiac evaluation but their genetic status is unknown, the risk to sibs of inheriting an LQTS-related pathogenic variant is estimated to be 50% because a heterozygous parent may be clinically unaffected due to reduced penetrance of LQTS-related EKG changes and symptoms. The likelihood that the proband has LQTS as the result of a pathogenic variant inherited from a heterozygous asymptomatic parent is far greater than the likelihood that the proband has LQTS as the result of a
## Evaluation of Relatives at Risk
Predictive genetic testing can be used to identify relatives who are heterozygous for a familial LQTS-related pathogenic variant and at risk for LQTS-related manifestations but cannot be used to predict disease course (i.e., whether LQTS-related EKG changes and symptoms will occur and, if so, the age of onset and severity).
Note: Because LQTS exhibits reduced penetrance for EKG changes and symptoms, the absence of LQTS-related findings on EKG evaluation cannot be used to assess genetic status (i.e., an individual who is heterozygous for an LQTS-related pathogenic variant may have a normal QTc on baseline EKG).
## Resources
Canada
Heart Research Follow-Up Program
•
•
•
• Canada
•
•
•
•
• Heart Research Follow-Up Program
•
## Chapter Notes
Mariëlle Alders, PhD; Amsterdam University Medical Center (2012-2024)Hennie Bikker, PhD (2018-present)Imke Christiaans, PhD, MD (2015-present)Alexander J Groffen, PhD (2024-present)Marcel MAM Mannens, PhD; University of Amsterdam (2012-2015)G Michael Vincent, MD; University of Utah School of Medicine (2003-2012)
21 March 2024 (sw) Comprehensive update posted live; scope changed to overview
8 February 2018 (ha) Comprehensive update posted live
18 June 2015 (me) Comprehensive update posted live (title change)
31 May 2012 (me) Comprehensive update posted live
21 May 2008 (me) Comprehensive update posted live
7 July 2005 (me) Comprehensive update posted live
20 February 2003 (me) Review posted live
25 October 2002 (gmv) Original submission
• 21 March 2024 (sw) Comprehensive update posted live; scope changed to overview
• 8 February 2018 (ha) Comprehensive update posted live
• 18 June 2015 (me) Comprehensive update posted live (title change)
• 31 May 2012 (me) Comprehensive update posted live
• 21 May 2008 (me) Comprehensive update posted live
• 7 July 2005 (me) Comprehensive update posted live
• 20 February 2003 (me) Review posted live
• 25 October 2002 (gmv) Original submission
## Author History
Mariëlle Alders, PhD; Amsterdam University Medical Center (2012-2024)Hennie Bikker, PhD (2018-present)Imke Christiaans, PhD, MD (2015-present)Alexander J Groffen, PhD (2024-present)Marcel MAM Mannens, PhD; University of Amsterdam (2012-2015)G Michael Vincent, MD; University of Utah School of Medicine (2003-2012)
## Revision History
21 March 2024 (sw) Comprehensive update posted live; scope changed to overview
8 February 2018 (ha) Comprehensive update posted live
18 June 2015 (me) Comprehensive update posted live (title change)
31 May 2012 (me) Comprehensive update posted live
21 May 2008 (me) Comprehensive update posted live
7 July 2005 (me) Comprehensive update posted live
20 February 2003 (me) Review posted live
25 October 2002 (gmv) Original submission
• 21 March 2024 (sw) Comprehensive update posted live; scope changed to overview
• 8 February 2018 (ha) Comprehensive update posted live
• 18 June 2015 (me) Comprehensive update posted live (title change)
• 31 May 2012 (me) Comprehensive update posted live
• 21 May 2008 (me) Comprehensive update posted live
• 7 July 2005 (me) Comprehensive update posted live
• 20 February 2003 (me) Review posted live
• 25 October 2002 (gmv) Original submission
## References
American College of Cardiology/American Heart Association Task Force, and the European Society of Cardiology/Committee for Practice Guidelines. Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Available
Fellmann F, van El CG, Charron P, Michaud K, Howard HC, Boers SN, Clarke AJ, Duguet AM, Forzano F, Kauferstein S, Kayserili H, Lucassen A, Mendes A, Patch C, Radojkovic D, Rial-Sebbag E, Sheppard MN, Tasse AM, Temel SG, Sajantila A, Basso C, Wilde AAM, Cornel MC, on behalf of European Society of Human Genetics ECoLMESoCwgom, pericardial diseases ERNfrlp, complex diseases of the heart AfECP. European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death. Eur J Hum Genet. 2019;27:1763-73.
Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10:1932-63.
Stiles MK, Wilde AAM, Abrams DJ, Ackerman MJ, Albert CM, Behr ER, Chugh SS, Cornel MC, Gardner K, Ingles J, James CA, Juang JJ, Kaab S, Kaufman ES, Krahn AD, Lubitz SA, MacLeod H, Morillo CA, Nademanee K, Probst V, Saarel EV, Sacilotto L, Semsarian C, Sheppard MN, Shimizu W, Skinner JR, Tfelt-Hansen J, Wang DW. 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families. J Arrhythm. 2021;37:481-534.
Vincent GM. Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. Available
Wilde AAM, Semsarian C, Marquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Group ESCSD. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace. 2022;24:1307-67.
Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, Charron P, Corrado D, Dagres N, de Chillou C, Eckardt L, Friede T, Haugaa KH, Hocini M, Lambiase PD, Marijon E, Merino JL, Peichl P, Priori SG, Reichlin T, Schulz-Menger J, Sticherling C, Tzeis S, Verstrael A, Volterrani M, Group ESCSD. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43:3997-4126.
• American College of Cardiology/American Heart Association Task Force, and the European Society of Cardiology/Committee for Practice Guidelines. Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Available
• Fellmann F, van El CG, Charron P, Michaud K, Howard HC, Boers SN, Clarke AJ, Duguet AM, Forzano F, Kauferstein S, Kayserili H, Lucassen A, Mendes A, Patch C, Radojkovic D, Rial-Sebbag E, Sheppard MN, Tasse AM, Temel SG, Sajantila A, Basso C, Wilde AAM, Cornel MC, on behalf of European Society of Human Genetics ECoLMESoCwgom, pericardial diseases ERNfrlp, complex diseases of the heart AfECP. European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death. Eur J Hum Genet. 2019;27:1763-73.
• Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10:1932-63.
• Stiles MK, Wilde AAM, Abrams DJ, Ackerman MJ, Albert CM, Behr ER, Chugh SS, Cornel MC, Gardner K, Ingles J, James CA, Juang JJ, Kaab S, Kaufman ES, Krahn AD, Lubitz SA, MacLeod H, Morillo CA, Nademanee K, Probst V, Saarel EV, Sacilotto L, Semsarian C, Sheppard MN, Shimizu W, Skinner JR, Tfelt-Hansen J, Wang DW. 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families. J Arrhythm. 2021;37:481-534.
• Vincent GM. Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. Available
• Wilde AAM, Semsarian C, Marquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Group ESCSD. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace. 2022;24:1307-67.
• Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, Charron P, Corrado D, Dagres N, de Chillou C, Eckardt L, Friede T, Haugaa KH, Hocini M, Lambiase PD, Marijon E, Merino JL, Peichl P, Priori SG, Reichlin T, Schulz-Menger J, Sticherling C, Tzeis S, Verstrael A, Volterrani M, Group ESCSD. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43:3997-4126.
## Published Guidelines / Consensus Statements
American College of Cardiology/American Heart Association Task Force, and the European Society of Cardiology/Committee for Practice Guidelines. Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Available
Fellmann F, van El CG, Charron P, Michaud K, Howard HC, Boers SN, Clarke AJ, Duguet AM, Forzano F, Kauferstein S, Kayserili H, Lucassen A, Mendes A, Patch C, Radojkovic D, Rial-Sebbag E, Sheppard MN, Tasse AM, Temel SG, Sajantila A, Basso C, Wilde AAM, Cornel MC, on behalf of European Society of Human Genetics ECoLMESoCwgom, pericardial diseases ERNfrlp, complex diseases of the heart AfECP. European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death. Eur J Hum Genet. 2019;27:1763-73.
Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10:1932-63.
Stiles MK, Wilde AAM, Abrams DJ, Ackerman MJ, Albert CM, Behr ER, Chugh SS, Cornel MC, Gardner K, Ingles J, James CA, Juang JJ, Kaab S, Kaufman ES, Krahn AD, Lubitz SA, MacLeod H, Morillo CA, Nademanee K, Probst V, Saarel EV, Sacilotto L, Semsarian C, Sheppard MN, Shimizu W, Skinner JR, Tfelt-Hansen J, Wang DW. 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families. J Arrhythm. 2021;37:481-534.
Vincent GM. Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. Available
Wilde AAM, Semsarian C, Marquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Group ESCSD. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace. 2022;24:1307-67.
Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, Charron P, Corrado D, Dagres N, de Chillou C, Eckardt L, Friede T, Haugaa KH, Hocini M, Lambiase PD, Marijon E, Merino JL, Peichl P, Priori SG, Reichlin T, Schulz-Menger J, Sticherling C, Tzeis S, Verstrael A, Volterrani M, Group ESCSD. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43:3997-4126.
• American College of Cardiology/American Heart Association Task Force, and the European Society of Cardiology/Committee for Practice Guidelines. Guidelines for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Available
• Fellmann F, van El CG, Charron P, Michaud K, Howard HC, Boers SN, Clarke AJ, Duguet AM, Forzano F, Kauferstein S, Kayserili H, Lucassen A, Mendes A, Patch C, Radojkovic D, Rial-Sebbag E, Sheppard MN, Tasse AM, Temel SG, Sajantila A, Basso C, Wilde AAM, Cornel MC, on behalf of European Society of Human Genetics ECoLMESoCwgom, pericardial diseases ERNfrlp, complex diseases of the heart AfECP. European recommendations integrating genetic testing into multidisciplinary management of sudden cardiac death. Eur J Hum Genet. 2019;27:1763-73.
• Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C. HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm. 2013;10:1932-63.
• Stiles MK, Wilde AAM, Abrams DJ, Ackerman MJ, Albert CM, Behr ER, Chugh SS, Cornel MC, Gardner K, Ingles J, James CA, Juang JJ, Kaab S, Kaufman ES, Krahn AD, Lubitz SA, MacLeod H, Morillo CA, Nademanee K, Probst V, Saarel EV, Sacilotto L, Semsarian C, Sheppard MN, Shimizu W, Skinner JR, Tfelt-Hansen J, Wang DW. 2020 APHRS/HRS expert consensus statement on the investigation of decedents with sudden unexplained death and patients with sudden cardiac arrest, and of their families. J Arrhythm. 2021;37:481-534.
• Vincent GM. Role of DNA testing for diagnosis, management, and genetic screening in long QT syndrome, hypertrophic cardiomyopathy, and Marfan syndrome. Available
• Wilde AAM, Semsarian C, Marquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Group ESCSD. European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases. Europace. 2022;24:1307-67.
• Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, Charron P, Corrado D, Dagres N, de Chillou C, Eckardt L, Friede T, Haugaa KH, Hocini M, Lambiase PD, Marijon E, Merino JL, Peichl P, Priori SG, Reichlin T, Schulz-Menger J, Sticherling C, Tzeis S, Verstrael A, Volterrani M, Group ESCSD. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J. 2022;43:3997-4126.
## Literature Cited
|
[] |
20/2/2003
|
21/3/2024
|
4/8/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
salih-myo
|
salih-myo
|
[
"Titin",
"TTN",
"Salih Myopathy"
] |
Salih Myopathy
|
Peter Hackman, Marco Savarese, Maria Francesca Di Feo, Bjarne Udd, Mustafa A Salih
|
Summary Salih myopathy is characterized by muscle weakness (manifesting during the neonatal period or in very early infancy) and delayed motor development; children acquire independent walking between ages 20 months and four years. In the first decade of life, global motor performance is stable or tends to improve. Moderate joint and neck contractures and spinal rigidity may manifest in the first decade but become more obvious in the second decade. Scoliosis develops after age 11 years. Cardiac dysfunction manifests between ages five and 16 years, progresses rapidly, and leads to death between ages eight and 20 years, usually from heart rhythm disturbances. The diagnosis of Salih myopathy is established in a proband with corresponding clinical phenotype and biallelic pathogenic truncating variants in exons 359, 360, and 361 of Salih myopathy is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for Salih myopathy have been published.
Salih myopathy
Muscle weakness manifesting during the neonatal period or in very early infancy
Delayed motor milestones but normal cognitive development
Muscle weakness of limb-girdle distribution, myopathic face, variable degree of ptosis, and relative calf muscle hypertrophy
Development of dilated cardiomyopathy between ages five and 16 years
Major heart rhythm disturbances leading to sudden death before age 20 years
The diagnosis of Salih myopathy
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 myopathy,
For an introduction to comprehensive genomic testing click
Note: If biallelic
Molecular Genetic Testing Used in Salih Myopathy
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
To date, pathogenic variants reported to cause Salih myopathy are truncating variants in specific
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.
• Muscle weakness manifesting during the neonatal period or in very early infancy
• Delayed motor milestones but normal cognitive development
• Muscle weakness of limb-girdle distribution, myopathic face, variable degree of ptosis, and relative calf muscle hypertrophy
• Development of dilated cardiomyopathy between ages five and 16 years
• Major heart rhythm disturbances leading to sudden death before age 20 years
## Suggestive Findings
Salih myopathy
Muscle weakness manifesting during the neonatal period or in very early infancy
Delayed motor milestones but normal cognitive development
Muscle weakness of limb-girdle distribution, myopathic face, variable degree of ptosis, and relative calf muscle hypertrophy
Development of dilated cardiomyopathy between ages five and 16 years
Major heart rhythm disturbances leading to sudden death before age 20 years
• Muscle weakness manifesting during the neonatal period or in very early infancy
• Delayed motor milestones but normal cognitive development
• Muscle weakness of limb-girdle distribution, myopathic face, variable degree of ptosis, and relative calf muscle hypertrophy
• Development of dilated cardiomyopathy between ages five and 16 years
• Major heart rhythm disturbances leading to sudden death before age 20 years
## Establishing the Diagnosis
The diagnosis of Salih myopathy
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 myopathy,
For an introduction to comprehensive genomic testing click
Note: If biallelic
Molecular Genetic Testing Used in Salih Myopathy
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
To date, pathogenic variants reported to cause Salih myopathy are truncating variants in specific
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 myopathy,
For an introduction to comprehensive genomic testing click
Note: If biallelic
Molecular Genetic Testing Used in Salih Myopathy
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
To date, pathogenic variants reported to cause Salih myopathy are truncating variants in specific
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
Salih myopathy is characterized by early-onset muscle weakness, delayed gross motor development, development of moderate joint and neck contractures and spinal rigidity, cardiomyopathy, and heart rhythm disturbances leading to early demise. Cognition is normal.
Heart muscle biopsies (taken from 2 individuals) showed increased interstitial fibrosis compatible with dilated cardiomyopathy [
Radionuclide angiography using MUGA (
Major rhythm disturbances become evident on EKG and Holter monitoring, including polymorphic premature ventricular complexes, bigeminism and trigeminism, couplets, triplets, atrioventricular heart block, atrioventricular nodal reentrant tachycardia, premature atrial complexes, premature ventricular complexes, and ventricular tachycardia.
No exact genotype-phenotype correlations are known. There are individuals with biallelic
Salih myopathy was initially referred to as Salih congenital muscular dystrophy [
Although the designation "early-onset titinopathy with fatal cardiomyopathy" is sometimes used synonymously with the designation Salih myopathy, Salih myopathy is one of several titinopathies characterized by early onset and fatal cardiomyopathy.
Salih myopathy is thought to be rare. It was originally described in consanguineous families of Arab descent originating from Sudan and Morocco. Subsequently, the disease has been identified in many populations [
## Clinical Description
Salih myopathy is characterized by early-onset muscle weakness, delayed gross motor development, development of moderate joint and neck contractures and spinal rigidity, cardiomyopathy, and heart rhythm disturbances leading to early demise. Cognition is normal.
Heart muscle biopsies (taken from 2 individuals) showed increased interstitial fibrosis compatible with dilated cardiomyopathy [
Radionuclide angiography using MUGA (
Major rhythm disturbances become evident on EKG and Holter monitoring, including polymorphic premature ventricular complexes, bigeminism and trigeminism, couplets, triplets, atrioventricular heart block, atrioventricular nodal reentrant tachycardia, premature atrial complexes, premature ventricular complexes, and ventricular tachycardia.
## Genotype-Phenotype Correlations
No exact genotype-phenotype correlations are known. There are individuals with biallelic
## Nomenclature
Salih myopathy was initially referred to as Salih congenital muscular dystrophy [
Although the designation "early-onset titinopathy with fatal cardiomyopathy" is sometimes used synonymously with the designation Salih myopathy, Salih myopathy is one of several titinopathies characterized by early onset and fatal cardiomyopathy.
## Prevalence
Salih myopathy is thought to be rare. It was originally described in consanguineous families of Arab descent originating from Sudan and Morocco. Subsequently, the disease has been identified in many populations [
## Genetically Related (Allelic) Disorders
Other phenotypes associated with germline pathogenic variants in
Of note, all of the congenital autosomal recessive titinopathies should be considered in the
MOI = mode of inheritance;
Autosomal recessive congenital titinopathies include range of phenotypes
For a comprehensive review of
## Differential Diagnosis
Genetic disorders with early-onset muscle involvement in the differential diagnosis of Salih myopathy are listed in
Early-Onset Genetic Muscle Disorders of Interest in the Differential Diagnosis of Salih Myopathy
Usually manifests in early childhood w/delayed milestones
Subclinical or clinical cardiac involvement presents in ~90% of affected persons.
Serum CK: ↑ (>10-300x normal)
EKG: characteristic pattern w/tall right precordial (leads VI & V2) R waves, & deep & narrow Q waves in inferolateral leads (II, III, aVF, V5, & V6) early in course of disease
Skeletal muscle histology: established dystrophic morphology early in childhood
Immunohistochemical staining of skeletal muscle: negative for dystrophin
Onset: age <1 yr
In some, infantile CM
Muscle weakness & calf muscle hypertrophy
Absence of ptosis
Serum CK: ↑
EKG: dysmorphic notched P waves, complete or incomplete right BBB or incomplete left BBB, & Q waves in lateral leads
Muscle weakness typically begins at birth or in early infancy.
Children present w/delay or arrest of gross motor development.
Dilated CM
Intellectual disability
Epilepsy
Variable eye malformations
Brain MRI: CNS malformations
Congenital hypotonia
Delayed or arrested motor milestones
Progressive diffuse joint contractures
Spinal rigidity
Usually normal intellect
~1/3 of persons develop left ventricular dysfunction
Myopathic facies
± calf muscle hypertrophy
Infantile hypotonia & weakness of axial-cervical muscles
Dilated CM
Facial weakness
Ptosis
Muscle pseudohypertrophy
Neonatal hypotonia & early-onset motor delay
Weakness of trunk & neck flexors > pelvic & shoulder girdle muscles
Affected persons are usually ambulatory.
Facial muscle weakness ranging from absent to severe
Serum CK: may be slightly ↑
Similar skeletal muscle histology
Major respiratory involvement requiring respiratory support
Cardiac involvement (right ventricular failure, CM) secondary to respiratory impairment
Onset: age 3-15 yrs
In some, delayed walking & frequent falling
CM
EKG: left anterior fascicular block
Serum CK: ↑ (10-70x normal)
EKG: tall R wave in V1 & V2 (vs Salih myopathy, in which deep S waves are seen in right precordial leads assoc w/↓ R:S ratio) (See
Echocardiogram: left ventricular dysfunction assoc w/regional wall motion abnormalities (e.g., inferior wall & posterior septum hypokinesia) (vs Salih myopathy, in which contractile dysfunction & dilatation, initially restricted to left ventricle, subsequently affects all chambers)
Early-onset muscle weakness (age 6-12 mos) (SMA II)
Weakness leading to frequent falls & difficulty walking up & down stairs (SMA III)
Normal intelligence
Onset: age >18 mos (SMA III)
Postural tremor of fingers
Sparing of facial muscles
Serum CK: normal
EKG: frequent background tremors but no cardiac involvement
EMG: neurogenic features (polyphasic waves, positive sharp waves & fibrillations) (vs myopathic EMG features in Salih myopathy)
Later onset (childhood or older) w/loss of walking age >15 yrs
Not assoc w/significant CM or respiratory failure
Muscle weakness in childhood or earlier
Pattern of weakness predominantly proximal & axial
Respiratory impairment is common, leading to respiratory failure.
Dilated CM is rare (<10%).
AD = autosomal dominant; AR = autosomal recessive; BBB = bundle branch block; CK = creatine kinase; CM = cardiomyopathy; CNS = central nervous system; EMG = electromyography; LGMD = limb-girdle muscular dystrophy; MOI = mode of inheritance;
• Usually manifests in early childhood w/delayed milestones
• Subclinical or clinical cardiac involvement presents in ~90% of affected persons.
• Serum CK: ↑ (>10-300x normal)
• EKG: characteristic pattern w/tall right precordial (leads VI & V2) R waves, & deep & narrow Q waves in inferolateral leads (II, III, aVF, V5, & V6) early in course of disease
• Skeletal muscle histology: established dystrophic morphology early in childhood
• Immunohistochemical staining of skeletal muscle: negative for dystrophin
• Onset: age <1 yr
• In some, infantile CM
• Muscle weakness & calf muscle hypertrophy
• Absence of ptosis
• Serum CK: ↑
• EKG: dysmorphic notched P waves, complete or incomplete right BBB or incomplete left BBB, & Q waves in lateral leads
• Muscle weakness typically begins at birth or in early infancy.
• Children present w/delay or arrest of gross motor development.
• Dilated CM
• Intellectual disability
• Epilepsy
• Variable eye malformations
• Brain MRI: CNS malformations
• Congenital hypotonia
• Delayed or arrested motor milestones
• Progressive diffuse joint contractures
• Spinal rigidity
• Usually normal intellect
• ~1/3 of persons develop left ventricular dysfunction
• Myopathic facies
• ± calf muscle hypertrophy
• Infantile hypotonia & weakness of axial-cervical muscles
• Dilated CM
• Facial weakness
• Ptosis
• Muscle pseudohypertrophy
• Neonatal hypotonia & early-onset motor delay
• Weakness of trunk & neck flexors > pelvic & shoulder girdle muscles
• Affected persons are usually ambulatory.
• Facial muscle weakness ranging from absent to severe
• Serum CK: may be slightly ↑
• Similar skeletal muscle histology
• Major respiratory involvement requiring respiratory support
• Cardiac involvement (right ventricular failure, CM) secondary to respiratory impairment
• Onset: age 3-15 yrs
• In some, delayed walking & frequent falling
• CM
• EKG: left anterior fascicular block
• Serum CK: ↑ (10-70x normal)
• EKG: tall R wave in V1 & V2 (vs Salih myopathy, in which deep S waves are seen in right precordial leads assoc w/↓ R:S ratio) (See
• Echocardiogram: left ventricular dysfunction assoc w/regional wall motion abnormalities (e.g., inferior wall & posterior septum hypokinesia) (vs Salih myopathy, in which contractile dysfunction & dilatation, initially restricted to left ventricle, subsequently affects all chambers)
• Early-onset muscle weakness (age 6-12 mos) (SMA II)
• Weakness leading to frequent falls & difficulty walking up & down stairs (SMA III)
• Normal intelligence
• Onset: age >18 mos (SMA III)
• Postural tremor of fingers
• Sparing of facial muscles
• Serum CK: normal
• EKG: frequent background tremors but no cardiac involvement
• EMG: neurogenic features (polyphasic waves, positive sharp waves & fibrillations) (vs myopathic EMG features in Salih myopathy)
• Later onset (childhood or older) w/loss of walking age >15 yrs
• Not assoc w/significant CM or respiratory failure
• Muscle weakness in childhood or earlier
• Pattern of weakness predominantly proximal & axial
• Respiratory impairment is common, leading to respiratory failure.
• Dilated CM is rare (<10%).
## Management
No clinical practice guidelines for Salih myopathy 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 and needs in an individual diagnosed with Salih myopathy, the evaluations summarized in
Salih Myopathy: Recommended Evaluations Following Initial Diagnosis
Respiratory rate assessment
Pulmonary function testing
Referral tocardiologist
EKG
24-hr Holter EKG
Echocardiogram
Community or
Social work involvement for parental support
Home nursing referral
CNS = central nervous system; EKG = electrocardiogram; 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)
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This ideally involves multidisciplinary care by specialists in pediatric neurology, physical therapy, occupational therapy, orthopedics, cardiology, and pulmonology (see
Salih Myopathy: Treatment of Manifestations
Stretching exercises & PT to prevent contractures & promote mobility
Assistive mechanical devices incl orthotics, canes, & walkers as needed
Education re correct posture for lying prone & sitting
Garchois brace (made of plexidur, a rigid but light & heat-deformable material) to ↓ degree of deformity & slow progression of scoliosis
Annual influenza vaccine & other respiratory infection-related immunizations are advised.
Lower respiratory tract infections should be treated aggressively.
Treat heart failure & cardiac arrhythmia as soon as they are evident using standard therapies per cardiologist.
Educate parents/caregivers on symptoms of heart failure, arrhythmia (incl presyncope & syncope), & thromboembolic disease, & need to urgently seek medical care when any of these symptoms appear.
Train caregivers in CPR once symptoms of cardiomyopathy start.
Cardiac transplantation should be considered for progressive dilated cardiomyopathy & heart failure refractory to medical therapy.
Persons w/Salih myopathy have normal cognition.
Technical support should be provided in school environment.
Stimulation & emotional support can improve school performance & sense of social involvement.
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
CPR = cardiopulmonary resuscitation; PT = physical therapy
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Salih Myopathy: Recommended Surveillance
Neurologic eval for hypotonia & weakness
Assessment of mobility
EKG
24-hr Holter EKG
Echocardiogram
EKG = electrocardiogram
Avoid ibuprofen (Brufen
It is appropriate to clarify the genetic 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 monitoring of motor development and cardiac function so that treatment can be instituted promptly.
See
If a fetus is diagnosed prenatally with Salih myopathy, special considerations are needed at and following delivery, as muscle weakness may manifest during the neonatal period.
Search
• Respiratory rate assessment
• Pulmonary function testing
• Referral tocardiologist
• EKG
• 24-hr Holter EKG
• Echocardiogram
• Community or
• Social work involvement for parental support
• Home nursing referral
• Stretching exercises & PT to prevent contractures & promote mobility
• Assistive mechanical devices incl orthotics, canes, & walkers as needed
• Education re correct posture for lying prone & sitting
• Garchois brace (made of plexidur, a rigid but light & heat-deformable material) to ↓ degree of deformity & slow progression of scoliosis
• Annual influenza vaccine & other respiratory infection-related immunizations are advised.
• Lower respiratory tract infections should be treated aggressively.
• Treat heart failure & cardiac arrhythmia as soon as they are evident using standard therapies per cardiologist.
• Educate parents/caregivers on symptoms of heart failure, arrhythmia (incl presyncope & syncope), & thromboembolic disease, & need to urgently seek medical care when any of these symptoms appear.
• Train caregivers in CPR once symptoms of cardiomyopathy start.
• Cardiac transplantation should be considered for progressive dilated cardiomyopathy & heart failure refractory to medical therapy.
• Persons w/Salih myopathy have normal cognition.
• Technical support should be provided in school environment.
• Stimulation & emotional support can improve school performance & sense of social involvement.
• 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
• Neurologic eval for hypotonia & weakness
• Assessment of mobility
• EKG
• 24-hr Holter EKG
• Echocardiogram
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Salih myopathy, the evaluations summarized in
Salih Myopathy: Recommended Evaluations Following Initial Diagnosis
Respiratory rate assessment
Pulmonary function testing
Referral tocardiologist
EKG
24-hr Holter EKG
Echocardiogram
Community or
Social work involvement for parental support
Home nursing referral
CNS = central nervous system; EKG = electrocardiogram; 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)
• Respiratory rate assessment
• Pulmonary function testing
• Referral tocardiologist
• EKG
• 24-hr Holter EKG
• Echocardiogram
• 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 pediatric neurology, physical therapy, occupational therapy, orthopedics, cardiology, and pulmonology (see
Salih Myopathy: Treatment of Manifestations
Stretching exercises & PT to prevent contractures & promote mobility
Assistive mechanical devices incl orthotics, canes, & walkers as needed
Education re correct posture for lying prone & sitting
Garchois brace (made of plexidur, a rigid but light & heat-deformable material) to ↓ degree of deformity & slow progression of scoliosis
Annual influenza vaccine & other respiratory infection-related immunizations are advised.
Lower respiratory tract infections should be treated aggressively.
Treat heart failure & cardiac arrhythmia as soon as they are evident using standard therapies per cardiologist.
Educate parents/caregivers on symptoms of heart failure, arrhythmia (incl presyncope & syncope), & thromboembolic disease, & need to urgently seek medical care when any of these symptoms appear.
Train caregivers in CPR once symptoms of cardiomyopathy start.
Cardiac transplantation should be considered for progressive dilated cardiomyopathy & heart failure refractory to medical therapy.
Persons w/Salih myopathy have normal cognition.
Technical support should be provided in school environment.
Stimulation & emotional support can improve school performance & sense of social involvement.
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
CPR = cardiopulmonary resuscitation; PT = physical therapy
• Stretching exercises & PT to prevent contractures & promote mobility
• Assistive mechanical devices incl orthotics, canes, & walkers as needed
• Education re correct posture for lying prone & sitting
• Garchois brace (made of plexidur, a rigid but light & heat-deformable material) to ↓ degree of deformity & slow progression of scoliosis
• Annual influenza vaccine & other respiratory infection-related immunizations are advised.
• Lower respiratory tract infections should be treated aggressively.
• Treat heart failure & cardiac arrhythmia as soon as they are evident using standard therapies per cardiologist.
• Educate parents/caregivers on symptoms of heart failure, arrhythmia (incl presyncope & syncope), & thromboembolic disease, & need to urgently seek medical care when any of these symptoms appear.
• Train caregivers in CPR once symptoms of cardiomyopathy start.
• Cardiac transplantation should be considered for progressive dilated cardiomyopathy & heart failure refractory to medical therapy.
• Persons w/Salih myopathy have normal cognition.
• Technical support should be provided in school environment.
• Stimulation & emotional support can improve school performance & sense of social involvement.
• 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
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Salih Myopathy: Recommended Surveillance
Neurologic eval for hypotonia & weakness
Assessment of mobility
EKG
24-hr Holter EKG
Echocardiogram
EKG = electrocardiogram
• Neurologic eval for hypotonia & weakness
• Assessment of mobility
• EKG
• 24-hr Holter EKG
• Echocardiogram
## Agents/Circumstances to Avoid
Avoid ibuprofen (Brufen
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic 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 monitoring of motor development and cardiac function so that treatment can be instituted promptly.
See
## Pregnancy Management
If a fetus is diagnosed prenatally with Salih myopathy, special considerations are needed at and following delivery, as muscle weakness may manifest during the neonatal period.
## Therapies Under Investigation
Search
## Genetic Counseling
Salih myopathy is caused by biallelic truncating pathogenic variants in specific
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.
The heterozygous parents of individuals with Salih myopathy are usually asymptomatic without muscle disorder; however, individuals heterozygous for a
If both parents are known to be heterozygous for a
The heterozygous sibs of an individual with Salih myopathy are usually asymptomatic without muscle disorder; however, individuals heterozygous for a
Heterozygote testing for at-risk family members 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 heterozygous or are at risk of being heterozygous.
It is appropriate to offer
Once the causative
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
• 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 individuals with Salih myopathy are usually asymptomatic without muscle disorder; however, individuals heterozygous for 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.
• If both parents are known to be heterozygous for a
• The heterozygous sibs of an individual with Salih myopathy are usually asymptomatic without muscle disorder; however, individuals heterozygous for 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 young adults who are heterozygous or are at risk of being heterozygous.
• It is appropriate to offer
## Mode of Inheritance
Salih myopathy is caused by biallelic truncating pathogenic variants in specific
## 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.
The heterozygous parents of individuals with Salih myopathy are usually asymptomatic without muscle disorder; however, individuals heterozygous for a
If both parents are known to be heterozygous for a
The heterozygous sibs of an individual with Salih myopathy are usually asymptomatic without muscle disorder; however, individuals heterozygous for a
• 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.
• The heterozygous parents of individuals with Salih myopathy are usually asymptomatic without muscle disorder; however, individuals heterozygous for 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.
• If both parents are known to be heterozygous for a
• The heterozygous sibs of an individual with Salih myopathy are usually asymptomatic without muscle disorder; however, individuals heterozygous for a
## Heterozygote Detection
Heterozygote testing for at-risk family members 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 heterozygous or are at risk of being heterozygous.
It is appropriate to offer
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is 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.
• It is appropriate to offer
## Prenatal and Preimplantation Genetic Testing
Once the causative
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
CMDIR/Cure CMD
•
•
•
•
•
• Canada
•
•
• United Kingdom
•
•
•
• CMDIR/Cure CMD
•
## Molecular Genetics
Salih Myopathy: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Salih Myopathy (
Titin functions as a template in sarcomere assembly and for maintenance of sarcomere integrity. The titin protein is the third myofilament in the sarcomere along with myosin and actin filaments. Titin spans more than one half the length of a sarcomere in heart and skeletal muscle. Structurally different parts of the protein perform distinct functions (mechanical, developmental, and regulatory) [
To date, biallelic pathogenic variants reported to cause Salih myopathy are small frameshift deletions in
## Molecular Pathogenesis
Titin functions as a template in sarcomere assembly and for maintenance of sarcomere integrity. The titin protein is the third myofilament in the sarcomere along with myosin and actin filaments. Titin spans more than one half the length of a sarcomere in heart and skeletal muscle. Structurally different parts of the protein perform distinct functions (mechanical, developmental, and regulatory) [
To date, biallelic pathogenic variants reported to cause Salih myopathy are small frameshift deletions in
## Chapter Notes
The authors would like to thank Ana Ferreiro, MD, PhD, Virginie Carmignac, PhD, and Saad Subahi, MD, who have contributed to the understanding of this disorder. Thanks are also due to Loida M Sese for secretarial work, and Sayed Taha and Vir Salvador for medical illustration.
Virginie Carmignac, PhD (2012-2025)Maria Francesca Di Feo, MD (2025-present)Peter Hackman, PhD (2012-present)Mustafa Salih, MB BS, MPCH, MD, Dr Med Sci, FRCPCH, FAAN (2012-present)Marco Savarese, PhD (2019-present)Tiina Suominen, MSc; University of Helsinki (2012-2019)Bjarne Udd, MD, PhD (2012-present)
3 April 2025 (sw) Comprehensive update posted live
11 April 2019 (sw) Comprehensive update posted live
12 January 2012 (me) Review posted live
28 October 2011 (mas) Original submission
• 3 April 2025 (sw) Comprehensive update posted live
• 11 April 2019 (sw) Comprehensive update posted live
• 12 January 2012 (me) Review posted live
• 28 October 2011 (mas) Original submission
## Acknowledgments
The authors would like to thank Ana Ferreiro, MD, PhD, Virginie Carmignac, PhD, and Saad Subahi, MD, who have contributed to the understanding of this disorder. Thanks are also due to Loida M Sese for secretarial work, and Sayed Taha and Vir Salvador for medical illustration.
## Author History
Virginie Carmignac, PhD (2012-2025)Maria Francesca Di Feo, MD (2025-present)Peter Hackman, PhD (2012-present)Mustafa Salih, MB BS, MPCH, MD, Dr Med Sci, FRCPCH, FAAN (2012-present)Marco Savarese, PhD (2019-present)Tiina Suominen, MSc; University of Helsinki (2012-2019)Bjarne Udd, MD, PhD (2012-present)
## Revision History
3 April 2025 (sw) Comprehensive update posted live
11 April 2019 (sw) Comprehensive update posted live
12 January 2012 (me) Review posted live
28 October 2011 (mas) Original submission
• 3 April 2025 (sw) Comprehensive update posted live
• 11 April 2019 (sw) Comprehensive update posted live
• 12 January 2012 (me) Review posted live
• 28 October 2011 (mas) Original submission
## References
## Literature Cited
Electrocardiogram in individual with Salih myopathy at age four years showing left axis deviation (left anterior fascicular block)
Skeletal muscle histology of two children with Salih myopathy taken at age four years (A and D) and 14 years (B and C).
A and D. The early muscle biopsy in an individual with Salih myopathy shows (A) increased fiber size variability, abundant centrally located nuclei (CNLs) but no endomyseal fibrosis or necrosis (Van Gieson's stain; original magnification x250). (D) Type 1 fibers (dark) predominate and type 2 fibers (pale, arrows) are scanty (myofibrillar ATPase [4.3]; original magnification x250).
B and C. At age 14 years there is also a remarkable number of CNLs (B), associated with endomyseal fibrosis and few necrotic fibers (arrow) (GT; original magnification x250). (C) Oxidative staining reveals the minicore-like lesions (arrowheads; original magnification x250).
Longitudinal electron microscopy section of skeletal muscle taken at age ten years in an individual with Salih myopathy reveals focal disruptions of sarcomeric structures (arrows), Z-disk abnormalities including focal loss of dark Z-disk material, and early dissolution of I-band filaments (original magnification x6000).
Mid-calf muscle MRI of parents of a proband at age (A) 55 years and (B) 44 years were normal and showed no fatty degeneration of the anterior tibial muscles.
|
[] |
12/1/2012
|
3/4/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
samd9l-ap
|
samd9l-ap
|
[
"SAMD9L-ATXPC Syndrome",
"SAMD9L-ATXPC Syndrome",
"Sterile alpha motif domain-containing protein 9-like",
"SAMD9L",
"SAMD9L Ataxia-Pancytopenia Syndrome"
] |
Wendy H Raskind, Dong-Hui Chen, Thomas Bird
|
Summary The diagnosis of
|
## Diagnosis
Formal clinical diagnostic criteria for
Cerebellar ataxia
Variable hematopoietic cytopenias affecting one or more lineages (e.g., anemia, neutropenia, thrombocytopenia)
Myeloid leukemia or myelodysplasia with partial or complete monosomy 7
The diagnosis of
Note: Identification of a heterozygous
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 phenotype is indistinguishable from many other inherited disorders characterized by cerebellar ataxia and/or hematopoietic cytopenias or myelodysplasia,
For an introduction to comprehensive genomic testing click
Note: The hematopoietic system may undergo somatic reversion via copy-neutral loss of the pathogenic
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
Authors, unpublished observations
See
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. However, as
• Cerebellar ataxia
• Variable hematopoietic cytopenias affecting one or more lineages (e.g., anemia, neutropenia, thrombocytopenia)
• Myeloid leukemia or myelodysplasia with partial or complete monosomy 7
• For an introduction to multigene panels click
## Suggestive Findings
Cerebellar ataxia
Variable hematopoietic cytopenias affecting one or more lineages (e.g., anemia, neutropenia, thrombocytopenia)
Myeloid leukemia or myelodysplasia with partial or complete monosomy 7
• Cerebellar ataxia
• Variable hematopoietic cytopenias affecting one or more lineages (e.g., anemia, neutropenia, thrombocytopenia)
• Myeloid leukemia or myelodysplasia with partial or complete monosomy 7
## Establishing the Diagnosis
The diagnosis of
Note: Identification of a heterozygous
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 phenotype is indistinguishable from many other inherited disorders characterized by cerebellar ataxia and/or hematopoietic cytopenias or myelodysplasia,
For an introduction to comprehensive genomic testing click
Note: The hematopoietic system may undergo somatic reversion via copy-neutral loss of the pathogenic
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
Authors, unpublished observations
See
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. However, as
• 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 phenotype is indistinguishable from many other inherited disorders characterized by cerebellar ataxia and/or hematopoietic cytopenias or myelodysplasia,
For an introduction to comprehensive genomic testing click
Note: The hematopoietic system may undergo somatic reversion via copy-neutral loss of the pathogenic
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
Authors, unpublished observations
See
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. However, as
## Clinical Characteristics
To date, 85 individuals from 36 families have been identified with a pathogenic variant in
Select Features of
HSCT = hematopoietic stem cell transplant; MDS = myelodysplasia
One or more of nystagmus, ataxia, pyramidal signs, neuropathy, abnormal brain imaging
Not all persons had neurologic evaluations or neuroimaging.
Biased by pediatric hematology ascertainment. Additional somatic genetic events (monosomy 7/7q, uniparental disomy 7, or pathogenic intragenic inactivating variants) may be found in cases without hematologic manifestations [
One additional case developed acute lymphocytic leukemia; it is unclear if this is related to
The manifestations of
The severities of hematologic and neurologic abnormalities are not concordant. An individual who died at age 16 years from a retroperitoneal bleed secondary to thrombocytopenia had no clinically reported neurologic manifestations, despite the presence of cerebellar atrophy. Several individuals had moderate-to-severe neurologic involvement with only mild or undetected hematologic involvement [
Mild thrombocytopenia or anemia and/or mild macrocytosis (maximum recorded mean corpuscular volume: 108 fL) were documented in many affected individuals.
Immunodeficiency was documented in two families [
Non-leukemic marrows were hypoplastic in multiple individuals examined.
Partial or complete monosomy 7 is frequent, with some having myelodysplasia; a few eventually developed leukemia [
The effect of the disease on the hematopoietic system accounts for the increased mortality. Of eight published cases of hematopoietic stem cell transplant for myelodysplasia, six survived the procedure and have been followed for as long as 14 years post transplant [
Onset of neurologic impairment ranged from infancy to age 62 years.
Horizontal and vertical nystagmus and dysmetria were evident in most individuals.
Deep tendon reflexes were usually increased, ankle clonus was easily elicited, and some affected individuals had extensor plantar responses [
Strength and sensation were infrequently impaired [
Gait impairment and other neurologic abnormalities were slowly progressive. Some individuals eventually required a wheelchair [
Multifocal electroretinography has identified mostly intact central function with paracentral retinal dysfunction in at least two affected individuals [
In the second family reported by
With respect to validated pathogenic variants in
Given the variable expressivity of both hematologic and neurologic manifestations, the sometimes episodic asymptomatic cytopenias, the paucity of detailed neurologic/neuroimaging evaluations, and the effect of additional somatic genetic events on the hematologic manifestations (see
The phenomena of hematopoietic clones with additional genetic alterations repopulating the bone marrow appear to explain striking reports of non-penetrance or spontaneous and long-term disease remission in some affected individuals and some unaffected carrier parents of affected children [
The disorder was initially called myelocerebellar syndrome by
True prevalence is unknown, but the disorder is rare. With increasing testing of children with myelodysplasia and individuals with both mild hematologic cytopenias and ataxia, additional cases continue to be diagnosed. Approximately 12% of childhood myelodysplasia is attributable to germline pathogenic variants in
• Mild thrombocytopenia or anemia and/or mild macrocytosis (maximum recorded mean corpuscular volume: 108 fL) were documented in many affected individuals.
• Immunodeficiency was documented in two families [
• Non-leukemic marrows were hypoplastic in multiple individuals examined.
• Partial or complete monosomy 7 is frequent, with some having myelodysplasia; a few eventually developed leukemia [
• The effect of the disease on the hematopoietic system accounts for the increased mortality. Of eight published cases of hematopoietic stem cell transplant for myelodysplasia, six survived the procedure and have been followed for as long as 14 years post transplant [
• Onset of neurologic impairment ranged from infancy to age 62 years.
• Horizontal and vertical nystagmus and dysmetria were evident in most individuals.
• Deep tendon reflexes were usually increased, ankle clonus was easily elicited, and some affected individuals had extensor plantar responses [
• Strength and sensation were infrequently impaired [
• Gait impairment and other neurologic abnormalities were slowly progressive. Some individuals eventually required a wheelchair [
## Clinical Description
To date, 85 individuals from 36 families have been identified with a pathogenic variant in
Select Features of
HSCT = hematopoietic stem cell transplant; MDS = myelodysplasia
One or more of nystagmus, ataxia, pyramidal signs, neuropathy, abnormal brain imaging
Not all persons had neurologic evaluations or neuroimaging.
Biased by pediatric hematology ascertainment. Additional somatic genetic events (monosomy 7/7q, uniparental disomy 7, or pathogenic intragenic inactivating variants) may be found in cases without hematologic manifestations [
One additional case developed acute lymphocytic leukemia; it is unclear if this is related to
The manifestations of
The severities of hematologic and neurologic abnormalities are not concordant. An individual who died at age 16 years from a retroperitoneal bleed secondary to thrombocytopenia had no clinically reported neurologic manifestations, despite the presence of cerebellar atrophy. Several individuals had moderate-to-severe neurologic involvement with only mild or undetected hematologic involvement [
Mild thrombocytopenia or anemia and/or mild macrocytosis (maximum recorded mean corpuscular volume: 108 fL) were documented in many affected individuals.
Immunodeficiency was documented in two families [
Non-leukemic marrows were hypoplastic in multiple individuals examined.
Partial or complete monosomy 7 is frequent, with some having myelodysplasia; a few eventually developed leukemia [
The effect of the disease on the hematopoietic system accounts for the increased mortality. Of eight published cases of hematopoietic stem cell transplant for myelodysplasia, six survived the procedure and have been followed for as long as 14 years post transplant [
Onset of neurologic impairment ranged from infancy to age 62 years.
Horizontal and vertical nystagmus and dysmetria were evident in most individuals.
Deep tendon reflexes were usually increased, ankle clonus was easily elicited, and some affected individuals had extensor plantar responses [
Strength and sensation were infrequently impaired [
Gait impairment and other neurologic abnormalities were slowly progressive. Some individuals eventually required a wheelchair [
Multifocal electroretinography has identified mostly intact central function with paracentral retinal dysfunction in at least two affected individuals [
In the second family reported by
• Mild thrombocytopenia or anemia and/or mild macrocytosis (maximum recorded mean corpuscular volume: 108 fL) were documented in many affected individuals.
• Immunodeficiency was documented in two families [
• Non-leukemic marrows were hypoplastic in multiple individuals examined.
• Partial or complete monosomy 7 is frequent, with some having myelodysplasia; a few eventually developed leukemia [
• The effect of the disease on the hematopoietic system accounts for the increased mortality. Of eight published cases of hematopoietic stem cell transplant for myelodysplasia, six survived the procedure and have been followed for as long as 14 years post transplant [
• Onset of neurologic impairment ranged from infancy to age 62 years.
• Horizontal and vertical nystagmus and dysmetria were evident in most individuals.
• Deep tendon reflexes were usually increased, ankle clonus was easily elicited, and some affected individuals had extensor plantar responses [
• Strength and sensation were infrequently impaired [
• Gait impairment and other neurologic abnormalities were slowly progressive. Some individuals eventually required a wheelchair [
## Genotype-Phenotype Correlations
With respect to validated pathogenic variants in
## Penetrance
Given the variable expressivity of both hematologic and neurologic manifestations, the sometimes episodic asymptomatic cytopenias, the paucity of detailed neurologic/neuroimaging evaluations, and the effect of additional somatic genetic events on the hematologic manifestations (see
The phenomena of hematopoietic clones with additional genetic alterations repopulating the bone marrow appear to explain striking reports of non-penetrance or spontaneous and long-term disease remission in some affected individuals and some unaffected carrier parents of affected children [
## Nomenclature
The disorder was initially called myelocerebellar syndrome by
## Prevalence
True prevalence is unknown, but the disorder is rare. With increasing testing of children with myelodysplasia and individuals with both mild hematologic cytopenias and ataxia, additional cases continue to be diagnosed. Approximately 12% of childhood myelodysplasia is attributable to germline pathogenic variants in
## Genetically Related (Allelic) Disorders
Trio exome sequencing identified heterozygous
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of
Moderate hypochromic & microcytic anemia w/o progression to marrow failure
Not assoc w/malignancy
Progressive bone marrow failure
Myelodysplasia
Acute myeloid leukemia
Normal psychomotor development & neurologic function in most persons
See footnote 2 for exceptions.
Dysplastic nails
Lacy reticular pigmentation
Oral leukoplakia
Squamous cell carcinomas
Other solid tumors
Pulmonary fibrosis
Bone marrow failure
↑ risk for malignancy, particularly lymphocytic leukemia & lymphoma
Progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis
Early-onset dystonia in non-classic form
Immunodeficiency
Sensitivity to ionizing radiation
Telangiectasias
Progressive bone marrow failure
Myelodysplasia
Acute myeloid leukemia
Microcephaly
Ophthalmic abnormalities
Solid tumors
Congenital abnormalities
Chromosome breakage/radial forms on lymphocyte cytogenetic testing w/DEB & MMC
Myelodysplasia
Cytopenias
Adrenal hypoplasia
Growth restriction
Enteropathy
Genital abnormalities
AR = autosomal recessive; AD = autosomal dominant; DEB = diepoxybutane; MMC = mitomycin C; MOI = mode of inheritance; XL = X-linked
Spinocerebellar syndrome in males manifest primarily as delayed walking, ataxia evident in early childhood, dysmetria, and dysdiadochokinesis. When present the intention tremor is mild and the dysarthria is mild to moderately severe. The ataxia has been described as either non-progressive or slowly progressive.
Although most persons with dyskeratosis congenita have normal psychomotor development and normal neurologic function, significant developmental delay is present in the two variants in which additional findings include cerebellar hypoplasia (Hoyeraal Hreidarsson syndrome) and bilateral exudative retinopathy and intracranial calcifications (Revesz syndrome).
Twenty-one genes are known to be associated with Fanconi anemia (FA). Listed genes represent the most commonly associated genes. FA is inherited in an autosomal recessive manner with the exception of
The majority of individuals with FA have congenital abnormalities, most commonly short stature and skeletal, craniofacial, and genitourinary tract malformations. Abnormal skin pigmentation and microcephaly are also common. Other anomalies include developmental delay, hearing loss, congenital heart disease, and CNS anomalies.
• Moderate hypochromic & microcytic anemia w/o progression to marrow failure
• Not assoc w/malignancy
• Progressive bone marrow failure
• Myelodysplasia
• Acute myeloid leukemia
• Normal psychomotor development & neurologic function in most persons
• See footnote 2 for exceptions.
• Dysplastic nails
• Lacy reticular pigmentation
• Oral leukoplakia
• Squamous cell carcinomas
• Other solid tumors
• Pulmonary fibrosis
• Bone marrow failure
• ↑ risk for malignancy, particularly lymphocytic leukemia & lymphoma
• Progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis
• Early-onset dystonia in non-classic form
• Immunodeficiency
• Sensitivity to ionizing radiation
• Telangiectasias
• Progressive bone marrow failure
• Myelodysplasia
• Acute myeloid leukemia
• Microcephaly
• Ophthalmic abnormalities
• Solid tumors
• Congenital abnormalities
• Chromosome breakage/radial forms on lymphocyte cytogenetic testing w/DEB & MMC
• Myelodysplasia
• Cytopenias
• Adrenal hypoplasia
• Growth restriction
• Enteropathy
• Genital abnormalities
## Management
To establish the extent of disease and guide clinical care in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Bone marrow exam, incl FISH for chromosome 7
Consider referral to hematologist/oncologist.
Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades & smooth pursuit)
UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperrefflexia, amyotrophy, fasciculations)
Vibration loss or polyneuropathy based on clinical findings
Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).
Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy if sensory or motor abnormalities are detected.
Brain MRI to evaluate presence & severity of cerebellar atrophy
BARS = Brief Ataxia Rating Scale; FISH = fluorescent in situ hybridization; EMG = electromyogram; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; NCS = nerve conduction study; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
For example, fatigue, pallor, unexpected bleeding, recurrent infections
Treatment of Manifestations in Individuals with
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
Inpatient rehab w/OT/PT may improve ataxia & functional abilities in those w/severe ataxia.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
OT = occupational therapy; PT = physical therapy
There are no data to support use of erythropoietin or granulocyte-stimulating factor in
In ATXPC the red cells may be macrocytic and mimic B
Recommended Surveillance for Individuals with
Neurologic assessment for progression of ataxia
Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia & peripheral neuropathy
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
More frequent monitoring is required if an affected individual develops signs or symptoms of a cytopenia (e.g., fatigue, pallor, unexpected bleeding, recurrent infections) or if cytopenias are identified.
Nonsteroidal anti-inflammatory agents, anticoagulants, and thrombolytic agents are contraindicated if thrombocytopenia is present and should be used with caution given the fluctuating nature of the cytopenias.
Avoid consuming alcohol and medications that cause sedation, which can increase problems with gait and coordination.
It is appropriate to clarify the genetic status of the proband's parents and apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the
See
There is no information on the effect of pregnancy on manifestations of
Search
• Bone marrow exam, incl FISH for chromosome 7
• Consider referral to hematologist/oncologist.
• Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades & smooth pursuit)
• UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperrefflexia, amyotrophy, fasciculations)
• Vibration loss or polyneuropathy based on clinical findings
• Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).
• Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy if sensory or motor abnormalities are detected.
• Brain MRI to evaluate presence & severity of cerebellar atrophy
• 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
• Inpatient rehab w/OT/PT may improve ataxia & functional abilities in those w/severe ataxia.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Neurologic assessment for progression of ataxia
• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
• Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia & peripheral neuropathy
## Evaluations Following Initial Diagnosis
To establish the extent of disease and guide clinical care in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
Bone marrow exam, incl FISH for chromosome 7
Consider referral to hematologist/oncologist.
Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades & smooth pursuit)
UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperrefflexia, amyotrophy, fasciculations)
Vibration loss or polyneuropathy based on clinical findings
Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).
Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy if sensory or motor abnormalities are detected.
Brain MRI to evaluate presence & severity of cerebellar atrophy
BARS = Brief Ataxia Rating Scale; FISH = fluorescent in situ hybridization; EMG = electromyogram; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; NCS = nerve conduction study; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
For example, fatigue, pallor, unexpected bleeding, recurrent infections
• Bone marrow exam, incl FISH for chromosome 7
• Consider referral to hematologist/oncologist.
• Cerebellar motor dysfunction (gait & postural ataxia, dysmetria, dysdiadochokinesis, tremor, dysarthria, nystagmus, saccades & smooth pursuit)
• UMN &/or LMN dysfunction (weakness, spasticity, Babinski signs, hyperrefflexia, amyotrophy, fasciculations)
• Vibration loss or polyneuropathy based on clinical findings
• Use standardized scale to establish baseline for ataxia (SARA, ICARS, or BARS).
• Consider electrophysiologic studies (EMG & NCS) to detect neurogenic changes or signs of neuropathy if sensory or motor abnormalities are detected.
• Brain MRI to evaluate presence & severity of cerebellar atrophy
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
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
Inpatient rehab w/OT/PT may improve ataxia & functional abilities in those w/severe ataxia.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
OT = occupational therapy; PT = physical therapy
There are no data to support use of erythropoietin or granulocyte-stimulating factor in
In ATXPC the red cells may be macrocytic and mimic B
• 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
• Inpatient rehab w/OT/PT may improve ataxia & functional abilities in those w/severe ataxia.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
## Surveillance
Recommended Surveillance for Individuals with
Neurologic assessment for progression of ataxia
Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia & peripheral neuropathy
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
More frequent monitoring is required if an affected individual develops signs or symptoms of a cytopenia (e.g., fatigue, pallor, unexpected bleeding, recurrent infections) or if cytopenias are identified.
• Neurologic assessment for progression of ataxia
• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
• Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia & peripheral neuropathy
## Agents/Circumstances to Avoid
Nonsteroidal anti-inflammatory agents, anticoagulants, and thrombolytic agents are contraindicated if thrombocytopenia is present and should be used with caution given the fluctuating nature of the cytopenias.
Avoid consuming alcohol and medications that cause sedation, which can increase problems with gait and coordination.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of the proband's parents and apparently asymptomatic older and younger at-risk relatives of an affected individual by molecular genetic testing of the
See
## Pregnancy Management
There is no information on the effect of pregnancy on manifestations of
## Therapies Under Investigation
Search
## Genetic Counseling
Many individuals diagnosed with
Some individuals diagnosed with
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, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline mosaicism.
The proband inherited a
The family history of an individual diagnosed with
If a parent of the proband is heterozygous for the
If the
Parental germline mosaicism for the
A false negative result in a parent due to preferential loss of the chromosome with the
If the parents have not been tested for the
A parent has germline mosaicism; or
A parent is heterozygous but does not have apparent manifestations of
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.
• Many individuals diagnosed with
• Some individuals diagnosed with
• 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, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a
• The family history of an individual diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a
• If a parent of the proband is heterozygous for the
• If the
• Parental germline mosaicism for the
• A false negative result in a parent due to preferential loss of the chromosome with the
• Parental germline mosaicism for the
• A false negative result in a parent due to preferential loss of the chromosome with the
• If the parents have not been tested for the
• A parent has germline mosaicism; or
• A parent is heterozygous but does not have apparent manifestations of
• A parent has germline mosaicism; or
• A parent is heterozygous but does not have apparent manifestations of
• Parental germline mosaicism for the
• A false negative result in a parent due to preferential loss of the chromosome with the
• A parent has germline mosaicism; or
• A parent is heterozygous but does not have apparent manifestations 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.
## Mode of Inheritance
## Risk to Family Members
Many individuals diagnosed with
Some individuals diagnosed with
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, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a parent with germline mosaicism.
The proband inherited a
The family history of an individual diagnosed with
If a parent of the proband is heterozygous for the
If the
Parental germline mosaicism for the
A false negative result in a parent due to preferential loss of the chromosome with the
If the parents have not been tested for the
A parent has germline mosaicism; or
A parent is heterozygous but does not have apparent manifestations of
• Many individuals diagnosed with
• Some individuals diagnosed with
• 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, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a
• The family history of an individual diagnosed with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline mosaicism.
• The proband inherited a
• If a parent of the proband is heterozygous for the
• If the
• Parental germline mosaicism for the
• A false negative result in a parent due to preferential loss of the chromosome with the
• Parental germline mosaicism for the
• A false negative result in a parent due to preferential loss of the chromosome with the
• If the parents have not been tested for the
• A parent has germline mosaicism; or
• A parent is heterozygous but does not have apparent manifestations of
• A parent has germline mosaicism; or
• A parent is heterozygous but does not have apparent manifestations of
• Parental germline mosaicism for the
• A false negative result in a parent due to preferential loss of the chromosome with the
• A parent has germline mosaicism; or
• A parent is heterozygous but does not have apparent manifestations of
## 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
4330 East West Highway
Suite 230
Bethesda MD 20814
•
• 4330 East West Highway
• Suite 230
• Bethesda MD 20814
•
•
•
## Molecular Genetics
SAMD9L Ataxia-Pancytopenia Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SAMD9L Ataxia-Pancytopenia Syndrome (
The role of SAMD9L in human bone marrow failure and malignancies is not known with certainty nor is the underlying cause of the varied neurologic manifestations. Many lines of evidence in primary tumors, cell cultures, and murine models show that SAMD9L has a role in cell proliferation, most likely as a tumor suppressor [
There are two prevailing hypotheses regarding the mechanism by which mutated SAMD9L impairs cell growth. One theory is that SAMD9L is involved in endosomal degradation of cytokine receptors [
Studies in EBV-transformed leukocyte cell lines [
The loss of all or part of the chromosome 7 that bears the pathogenic allele. Unfortunately, monosomy for chromosome 7q also causes haploinsufficiency for
All or part of the chromosome 7 bearing the gain-of-function pathogenic variant can be replaced by the normal copy of chromosome 7 via copy-neutral loss of heterozygosity (cnLOH; uniparental disomy) [
The latter two phenomena, of somatic revertant clones repopulating the bone marrow, appear to explain striking reports of spontaneous long-term disease remission and of non-penetrance in some affected individuals and some unaffected carrier parents of affected children, respectively [
• The loss of all or part of the chromosome 7 that bears the pathogenic allele. Unfortunately, monosomy for chromosome 7q also causes haploinsufficiency for
• All or part of the chromosome 7 bearing the gain-of-function pathogenic variant can be replaced by the normal copy of chromosome 7 via copy-neutral loss of heterozygosity (cnLOH; uniparental disomy) [
## Molecular Pathogenesis
The role of SAMD9L in human bone marrow failure and malignancies is not known with certainty nor is the underlying cause of the varied neurologic manifestations. Many lines of evidence in primary tumors, cell cultures, and murine models show that SAMD9L has a role in cell proliferation, most likely as a tumor suppressor [
There are two prevailing hypotheses regarding the mechanism by which mutated SAMD9L impairs cell growth. One theory is that SAMD9L is involved in endosomal degradation of cytokine receptors [
Studies in EBV-transformed leukocyte cell lines [
The loss of all or part of the chromosome 7 that bears the pathogenic allele. Unfortunately, monosomy for chromosome 7q also causes haploinsufficiency for
All or part of the chromosome 7 bearing the gain-of-function pathogenic variant can be replaced by the normal copy of chromosome 7 via copy-neutral loss of heterozygosity (cnLOH; uniparental disomy) [
The latter two phenomena, of somatic revertant clones repopulating the bone marrow, appear to explain striking reports of spontaneous long-term disease remission and of non-penetrance in some affected individuals and some unaffected carrier parents of affected children, respectively [
• The loss of all or part of the chromosome 7 that bears the pathogenic allele. Unfortunately, monosomy for chromosome 7q also causes haploinsufficiency for
• All or part of the chromosome 7 bearing the gain-of-function pathogenic variant can be replaced by the normal copy of chromosome 7 via copy-neutral loss of heterozygosity (cnLOH; uniparental disomy) [
## Chapter Notes
The focus of research in the Raskind laboratory is to find and study genes responsible for inherited neurologic disorders. In a long-standing collaboration with Dr Thomas Bird, we identified
Thomas D Bird, MD (2017-present)Dong-Hui Chen, MD, PhD (2017-present)Prasit Phowthongkum, MD; University of Washington (2017-2021)Wendy H Raskind, MD, PhD (2017-present)
4 February 2021 (ma) Comprehensive update posted live
1 June 2017 (sw) Review posted live
5 December 2016 (whr) Original submission
• 4 February 2021 (ma) Comprehensive update posted live
• 1 June 2017 (sw) Review posted live
• 5 December 2016 (whr) Original submission
## Author Notes
The focus of research in the Raskind laboratory is to find and study genes responsible for inherited neurologic disorders. In a long-standing collaboration with Dr Thomas Bird, we identified
## Author History
Thomas D Bird, MD (2017-present)Dong-Hui Chen, MD, PhD (2017-present)Prasit Phowthongkum, MD; University of Washington (2017-2021)Wendy H Raskind, MD, PhD (2017-present)
## Revision History
4 February 2021 (ma) Comprehensive update posted live
1 June 2017 (sw) Review posted live
5 December 2016 (whr) Original submission
• 4 February 2021 (ma) Comprehensive update posted live
• 1 June 2017 (sw) Review posted live
• 5 December 2016 (whr) Original submission
## References
## Literature Cited
|
[] |
1/6/2017
|
4/2/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sandhoff
|
sandhoff
|
[
"Type II GM2 Gangliosidosis",
"Type II GM2 Gangliosidosis",
"Acute Infantile Sandhoff Disease",
"Subacute Juvenile Sandhoff Disease",
"Late-Onset Sandhoff Disease",
"Beta-hexosaminidase subunit beta",
"HEXB",
"Sandhoff Disease"
] |
Sandhoff Disease
|
Changrui Xiao, Cynthia Tifft, Camilo Toro
|
Summary Sandhoff disease comprises a phenotypic continuum encompassing acute infantile, subacute juvenile, and late-onset disease. Although classification into these phenotypes is somewhat arbitrary, it is helpful in understanding the variation observed in the timing of disease onset, presenting manifestations, rate of progression, and life span. In a proband, the diagnosis of Sandhoff disease is established by: (1) enzymatic testing that identifies abnormally low activity of the enzymes beta-hexosaminidase A (HEX A) and beta-hexosaminidase B (HEX B) combined with an increased contribution from HEX A; and (2) identification biallelic pathogenic variants in Sandhoff disease is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
Acute infantile Sandhoff disease
Subacute juvenile Sandhoff disease
Late-onset Sandhoff disease
For synonyms and outdated names see
For other genetic causes of these phenotypes see
• Acute infantile Sandhoff disease
• Subacute juvenile Sandhoff disease
• Late-onset Sandhoff disease
## Diagnosis
No consensus clinical diagnostic criteria for Sandhoff disease have been published.
Progressive weakness or loss of motor skills
Decreased attentiveness
Exaggerated startle response
Hypotonia
Hyperreflexia
Seizures
Cherry-red macula (seen in virtually all children with infantile disease)
Progressive macrocephaly
Hepatosplenomegaly
Hyperintense T
Cortical atrophy, thinning of the corpus callosum, and abnormal MRI signal intensity in the caudate, globus pallidus, putamen, cerebellum, and brain stem [
Developmental plateauing followed by regression
Progressive spasticity, dysarthria, and dysphagia
Seizures
Absence of hepatosplenomegaly
Progressive lower motor neuronopathy with progressive lower-extremity weakness (primarily knee extensors and hip flexors) with atrophy, fasciculations, balance issues, tremors, and/or ataxia
Distal sensory neuropathy
Progressive dysarthria
Neurocognitive decline including cognition
Absence of hepatosplenomegaly
Cerebellar atrophy, less prominent than in
Mild cortical atrophy [
Generalized spinal cord atrophy and normal imaging [
In all phenotypes, 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 Sandhoff disease
Abnormally low activity of the enzymes beta-hexosaminidase A (HEX A) and beta-hexosaminidase B (HEX B) combined with elevated-percent contribution from HEX A; and
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 [
In individuals with Sandhoff disease, testing of enzymatic activity of HEX A and HEX B in serum, white blood cells, or other tissues reveals absent to near-absent activity of HEX A and HEX B (i.e., total hexosaminidase), and a normal- or elevated-percent contribution from HEX A [
Individuals with acute infantile Sandhoff disease have absent to near-absent HEX A and HEX B activity.
Individuals with subacute juvenile or late-onset Sandhoff disease have some residual HEX A and HEX B activity.
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 Sandhoff disease is broad, infants with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of Sandhoff disease, 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 slowly progressive neurodegeneration,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sandhoff 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.
•
• Progressive weakness or loss of motor skills
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Progressive weakness or loss of motor skills
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
•
• Cherry-red macula (seen in virtually all children with infantile disease)
• Progressive macrocephaly
• Hepatosplenomegaly
• Cherry-red macula (seen in virtually all children with infantile disease)
• Progressive macrocephaly
• Hepatosplenomegaly
• Progressive weakness or loss of motor skills
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Cherry-red macula (seen in virtually all children with infantile disease)
• Progressive macrocephaly
• Hepatosplenomegaly
• Hyperintense T
• Cortical atrophy, thinning of the corpus callosum, and abnormal MRI signal intensity in the caudate, globus pallidus, putamen, cerebellum, and brain stem [
• Developmental plateauing followed by regression
• Progressive spasticity, dysarthria, and dysphagia
• Seizures
• Absence of hepatosplenomegaly
• Progressive lower motor neuronopathy with progressive lower-extremity weakness (primarily knee extensors and hip flexors) with atrophy, fasciculations, balance issues, tremors, and/or ataxia
• Distal sensory neuropathy
• Progressive dysarthria
• Neurocognitive decline including cognition
• Absence of hepatosplenomegaly
• Cerebellar atrophy, less prominent than in
• Mild cortical atrophy [
• Generalized spinal cord atrophy and normal imaging [
• Abnormally low activity of the enzymes beta-hexosaminidase A (HEX A) and beta-hexosaminidase B (HEX B) combined with elevated-percent contribution from HEX A; and
• Biallelic pathogenic (or likely pathogenic) variants in
• Individuals with acute infantile Sandhoff disease have absent to near-absent HEX A and HEX B activity.
• Individuals with subacute juvenile or late-onset Sandhoff disease have some residual HEX A and HEX B activity.
• For an introduction to multigene panels click
## Suggestive Findings
Progressive weakness or loss of motor skills
Decreased attentiveness
Exaggerated startle response
Hypotonia
Hyperreflexia
Seizures
Cherry-red macula (seen in virtually all children with infantile disease)
Progressive macrocephaly
Hepatosplenomegaly
Hyperintense T
Cortical atrophy, thinning of the corpus callosum, and abnormal MRI signal intensity in the caudate, globus pallidus, putamen, cerebellum, and brain stem [
Developmental plateauing followed by regression
Progressive spasticity, dysarthria, and dysphagia
Seizures
Absence of hepatosplenomegaly
Progressive lower motor neuronopathy with progressive lower-extremity weakness (primarily knee extensors and hip flexors) with atrophy, fasciculations, balance issues, tremors, and/or ataxia
Distal sensory neuropathy
Progressive dysarthria
Neurocognitive decline including cognition
Absence of hepatosplenomegaly
Cerebellar atrophy, less prominent than in
Mild cortical atrophy [
Generalized spinal cord atrophy and normal imaging [
In all phenotypes, 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.
•
• Progressive weakness or loss of motor skills
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Progressive weakness or loss of motor skills
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
•
• Cherry-red macula (seen in virtually all children with infantile disease)
• Progressive macrocephaly
• Hepatosplenomegaly
• Cherry-red macula (seen in virtually all children with infantile disease)
• Progressive macrocephaly
• Hepatosplenomegaly
• Progressive weakness or loss of motor skills
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Cherry-red macula (seen in virtually all children with infantile disease)
• Progressive macrocephaly
• Hepatosplenomegaly
• Hyperintense T
• Cortical atrophy, thinning of the corpus callosum, and abnormal MRI signal intensity in the caudate, globus pallidus, putamen, cerebellum, and brain stem [
• Developmental plateauing followed by regression
• Progressive spasticity, dysarthria, and dysphagia
• Seizures
• Absence of hepatosplenomegaly
• Progressive lower motor neuronopathy with progressive lower-extremity weakness (primarily knee extensors and hip flexors) with atrophy, fasciculations, balance issues, tremors, and/or ataxia
• Distal sensory neuropathy
• Progressive dysarthria
• Neurocognitive decline including cognition
• Absence of hepatosplenomegaly
• Cerebellar atrophy, less prominent than in
• Mild cortical atrophy [
• Generalized spinal cord atrophy and normal imaging [
## Acute Infantile Sandhoff Disease (onset age <6 months)
Progressive weakness or loss of motor skills
Decreased attentiveness
Exaggerated startle response
Hypotonia
Hyperreflexia
Seizures
Cherry-red macula (seen in virtually all children with infantile disease)
Progressive macrocephaly
Hepatosplenomegaly
Hyperintense T
Cortical atrophy, thinning of the corpus callosum, and abnormal MRI signal intensity in the caudate, globus pallidus, putamen, cerebellum, and brain stem [
•
• Progressive weakness or loss of motor skills
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Progressive weakness or loss of motor skills
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
•
• Cherry-red macula (seen in virtually all children with infantile disease)
• Progressive macrocephaly
• Hepatosplenomegaly
• Cherry-red macula (seen in virtually all children with infantile disease)
• Progressive macrocephaly
• Hepatosplenomegaly
• Progressive weakness or loss of motor skills
• Decreased attentiveness
• Exaggerated startle response
• Hypotonia
• Hyperreflexia
• Seizures
• Cherry-red macula (seen in virtually all children with infantile disease)
• Progressive macrocephaly
• Hepatosplenomegaly
• Hyperintense T
• Cortical atrophy, thinning of the corpus callosum, and abnormal MRI signal intensity in the caudate, globus pallidus, putamen, cerebellum, and brain stem [
## Subacute Juvenile Sandhoff Disease (onset age 2-5 years)
Developmental plateauing followed by regression
Progressive spasticity, dysarthria, and dysphagia
Seizures
Absence of hepatosplenomegaly
• Developmental plateauing followed by regression
• Progressive spasticity, dysarthria, and dysphagia
• Seizures
• Absence of hepatosplenomegaly
## Late-Onset Sandhoff Disease (onset later teens – young adulthood)
Progressive lower motor neuronopathy with progressive lower-extremity weakness (primarily knee extensors and hip flexors) with atrophy, fasciculations, balance issues, tremors, and/or ataxia
Distal sensory neuropathy
Progressive dysarthria
Neurocognitive decline including cognition
Absence of hepatosplenomegaly
Cerebellar atrophy, less prominent than in
Mild cortical atrophy [
Generalized spinal cord atrophy and normal imaging [
• Progressive lower motor neuronopathy with progressive lower-extremity weakness (primarily knee extensors and hip flexors) with atrophy, fasciculations, balance issues, tremors, and/or ataxia
• Distal sensory neuropathy
• Progressive dysarthria
• Neurocognitive decline including cognition
• Absence of hepatosplenomegaly
• Cerebellar atrophy, less prominent than in
• Mild cortical atrophy [
• Generalized spinal cord atrophy and normal imaging [
## Family History
In all phenotypes, 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 Sandhoff disease
Abnormally low activity of the enzymes beta-hexosaminidase A (HEX A) and beta-hexosaminidase B (HEX B) combined with elevated-percent contribution from HEX A; and
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 [
In individuals with Sandhoff disease, testing of enzymatic activity of HEX A and HEX B in serum, white blood cells, or other tissues reveals absent to near-absent activity of HEX A and HEX B (i.e., total hexosaminidase), and a normal- or elevated-percent contribution from HEX A [
Individuals with acute infantile Sandhoff disease have absent to near-absent HEX A and HEX B activity.
Individuals with subacute juvenile or late-onset Sandhoff disease have some residual HEX A and HEX B activity.
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 Sandhoff disease is broad, infants with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of Sandhoff disease, 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 slowly progressive neurodegeneration,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sandhoff 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.
• Abnormally low activity of the enzymes beta-hexosaminidase A (HEX A) and beta-hexosaminidase B (HEX B) combined with elevated-percent contribution from HEX A; and
• Biallelic pathogenic (or likely pathogenic) variants in
• Individuals with acute infantile Sandhoff disease have absent to near-absent HEX A and HEX B activity.
• Individuals with subacute juvenile or late-onset Sandhoff disease have some residual HEX A and HEX B activity.
• For an introduction to multigene panels click
## Enzymatic Activity Testing
In individuals with Sandhoff disease, testing of enzymatic activity of HEX A and HEX B in serum, white blood cells, or other tissues reveals absent to near-absent activity of HEX A and HEX B (i.e., total hexosaminidase), and a normal- or elevated-percent contribution from HEX A [
Individuals with acute infantile Sandhoff disease have absent to near-absent HEX A and HEX B activity.
Individuals with subacute juvenile or late-onset Sandhoff disease have some residual HEX A and HEX B activity.
• Individuals with acute infantile Sandhoff disease have absent to near-absent HEX A and HEX B activity.
• Individuals with subacute juvenile or late-onset Sandhoff disease have some residual HEX A and HEX B activity.
## 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. Because the phenotype of Sandhoff disease is broad, infants with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of Sandhoff disease, 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 slowly progressive neurodegeneration,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sandhoff 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.
• For an introduction to multigene panels click
##
When the phenotypic and laboratory findings suggest the diagnosis of Sandhoff disease, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
##
When the phenotype is indistinguishable from many other inherited disorders characterized by slowly progressive neurodegeneration,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sandhoff 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.
## Clinical Characteristics
The phenotypes of Sandhoff disease comprise a continuum ranging from acute infantile to subacute juvenile and late-onset Sandhoff disease. Although classification into these phenotypes is somewhat arbitrary, the classification is helpful in understanding the variation observed in the timing of disease onset, presenting manifestations, rate of progression, and life span.
Despite numerous case reports of individuals with Sandhoff disease from specific ethnic backgrounds, few prospective studies have delineated the progression of disease by phenotype.
Affected infants are generally normal at birth. Progressive weakness, exaggerated startle, and slowing of developmental progress is typically noted between ages three and six 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 children with infantile-onset disease.
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.
Typically, progressive enlargement of the head resulting from reactive cerebral gliosis beginning by age 18 months is eventually followed by ventriculomegaly [
Further deterioration in the second year of life results in decerebrate posturing, difficulty in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death from respiratory complications usually occurs between ages two and three year; however, the use of a gastrostomy tube to minimize aspiration events and the use of vibrating vests to improve pulmonary hygiene have extended the life span by five to seven years [
Children attain developmental milestones normally until about age two years. Between ages two and five years, the rate of motor and speech development slows and eventually plateaus. Abnormal gait and/or dysarthria begin to emerge, followed by loss of previously acquired skills and cognitive decline.
Spasticity, dysphagia, and seizures are present by age ten years [
Decreased visual acuity occurs much later than in the acute infantile form. A cherry-red macula is rarely observed. Optic atrophy and retinal pigmentation may be seen late in the disease course.
Episodic neuropathic pain or dysesthesia especially in the fingers and toes (acroparesthesia), neuropathy, and dysautonomia are common, and can be presenting manifestations [
By age ten to 15 years, many individuals are in a vegetative state with decerebrate posturing, followed within a few years by death usually from aspiration. Newer measures in supportive care that protect airways and improve pulmonary hygiene may extend the life span.
In some individuals, the disease course is particularly rapid, culminating in death within two to four years of initial manifestations.
Affected individuals present with a slowly progressive spectrum of neurologic and psychiatric manifestations as older teenagers or young adults. Following diagnosis, many affected individuals and/or parents/caregivers describe earlier nonspecific subtle manifestations, such as clumsiness or developmental concerns.
Most affected individuals achieve nearly normal milestones into adulthood and the disorder progresses slowly over decades. The presentation may resemble that of other neurodegenerative conditions of adults, especially
Progressive motor neuronopathy, experienced by most (if not all) affected individuals, leads to muscle weakness and wasting. Muscle cramps, atrophy, and fasciculations are common. Early weakness primarily involves the lower extremities, particularly the knee extensors and hip flexors. Affected individuals have progressive difficulty in climbing steps or long flights of stairs, eventually requiring the aid of handrails. As knee extensor weakness progresses, affected individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain the locked knees results in collapse and injury, which frequently leads to early need for assistive devices or knee braces.
Upper-extremity strength may be affected years later with a predilection for triceps weakness, which affects elbow extension.
Long tract findings including spasticity, extensor plantar reflexes, and brisk reflexes can be present, but may be obscured by lower motor neuron weakness.
A peripheral sensory neuropathy that starts distally but can expand proximally is common [
Dysarthria. The speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. While poor articulation results primarily from cerebellar dysfunction, associated features can include focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Some individuals do not develop dysarthria despite substantial weakness.
Note: Dysphagia and aspiration events are not common.
Cerebellar dysfunction. Decreased balance can be associated with a wide base of support, decreased dexterity, and tremors. These findings plus saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination are attributed – at least in part – to cerebellar dysfunction [
Deficits in executive function and memory, reported in some individuals, can be associated with progressive brain volume loss; however, decline in higher cortical functioning develops slowly, often over decades after onset of disease manifestations.
Psychiatric manifestations such as psychosis and mania have exclusively been reported in the context of hexosaminidase A (HEX A) deficiency (in contrast to other GM2 gangliosidoses) [
Affective manifestations such as depression and/or anxiety, which can be present in individuals with Sandhoff disease as well, may represent part of a cerebellar affective syndrome [
In the absence of dysphagia or frequent falls, life expectancy is not necessarily reduced.
The following
In general, individuals with two null (nonexpressing) variants have the acute infantile phenotype, individuals with one null variant and one missense variant have the subacute juvenile phenotype, and individuals with two missense variants have the late-onset phenotype. This reflects the inverse correlation of the level of the residual hexosaminidase B (HEX B) enzyme activity with disease severity: the lower the enzymatic activity, the more severe the phenotype is likely to be. Nonetheless, clinical variability can be observed among family members with the subacute juvenile and late-onset phenotypes.
Sandhoff disease was one of several disorders, including Tay-Sachs disease and GM2 activator deficiency, formerly referred to collectively as "amaurotic idiocy." Once GM2 ganglioside was identified as the major accumulating substrate, the terms "infantile ganglioside lipidosis" and "GM2 gangliosidosis" were introduced. Likewise, when the relationship between the enzymatic activity of HEX A and HEX B was identified, the terms "hexosaminidase B deficiency" and "hexosaminidase A and B deficiency" were introduced.
To distinguish Sandhoff disease from Tay-Sachs disease and GM2 activator deficiency – both of which also involve GM2 ganglioside accumulation due to a shared biochemical pathway for the enzymes involved – Sandhoff disease is also referred to as "GM2 gangliosidosis type II" or "GM2 gangliosidosis variant 0."
The prevalence of Sandhoff disease in the general population is not known. The estimated prevalence is around 1:500,000 to 1:1,500,000 depending on the population studied [
Populations reported to have an increased prevalence of acute infantile Sandhoff disease include the following (see
Maronite community in Cypress [
Individuals of Métis ancestry in northern Saskatchewan [
Creole population in northern Argentina [
• Progressive motor neuronopathy, experienced by most (if not all) affected individuals, leads to muscle weakness and wasting. Muscle cramps, atrophy, and fasciculations are common. Early weakness primarily involves the lower extremities, particularly the knee extensors and hip flexors. Affected individuals have progressive difficulty in climbing steps or long flights of stairs, eventually requiring the aid of handrails. As knee extensor weakness progresses, affected individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain the locked knees results in collapse and injury, which frequently leads to early need for assistive devices or knee braces.
• Upper-extremity strength may be affected years later with a predilection for triceps weakness, which affects elbow extension.
• Long tract findings including spasticity, extensor plantar reflexes, and brisk reflexes can be present, but may be obscured by lower motor neuron weakness.
• A peripheral sensory neuropathy that starts distally but can expand proximally is common [
• Dysarthria. The speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. While poor articulation results primarily from cerebellar dysfunction, associated features can include focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Some individuals do not develop dysarthria despite substantial weakness.
• Note: Dysphagia and aspiration events are not common.
• Cerebellar dysfunction. Decreased balance can be associated with a wide base of support, decreased dexterity, and tremors. These findings plus saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination are attributed – at least in part – to cerebellar dysfunction [
• Deficits in executive function and memory, reported in some individuals, can be associated with progressive brain volume loss; however, decline in higher cortical functioning develops slowly, often over decades after onset of disease manifestations.
• Psychiatric manifestations such as psychosis and mania have exclusively been reported in the context of hexosaminidase A (HEX A) deficiency (in contrast to other GM2 gangliosidoses) [
• Affective manifestations such as depression and/or anxiety, which can be present in individuals with Sandhoff disease as well, may represent part of a cerebellar affective syndrome [
•
•
•
• Maronite community in Cypress [
• Individuals of Métis ancestry in northern Saskatchewan [
• Creole population in northern Argentina [
## Clinical Description
The phenotypes of Sandhoff disease comprise a continuum ranging from acute infantile to subacute juvenile and late-onset Sandhoff disease. Although classification into these phenotypes is somewhat arbitrary, the classification is helpful in understanding the variation observed in the timing of disease onset, presenting manifestations, rate of progression, and life span.
Despite numerous case reports of individuals with Sandhoff disease from specific ethnic backgrounds, few prospective studies have delineated the progression of disease by phenotype.
Affected infants are generally normal at birth. Progressive weakness, exaggerated startle, and slowing of developmental progress is typically noted between ages three and six 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 children with infantile-onset disease.
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.
Typically, progressive enlargement of the head resulting from reactive cerebral gliosis beginning by age 18 months is eventually followed by ventriculomegaly [
Further deterioration in the second year of life results in decerebrate posturing, difficulty in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death from respiratory complications usually occurs between ages two and three year; however, the use of a gastrostomy tube to minimize aspiration events and the use of vibrating vests to improve pulmonary hygiene have extended the life span by five to seven years [
Children attain developmental milestones normally until about age two years. Between ages two and five years, the rate of motor and speech development slows and eventually plateaus. Abnormal gait and/or dysarthria begin to emerge, followed by loss of previously acquired skills and cognitive decline.
Spasticity, dysphagia, and seizures are present by age ten years [
Decreased visual acuity occurs much later than in the acute infantile form. A cherry-red macula is rarely observed. Optic atrophy and retinal pigmentation may be seen late in the disease course.
Episodic neuropathic pain or dysesthesia especially in the fingers and toes (acroparesthesia), neuropathy, and dysautonomia are common, and can be presenting manifestations [
By age ten to 15 years, many individuals are in a vegetative state with decerebrate posturing, followed within a few years by death usually from aspiration. Newer measures in supportive care that protect airways and improve pulmonary hygiene may extend the life span.
In some individuals, the disease course is particularly rapid, culminating in death within two to four years of initial manifestations.
Affected individuals present with a slowly progressive spectrum of neurologic and psychiatric manifestations as older teenagers or young adults. Following diagnosis, many affected individuals and/or parents/caregivers describe earlier nonspecific subtle manifestations, such as clumsiness or developmental concerns.
Most affected individuals achieve nearly normal milestones into adulthood and the disorder progresses slowly over decades. The presentation may resemble that of other neurodegenerative conditions of adults, especially
Progressive motor neuronopathy, experienced by most (if not all) affected individuals, leads to muscle weakness and wasting. Muscle cramps, atrophy, and fasciculations are common. Early weakness primarily involves the lower extremities, particularly the knee extensors and hip flexors. Affected individuals have progressive difficulty in climbing steps or long flights of stairs, eventually requiring the aid of handrails. As knee extensor weakness progresses, affected individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain the locked knees results in collapse and injury, which frequently leads to early need for assistive devices or knee braces.
Upper-extremity strength may be affected years later with a predilection for triceps weakness, which affects elbow extension.
Long tract findings including spasticity, extensor plantar reflexes, and brisk reflexes can be present, but may be obscured by lower motor neuron weakness.
A peripheral sensory neuropathy that starts distally but can expand proximally is common [
Dysarthria. The speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. While poor articulation results primarily from cerebellar dysfunction, associated features can include focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Some individuals do not develop dysarthria despite substantial weakness.
Note: Dysphagia and aspiration events are not common.
Cerebellar dysfunction. Decreased balance can be associated with a wide base of support, decreased dexterity, and tremors. These findings plus saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination are attributed – at least in part – to cerebellar dysfunction [
Deficits in executive function and memory, reported in some individuals, can be associated with progressive brain volume loss; however, decline in higher cortical functioning develops slowly, often over decades after onset of disease manifestations.
Psychiatric manifestations such as psychosis and mania have exclusively been reported in the context of hexosaminidase A (HEX A) deficiency (in contrast to other GM2 gangliosidoses) [
Affective manifestations such as depression and/or anxiety, which can be present in individuals with Sandhoff disease as well, may represent part of a cerebellar affective syndrome [
In the absence of dysphagia or frequent falls, life expectancy is not necessarily reduced.
• Progressive motor neuronopathy, experienced by most (if not all) affected individuals, leads to muscle weakness and wasting. Muscle cramps, atrophy, and fasciculations are common. Early weakness primarily involves the lower extremities, particularly the knee extensors and hip flexors. Affected individuals have progressive difficulty in climbing steps or long flights of stairs, eventually requiring the aid of handrails. As knee extensor weakness progresses, affected individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain the locked knees results in collapse and injury, which frequently leads to early need for assistive devices or knee braces.
• Upper-extremity strength may be affected years later with a predilection for triceps weakness, which affects elbow extension.
• Long tract findings including spasticity, extensor plantar reflexes, and brisk reflexes can be present, but may be obscured by lower motor neuron weakness.
• A peripheral sensory neuropathy that starts distally but can expand proximally is common [
• Dysarthria. The speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. While poor articulation results primarily from cerebellar dysfunction, associated features can include focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Some individuals do not develop dysarthria despite substantial weakness.
• Note: Dysphagia and aspiration events are not common.
• Cerebellar dysfunction. Decreased balance can be associated with a wide base of support, decreased dexterity, and tremors. These findings plus saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination are attributed – at least in part – to cerebellar dysfunction [
• Deficits in executive function and memory, reported in some individuals, can be associated with progressive brain volume loss; however, decline in higher cortical functioning develops slowly, often over decades after onset of disease manifestations.
• Psychiatric manifestations such as psychosis and mania have exclusively been reported in the context of hexosaminidase A (HEX A) deficiency (in contrast to other GM2 gangliosidoses) [
• Affective manifestations such as depression and/or anxiety, which can be present in individuals with Sandhoff disease as well, may represent part of a cerebellar affective syndrome [
## Acute Infantile Sandhoff Disease
Affected infants are generally normal at birth. Progressive weakness, exaggerated startle, and slowing of developmental progress is typically noted between ages three and six 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 children with infantile-onset disease.
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.
Typically, progressive enlargement of the head resulting from reactive cerebral gliosis beginning by age 18 months is eventually followed by ventriculomegaly [
Further deterioration in the second year of life results in decerebrate posturing, difficulty in swallowing, worsening seizures, and finally an unresponsive, vegetative state. Death from respiratory complications usually occurs between ages two and three year; however, the use of a gastrostomy tube to minimize aspiration events and the use of vibrating vests to improve pulmonary hygiene have extended the life span by five to seven years [
## Subacute Juvenile Sandhoff Disease
Children attain developmental milestones normally until about age two years. Between ages two and five years, the rate of motor and speech development slows and eventually plateaus. Abnormal gait and/or dysarthria begin to emerge, followed by loss of previously acquired skills and cognitive decline.
Spasticity, dysphagia, and seizures are present by age ten years [
Decreased visual acuity occurs much later than in the acute infantile form. A cherry-red macula is rarely observed. Optic atrophy and retinal pigmentation may be seen late in the disease course.
Episodic neuropathic pain or dysesthesia especially in the fingers and toes (acroparesthesia), neuropathy, and dysautonomia are common, and can be presenting manifestations [
By age ten to 15 years, many individuals are in a vegetative state with decerebrate posturing, followed within a few years by death usually from aspiration. Newer measures in supportive care that protect airways and improve pulmonary hygiene may extend the life span.
In some individuals, the disease course is particularly rapid, culminating in death within two to four years of initial manifestations.
## Late-Onset Sandhoff Disease
Affected individuals present with a slowly progressive spectrum of neurologic and psychiatric manifestations as older teenagers or young adults. Following diagnosis, many affected individuals and/or parents/caregivers describe earlier nonspecific subtle manifestations, such as clumsiness or developmental concerns.
Most affected individuals achieve nearly normal milestones into adulthood and the disorder progresses slowly over decades. The presentation may resemble that of other neurodegenerative conditions of adults, especially
Progressive motor neuronopathy, experienced by most (if not all) affected individuals, leads to muscle weakness and wasting. Muscle cramps, atrophy, and fasciculations are common. Early weakness primarily involves the lower extremities, particularly the knee extensors and hip flexors. Affected individuals have progressive difficulty in climbing steps or long flights of stairs, eventually requiring the aid of handrails. As knee extensor weakness progresses, affected individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain the locked knees results in collapse and injury, which frequently leads to early need for assistive devices or knee braces.
Upper-extremity strength may be affected years later with a predilection for triceps weakness, which affects elbow extension.
Long tract findings including spasticity, extensor plantar reflexes, and brisk reflexes can be present, but may be obscured by lower motor neuron weakness.
A peripheral sensory neuropathy that starts distally but can expand proximally is common [
Dysarthria. The speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. While poor articulation results primarily from cerebellar dysfunction, associated features can include focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Some individuals do not develop dysarthria despite substantial weakness.
Note: Dysphagia and aspiration events are not common.
Cerebellar dysfunction. Decreased balance can be associated with a wide base of support, decreased dexterity, and tremors. These findings plus saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination are attributed – at least in part – to cerebellar dysfunction [
Deficits in executive function and memory, reported in some individuals, can be associated with progressive brain volume loss; however, decline in higher cortical functioning develops slowly, often over decades after onset of disease manifestations.
Psychiatric manifestations such as psychosis and mania have exclusively been reported in the context of hexosaminidase A (HEX A) deficiency (in contrast to other GM2 gangliosidoses) [
Affective manifestations such as depression and/or anxiety, which can be present in individuals with Sandhoff disease as well, may represent part of a cerebellar affective syndrome [
In the absence of dysphagia or frequent falls, life expectancy is not necessarily reduced.
• Progressive motor neuronopathy, experienced by most (if not all) affected individuals, leads to muscle weakness and wasting. Muscle cramps, atrophy, and fasciculations are common. Early weakness primarily involves the lower extremities, particularly the knee extensors and hip flexors. Affected individuals have progressive difficulty in climbing steps or long flights of stairs, eventually requiring the aid of handrails. As knee extensor weakness progresses, affected individuals hyperextend ("lock") their knees to support their weight, producing a characteristic gait. Failure to maintain the locked knees results in collapse and injury, which frequently leads to early need for assistive devices or knee braces.
• Upper-extremity strength may be affected years later with a predilection for triceps weakness, which affects elbow extension.
• Long tract findings including spasticity, extensor plantar reflexes, and brisk reflexes can be present, but may be obscured by lower motor neuron weakness.
• A peripheral sensory neuropathy that starts distally but can expand proximally is common [
• Dysarthria. The speech rate is fast and almost "pressured," which, together with poor articulation, affects speech intelligibility. While poor articulation results primarily from cerebellar dysfunction, associated features can include focal laryngeal dystonia (spasmodic dysphonia), leading to a "strangled" voice and overflow activation of neck and facial muscles. Some individuals do not develop dysarthria despite substantial weakness.
• Note: Dysphagia and aspiration events are not common.
• Cerebellar dysfunction. Decreased balance can be associated with a wide base of support, decreased dexterity, and tremors. These findings plus saccadic dysmetria and abnormal saccadic gain during formal extraocular movement examination are attributed – at least in part – to cerebellar dysfunction [
• Deficits in executive function and memory, reported in some individuals, can be associated with progressive brain volume loss; however, decline in higher cortical functioning develops slowly, often over decades after onset of disease manifestations.
• Psychiatric manifestations such as psychosis and mania have exclusively been reported in the context of hexosaminidase A (HEX A) deficiency (in contrast to other GM2 gangliosidoses) [
• Affective manifestations such as depression and/or anxiety, which can be present in individuals with Sandhoff disease as well, may represent part of a cerebellar affective syndrome [
## Genotype-Phenotype Correlations
The following
In general, individuals with two null (nonexpressing) variants have the acute infantile phenotype, individuals with one null variant and one missense variant have the subacute juvenile phenotype, and individuals with two missense variants have the late-onset phenotype. This reflects the inverse correlation of the level of the residual hexosaminidase B (HEX B) enzyme activity with disease severity: the lower the enzymatic activity, the more severe the phenotype is likely to be. Nonetheless, clinical variability can be observed among family members with the subacute juvenile and late-onset phenotypes.
•
•
•
## Nomenclature
Sandhoff disease was one of several disorders, including Tay-Sachs disease and GM2 activator deficiency, formerly referred to collectively as "amaurotic idiocy." Once GM2 ganglioside was identified as the major accumulating substrate, the terms "infantile ganglioside lipidosis" and "GM2 gangliosidosis" were introduced. Likewise, when the relationship between the enzymatic activity of HEX A and HEX B was identified, the terms "hexosaminidase B deficiency" and "hexosaminidase A and B deficiency" were introduced.
To distinguish Sandhoff disease from Tay-Sachs disease and GM2 activator deficiency – both of which also involve GM2 ganglioside accumulation due to a shared biochemical pathway for the enzymes involved – Sandhoff disease is also referred to as "GM2 gangliosidosis type II" or "GM2 gangliosidosis variant 0."
## Prevalence
The prevalence of Sandhoff disease in the general population is not known. The estimated prevalence is around 1:500,000 to 1:1,500,000 depending on the population studied [
Populations reported to have an increased prevalence of acute infantile Sandhoff disease include the following (see
Maronite community in Cypress [
Individuals of Métis ancestry in northern Saskatchewan [
Creole population in northern Argentina [
• Maronite community in Cypress [
• Individuals of Métis ancestry in northern Saskatchewan [
• Creole population in northern Argentina [
## 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 Sandhoff Disease
DiffDx = differential diagnosis; ERG = electroretinogram; HSM = hepatosplenomegaly; SD = Sandhoff disease; TSD = Tay-Sachs disease
The disorders included in
In activator-deficient TSD, enzymatic activity of both beta-hexosaminidase A and beta-hexosaminidase 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
Genetic Disorders of Interest in the Differential Diagnosis of Subacute Juvenile Sandhoff Disease
DiffDx = differential diagnosis; ERG = electroretinogram; HEX A = beta-hexosaminidase A; HEX B = beta-hexosaminidase B; HSM = hepatosplenomegaly; SD = Sandhoff disease
The disorders included in
Genetic Disorders in the Differential Diagnosis of Late-Onset Sandhoff Disease
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; EKG = electrocardiogram; MOI = mode of inheritance; SD = Sandhoff disease; XL = X-linked
Lead and other heavy metal poisoning, infectious and postinfectious meningoencephalitis, subacute sclerosing panencephalitis, hydrocephalus, and neurologic manifestations of other systemic diseases may mimic the neurologic findings associated with Sandhoff disease.
## Acute Infantile Sandhoff Disease
Genetic Disorders of Interest in the Differential Diagnosis of Acute Infantile Sandhoff Disease
DiffDx = differential diagnosis; ERG = electroretinogram; HSM = hepatosplenomegaly; SD = Sandhoff disease; TSD = Tay-Sachs disease
The disorders included in
In activator-deficient TSD, enzymatic activity of both beta-hexosaminidase A and beta-hexosaminidase 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
## Subacute Juvenile Sandhoff Disease
Genetic Disorders of Interest in the Differential Diagnosis of Subacute Juvenile Sandhoff Disease
DiffDx = differential diagnosis; ERG = electroretinogram; HEX A = beta-hexosaminidase A; HEX B = beta-hexosaminidase B; HSM = hepatosplenomegaly; SD = Sandhoff disease
The disorders included in
## Late-Onset Sandhoff Disease
Genetic Disorders in the Differential Diagnosis of Late-Onset Sandhoff Disease
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; EKG = electrocardiogram; MOI = mode of inheritance; SD = Sandhoff disease; XL = X-linked
## Acquired Disorders
Lead and other heavy metal poisoning, infectious and postinfectious meningoencephalitis, subacute sclerosing panencephalitis, hydrocephalus, and neurologic manifestations of other systemic diseases may mimic the neurologic findings associated with Sandhoff disease.
## Management
No clinical practice guidelines for Sandhoff disease have been published.
To establish the extent of disease and needs in an individual diagnosed with Sandhoff disease, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Acute Infantile Sandhoff Disease
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 the context of the best interest of the child & values & preferences of the family.
For difficult life-prolonging decisions or for 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
Recommended Evaluations Following Initial Diagnosis in Individuals with Subacute Juvenile Sandhoff Disease
To incl brain MRI
Consider EEG if seizures are a concern.
Evaluate for spasticity.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for IEP
Gross motor & fine motor skills
Mobility, independence in ADL, & need for adaptive devices
Need for PT (to prevent fixed 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.
ADL = activities of daily living; EEG = electroencephalogram; 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 Late-Onset Sandhoff Disease
Assess for weakness, tremor, ataxia, & neuropathy.
To incl brain MRI
To incl EMG/NCS
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
Community or online
Social work involvement for support.
ADL = activities of daily living; EMG = electromyogram; MOI = mode of inheritance; NCS = nerve conduction studies; OT = occupational therapy; PT = physical therapy
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
For the most part, treatment for acute infantile Sandhoff disease is supportive and directed toward providing adequate nutrition and hydration, managing infectious disease, protecting the airway, and controlling seizures (see
Treatment of Manifestations in Individuals with Acute Infantile Sandhoff Disease
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 the context of the best interest of the child & values & preferences of the family.
For difficult life-prolonging decisions or for 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
Treatment for the subacute juvenile and late-onset Sandhoff disease phenotypes involves the supportive services of a physiatrist and team of physical therapists, occupational therapists, and speech-language pathologists in maximizing function and providing aids for activities of daily living (see
Treatment of Manifestations in Individuals with Subacute Juvenile Sandhoff Disease
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
ASM = anti-seizure medication; IEP = individualized education program
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 Late-Onset of Sandhoff Disease
Adaptive equipment & mobility assists
Knee braces may be of particular help for locking knees.
Focus on strategies to slow speech rate.
Consider eval for alternative means of communication (e.g., AAC) for those w/expressive language difficulties.
Antidepressant or antipsychotic medications may be used, but clinical response is variable & can be poor.
Cognitive behavioral therapy can ↑ coping skills.
AAC =
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.
There are no formal guidelines for surveillance for individuals with Sandhoff disease.
Recommended Surveillance for Individuals with Acute Infantile Sandhoff Disease
OT/PT assessment of ADL; need for splinting for contractures/scoliosis
Durable medical equipment for mobility
Social work involvement for parental support;
Palliative care referral;
Home nursing referral.
ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with Subacute Juvenile Sandhoff Disease
OT/PT assessment of ADL; need for splinting for contractures/scoliosis
Durable medical equipment for mobility
Ophthalmologic exam
Assess need for low vision services.
Social work involvement for parental support;
Palliative care referral;
Home nursing referral.
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with Late-Onset Sandhoff Disease
By speech-language pathologist
Consider eval for alternative means of communication (e.g., AAC).
OT/PT assessment of ADL; need for splinting for contractures/scoliosis
Durable medical equipment for mobility
AAC =
For individuals with
Positioning that increases aspiration risk during feedings;
Seizure medication dosages that result in excessive sedation.
For individuals with
Situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility;
Circumstances that exacerbate the risk of falls.
For individuals with
Situations that exacerbate fall risk (i.e., walking on uneven or unstable surfaces);
Psychiatric medications that have been associated with disease worsening in
See
In-progress or recently concluded studies:
A Phase II study (
A multicenter study (
A Phase I/II (
A combination therapy (
A survey (
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 the context of the best interest of the child & values & preferences of the family.
• For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
• To incl brain MRI
• Consider EEG if seizures are a concern.
• Evaluate for spasticity.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for IEP
• Gross motor & fine motor skills
• Mobility, independence in ADL, & need for adaptive devices
• Need for PT (to prevent fixed 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.
• Assess for weakness, tremor, ataxia, & neuropathy.
• To incl brain MRI
• To incl EMG/NCS
• 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
• Community or online
• Social work involvement for support.
• 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 the context of the best interest of the child & values & preferences of the family.
• For difficult life-prolonging decisions or for 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
• Adaptive equipment & mobility assists
• Knee braces may be of particular help for locking knees.
• Focus on strategies to slow speech rate.
• Consider eval for alternative means of communication (e.g., AAC) for those w/expressive language difficulties.
• Antidepressant or antipsychotic medications may be used, but clinical response is variable & can be poor.
• Cognitive behavioral therapy can ↑ coping skills.
• 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.
• OT/PT assessment of ADL; need for splinting for contractures/scoliosis
• Durable medical equipment for mobility
• Social work involvement for parental support;
• Palliative care referral;
• Home nursing referral.
• OT/PT assessment of ADL; need for splinting for contractures/scoliosis
• Durable medical equipment for mobility
• Ophthalmologic exam
• Assess need for low vision services.
• Social work involvement for parental support;
• Palliative care referral;
• Home nursing referral.
• By speech-language pathologist
• Consider eval for alternative means of communication (e.g., AAC).
• 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.
• Situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility;
• Circumstances that exacerbate the risk of falls.
• Situations that exacerbate fall risk (i.e., walking on uneven or unstable surfaces);
• Psychiatric medications that have been associated with disease worsening in
• A Phase II study (
• A multicenter study (
• A Phase I/II (
• A combination therapy (
• A survey (
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Sandhoff disease, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Acute Infantile Sandhoff Disease
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 the context of the best interest of the child & values & preferences of the family.
For difficult life-prolonging decisions or for 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
Recommended Evaluations Following Initial Diagnosis in Individuals with Subacute Juvenile Sandhoff Disease
To incl brain MRI
Consider EEG if seizures are a concern.
Evaluate for spasticity.
To incl motor, adaptive, cognitive, & speech-language eval
Eval for IEP
Gross motor & fine motor skills
Mobility, independence in ADL, & need for adaptive devices
Need for PT (to prevent fixed 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.
ADL = activities of daily living; EEG = electroencephalogram; 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 Late-Onset Sandhoff Disease
Assess for weakness, tremor, ataxia, & neuropathy.
To incl brain MRI
To incl EMG/NCS
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
Community or online
Social work involvement for support.
ADL = activities of daily living; EMG = electromyogram; MOI = mode of inheritance; NCS = nerve conduction studies; 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 the context of the best interest of the child & values & preferences of the family.
• For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
• To incl brain MRI
• Consider EEG if seizures are a concern.
• Evaluate for spasticity.
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for IEP
• Gross motor & fine motor skills
• Mobility, independence in ADL, & need for adaptive devices
• Need for PT (to prevent fixed 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.
• Assess for weakness, tremor, ataxia, & neuropathy.
• To incl brain MRI
• To incl EMG/NCS
• 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
• Community or online
• Social work involvement for support.
## Treatment of Manifestations – Acute Infantile Sandhoff Disease
For the most part, treatment for acute infantile Sandhoff disease is supportive and directed toward providing adequate nutrition and hydration, managing infectious disease, protecting the airway, and controlling seizures (see
Treatment of Manifestations in Individuals with Acute Infantile Sandhoff Disease
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 the context of the best interest of the child & values & preferences of the family.
For difficult life-prolonging decisions or for 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 the context of the best interest of the child & values & preferences of the family.
• For difficult life-prolonging decisions or for clarification of treatment options, consider further consultation w/independent clinical teams.
## Treatment of Manifestations – Subacute Juvenile and Late-Onset Sandhoff Disease
Treatment for the subacute juvenile and late-onset Sandhoff disease phenotypes involves the supportive services of a physiatrist and team of physical therapists, occupational therapists, and speech-language pathologists in maximizing function and providing aids for activities of daily living (see
Treatment of Manifestations in Individuals with Subacute Juvenile Sandhoff Disease
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
ASM = anti-seizure medication; IEP = individualized education program
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 Late-Onset of Sandhoff Disease
Adaptive equipment & mobility assists
Knee braces may be of particular help for locking knees.
Focus on strategies to slow speech rate.
Consider eval for alternative means of communication (e.g., AAC) for those w/expressive language difficulties.
Antidepressant or antipsychotic medications may be used, but clinical response is variable & can be poor.
Cognitive behavioral therapy can ↑ coping skills.
AAC =
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.
• 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
• Adaptive equipment & mobility assists
• Knee braces may be of particular help for locking knees.
• Focus on strategies to slow speech rate.
• Consider eval for alternative means of communication (e.g., AAC) for those w/expressive language difficulties.
• Antidepressant or antipsychotic medications may be used, but clinical response is variable & can be poor.
• Cognitive behavioral therapy can ↑ coping skills.
• 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 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.
## Surveillance
There are no formal guidelines for surveillance for individuals with Sandhoff disease.
Recommended Surveillance for Individuals with Acute Infantile Sandhoff Disease
OT/PT assessment of ADL; need for splinting for contractures/scoliosis
Durable medical equipment for mobility
Social work involvement for parental support;
Palliative care referral;
Home nursing referral.
ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with Subacute Juvenile Sandhoff Disease
OT/PT assessment of ADL; need for splinting for contractures/scoliosis
Durable medical equipment for mobility
Ophthalmologic exam
Assess need for low vision services.
Social work involvement for parental support;
Palliative care referral;
Home nursing referral.
ADL = activities of daily living; OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with Late-Onset Sandhoff Disease
By speech-language pathologist
Consider eval for alternative means of communication (e.g., AAC).
OT/PT assessment of ADL; need for splinting for contractures/scoliosis
Durable medical equipment for mobility
AAC =
• OT/PT assessment of ADL; need for splinting for contractures/scoliosis
• Durable medical equipment for mobility
• Social work involvement for parental support;
• Palliative care referral;
• Home nursing referral.
• OT/PT assessment of ADL; need for splinting for contractures/scoliosis
• Durable medical equipment for mobility
• Ophthalmologic exam
• Assess need for low vision services.
• Social work involvement for parental support;
• Palliative care referral;
• Home nursing referral.
• By speech-language pathologist
• Consider eval for alternative means of communication (e.g., AAC).
• OT/PT assessment of ADL; need for splinting for contractures/scoliosis
• Durable medical equipment for mobility
## Agents/Circumstances to Avoid
For individuals with
Positioning that increases aspiration risk during feedings;
Seizure medication dosages that result in excessive sedation.
For individuals with
Situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility;
Circumstances that exacerbate the risk of falls.
For individuals with
Situations that exacerbate fall risk (i.e., walking on uneven or unstable surfaces);
Psychiatric medications that have been associated with disease worsening in
• Positioning that increases aspiration risk during feedings;
• Seizure medication dosages that result in excessive sedation.
• Situations that increase the likelihood of contractures or pressure sores, such as extended periods of immobility;
• Circumstances that exacerbate the risk of falls.
• Situations that exacerbate fall risk (i.e., walking on uneven or unstable surfaces);
• Psychiatric medications that have been associated with disease worsening in
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
In-progress or recently concluded studies:
A Phase II study (
A multicenter study (
A Phase I/II (
A combination therapy (
A survey (
Search
• A Phase II study (
• A multicenter study (
• A Phase I/II (
• A combination therapy (
• A survey (
## Genetic Counseling
Acute infantile Sandhoff disease, subacute juvenile Sandhoff disease, and late-onset Sandhoff disease (comprising the clinical spectrum of Sandhoff disease) are 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 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
Sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
* 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 individual 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
• 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.
## Mode of Inheritance
Acute infantile Sandhoff disease, subacute juvenile Sandhoff disease, and late-onset Sandhoff disease (comprising the clinical spectrum of Sandhoff disease) are 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 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
Sibs who inherit biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
* See
• The parents of an affected individual 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
• Sibs who inherit biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
## 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 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
•
•
•
•
## Molecular Genetics
Sandhoff Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Sandhoff Disease (
The enzyme beta-hexosaminidase comprises an alpha subunit and a beta subunit encoded by the genes
The two main forms of GM2 gangliosidosis are
Since HEX A comprises both an alpha subunit and a beta subunit, HEX A activity will be decreased in both Tay-Sachs disease and Sandhoff disease.
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 (i.e., HEX A and HEX B) are decreased; however, the percent contribution from HEX A is increased, since the percent contribution from HEX B is disproportionately decreased by loss of the function of the beta subunit.
The molecular pathogenesis of these two GM2 gangliosidoses, Tay-Sachs disease and Sandhoff disease, is the following: gangliosides (normally present in neurons in very small quantities) are progressively stored in neurons leading to neuronal impairment and loss, causing the characteristic central nervous system and peripheral nervous system neurodegeneration.
Only HEX A (in the presence of the GM2 activator protein, GM2A) is responsible for the degradation of GM2 gangliosides.
HEX B is able to hydrolyze certain neutral oligosaccharides [
Notable
Variants listed in the table have been provided by the authors.
See
• 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 (i.e., HEX A and HEX B) are decreased; however, the percent contribution from HEX A is increased, since the percent contribution from HEX B is disproportionately decreased by loss of the function of the beta subunit.
## Molecular Pathogenesis
The enzyme beta-hexosaminidase comprises an alpha subunit and a beta subunit encoded by the genes
The two main forms of GM2 gangliosidosis are
Since HEX A comprises both an alpha subunit and a beta subunit, HEX A activity will be decreased in both Tay-Sachs disease and Sandhoff disease.
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 (i.e., HEX A and HEX B) are decreased; however, the percent contribution from HEX A is increased, since the percent contribution from HEX B is disproportionately decreased by loss of the function of the beta subunit.
The molecular pathogenesis of these two GM2 gangliosidoses, Tay-Sachs disease and Sandhoff disease, is the following: gangliosides (normally present in neurons in very small quantities) are progressively stored in neurons leading to neuronal impairment and loss, causing the characteristic central nervous system and peripheral nervous system neurodegeneration.
Only HEX A (in the presence of the GM2 activator protein, GM2A) is responsible for the degradation of GM2 gangliosides.
HEX B is able to hydrolyze certain neutral oligosaccharides [
Notable
Variants listed in the table have been provided by the authors.
See
• 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 (i.e., HEX A and HEX B) are decreased; however, the percent contribution from HEX A is increased, since the percent contribution from HEX B is disproportionately decreased by loss of the function of the beta subunit.
## Chapter Notes
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 (
14 April 2022 (bp) Review posted live
10 December 2021 (cx) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 14 April 2022 (bp) Review posted live
• 10 December 2021 (cx) Original submission
## 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
14 April 2022 (bp) Review posted live
10 December 2021 (cx) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 14 April 2022 (bp) Review posted live
• 10 December 2021 (cx) Original submission
## References
## Literature Cited
|
[] |
14/4/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
satb2-dis
|
satb2-dis
|
[
"2q32 Deletion Syndrome",
"2q33.1 Microdeletion Syndrome",
"Glass Syndrome",
"2q32 Deletion Syndrome",
"2q33.1 Microdeletion Syndrome",
"Glass Syndrome",
"DNA-binding protein SATB2",
"SATB2",
"SATB2-Associated Syndrome"
] |
Yuri A Zarate, Katherine Bosanko, Jennifer Fish
|
Summary The diagnosis of SAS is established in a proband with suggestive findings and identification of one of the following by molecular genetic testing: a heterozygous intragenic SAS is an autosomal dominant disorder. Almost all probands with SAS reported to date have the disorder as the result of a
|
## Diagnosis
No formal clinical diagnostic criteria have been established for
SAS
Typically moderate-to-profound developmental delay or intellectual disability, including severe speech delay and, in some, absence of speech; however, individuals with milder developmental delay affecting predominantly speech have been reported.
AND
Any of the following features presenting in infancy or childhood:
Infantile hypotonia and feeding difficulties (relatively common)
Neurobehavioral/psychiatric manifestations, including autistic tendencies, hyperactivity, and aggressiveness
Palatal anomalies, such as cleft palate, bifid uvula, and high-arched palate
Dental anomalies, including prominent upper incisors, crowding, and delayed eruption
Skeletal anomalies, including osteopenia, bowing of long bones, scoliosis, and increased risk of fractures
Dysmorphic facial features (See
Seizures
Note: Some of the common features can be described using the acronym SATB2:
The diagnosis of SAS
A heterozygous intragenic
A heterozygous non-recurrent deletion at 2q33.1 that includes
A chromosome translocation or inversion with a 2q33.1 breakpoint that disrupts
A chromosomal duplication with breakpoints that encompass
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 CMA 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.
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 may not be detected by some of these methods.
Note that, although gene-targeted deletion/duplication assays may detect smaller events than genomic deletion/duplication assays, they will detect larger events but may not be able to determine the size. In general, all deletions/duplications detectable through CMA should also be detectable through gene-targeted deletion/duplication assays.
CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
In addition to detecting the 2q33.1 deletion, CMA can identify intragenic deletions and duplications [
Six individuals with a
• Typically moderate-to-profound developmental delay or intellectual disability, including severe speech delay and, in some, absence of speech; however, individuals with milder developmental delay affecting predominantly speech have been reported.
• Any of the following features presenting in infancy or childhood:
• Infantile hypotonia and feeding difficulties (relatively common)
• Neurobehavioral/psychiatric manifestations, including autistic tendencies, hyperactivity, and aggressiveness
• Palatal anomalies, such as cleft palate, bifid uvula, and high-arched palate
• Dental anomalies, including prominent upper incisors, crowding, and delayed eruption
• Skeletal anomalies, including osteopenia, bowing of long bones, scoliosis, and increased risk of fractures
• Dysmorphic facial features (See
• Seizures
• Infantile hypotonia and feeding difficulties (relatively common)
• Neurobehavioral/psychiatric manifestations, including autistic tendencies, hyperactivity, and aggressiveness
• Palatal anomalies, such as cleft palate, bifid uvula, and high-arched palate
• Dental anomalies, including prominent upper incisors, crowding, and delayed eruption
• Skeletal anomalies, including osteopenia, bowing of long bones, scoliosis, and increased risk of fractures
• Dysmorphic facial features (See
• Seizures
• Infantile hypotonia and feeding difficulties (relatively common)
• Neurobehavioral/psychiatric manifestations, including autistic tendencies, hyperactivity, and aggressiveness
• Palatal anomalies, such as cleft palate, bifid uvula, and high-arched palate
• Dental anomalies, including prominent upper incisors, crowding, and delayed eruption
• Skeletal anomalies, including osteopenia, bowing of long bones, scoliosis, and increased risk of fractures
• Dysmorphic facial features (See
• Seizures
• A heterozygous intragenic
• A heterozygous non-recurrent deletion at 2q33.1 that includes
• A chromosome translocation or inversion with a 2q33.1 breakpoint that disrupts
• A chromosomal duplication with breakpoints that encompass
• For an introduction to comprehensive genomic testing click
• For an introduction to CMA click
• For an introduction to multigene panels click
## Suggestive Findings
SAS
Typically moderate-to-profound developmental delay or intellectual disability, including severe speech delay and, in some, absence of speech; however, individuals with milder developmental delay affecting predominantly speech have been reported.
AND
Any of the following features presenting in infancy or childhood:
Infantile hypotonia and feeding difficulties (relatively common)
Neurobehavioral/psychiatric manifestations, including autistic tendencies, hyperactivity, and aggressiveness
Palatal anomalies, such as cleft palate, bifid uvula, and high-arched palate
Dental anomalies, including prominent upper incisors, crowding, and delayed eruption
Skeletal anomalies, including osteopenia, bowing of long bones, scoliosis, and increased risk of fractures
Dysmorphic facial features (See
Seizures
Note: Some of the common features can be described using the acronym SATB2:
• Typically moderate-to-profound developmental delay or intellectual disability, including severe speech delay and, in some, absence of speech; however, individuals with milder developmental delay affecting predominantly speech have been reported.
• Any of the following features presenting in infancy or childhood:
• Infantile hypotonia and feeding difficulties (relatively common)
• Neurobehavioral/psychiatric manifestations, including autistic tendencies, hyperactivity, and aggressiveness
• Palatal anomalies, such as cleft palate, bifid uvula, and high-arched palate
• Dental anomalies, including prominent upper incisors, crowding, and delayed eruption
• Skeletal anomalies, including osteopenia, bowing of long bones, scoliosis, and increased risk of fractures
• Dysmorphic facial features (See
• Seizures
• Infantile hypotonia and feeding difficulties (relatively common)
• Neurobehavioral/psychiatric manifestations, including autistic tendencies, hyperactivity, and aggressiveness
• Palatal anomalies, such as cleft palate, bifid uvula, and high-arched palate
• Dental anomalies, including prominent upper incisors, crowding, and delayed eruption
• Skeletal anomalies, including osteopenia, bowing of long bones, scoliosis, and increased risk of fractures
• Dysmorphic facial features (See
• Seizures
• Infantile hypotonia and feeding difficulties (relatively common)
• Neurobehavioral/psychiatric manifestations, including autistic tendencies, hyperactivity, and aggressiveness
• Palatal anomalies, such as cleft palate, bifid uvula, and high-arched palate
• Dental anomalies, including prominent upper incisors, crowding, and delayed eruption
• Skeletal anomalies, including osteopenia, bowing of long bones, scoliosis, and increased risk of fractures
• Dysmorphic facial features (See
• Seizures
## Establishing the Diagnosis
The diagnosis of SAS
A heterozygous intragenic
A heterozygous non-recurrent deletion at 2q33.1 that includes
A chromosome translocation or inversion with a 2q33.1 breakpoint that disrupts
A chromosomal duplication with breakpoints that encompass
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 CMA 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.
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 may not be detected by some of these methods.
Note that, although gene-targeted deletion/duplication assays may detect smaller events than genomic deletion/duplication assays, they will detect larger events but may not be able to determine the size. In general, all deletions/duplications detectable through CMA should also be detectable through gene-targeted deletion/duplication assays.
CMA uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
In addition to detecting the 2q33.1 deletion, CMA can identify intragenic deletions and duplications [
Six individuals with a
• A heterozygous intragenic
• A heterozygous non-recurrent deletion at 2q33.1 that includes
• A chromosome translocation or inversion with a 2q33.1 breakpoint that disrupts
• A chromosomal duplication with breakpoints that encompass
• For an introduction to comprehensive genomic testing click
• For an introduction to CMA click
• For an introduction to multigene panels click
## Clinical Characteristics
To date, more than 500 individuals have been identified with a pathogenic variant in
Complete information was not available for some individuals.
Most individuals are nonverbal communicators and use gestures, signs, or augmentative and alternative communication (AAC) devices as their primary way to communicate [
For individuals with a heterozygous pathogenic variant within
In a single study analyzing the long-term history of 49 individuals age 12 years or older with SAS, difficulties with speech were persistent, with 69% of individuals having ten or fewer words of total speech [
More than half of the cohort was able to read single words and type letters on a keyboard independently;
For 79% of adults (n=24), the highest level of education was high school, and only one individual was employed;
Most individuals required some degree of assistance for activities of daily living and needed supervision to remain home on their own.
Developmental regression and/or cognitive decline has been described once in an adult female with an 8.6-Mb deletion of 2q32.2-q33.1 who progressed from mild to severe intellectual disability and from poor to absent speech between ages six and 12 years [
Hypotonia, particularly during infancy (59%)
Clinical seizures (20%)
EEG abnormalities are frequent but may be without clinically recognizable seizures [
Less common neurologic issues include gait abnormalities / ataxia (17%), hypertonicity and/or spasticity (4%), and hyperreflexia (3%).
Deep-set eyes
Long, smooth philtrum
Thin vermilion of the upper lip
Abnormal chin morphology
In those with larger 2q33.1 deletions, additional features can include a prominent forehead, high anterior hairline, triangular appearance of the lower face, low-set ears, and/or long face (see
Palatal abnormalities documented in 76% of individuals include cleft palate (45%), high-arched palate, velopharyngeal insufficiency, and bifid uvula (3%) [
Micrognathia, diagnosed in 42% of individuals, has rarely required surgical correction.
Mandibular hypoplasia and asymmetric jaw have also been documented radiographically [
Abnormal shape or size or the upper central incisors (67%)
Dental crowding, hypodontia, and delayed teeth eruption (76%)
Pulp stones
Malformed crowns and/or diastema
Fused incisors
Sialorrhea
Bruxism
Malocclusion
Frequent trauma to maxillary anterior teeth
Delayed development of the mandibular second bicuspids (83%)
Delayed development of the roots of the permanent teeth (78%)
Rotated (56%) or malformed (44%) teeth
Taurodontism (44%)
Bone mineral density is reported to be low (z scores two or more standard deviations below the mean on DXA scan) in 26% of affected individuals.
Detailed skeletal radiographic characterization in a cohort of individuals with SAS revealed frequent abnormalities such as skeletal demineralization (94%), calvaria digitiform impressions (57%), vertebral compression fractures (35%), metaphyseal long bone striations (68%), and small epiphyses (63%), among others [
Biochemically, markers of bone formation and resorption are often elevated in individuals with SAS; 62% of affected individuals have elevated alkaline phosphatase levels, often with low vitamin D and high phosphate levels. However, high alkaline phosphatase levels do not seem to predict the presence of low bone density [
Pectus deformities
Kyphosis/lordosis
Scoliosis
Small hands/feet
Arachnodactyly
Broad thumbs or halluces
Clinodactyly
Finger contractures
Tibial bowing
Null pathogenic variants located after amino acid 350 (the start of the CUT1 domain)
The recurrent missense
The
Intragenic deletions
Genitourinary anomalies
Cardiac defects
In some individuals with large deletions including
Aortic dilatation has been described in individuals with large deletions encompassing
Ectodermal changes (other than dental)
Growth restriction (65% of individuals with large deletions vs 31% of individuals with intragenic pathogenic variants) [
The term "Glass syndrome" was suggested after a report of a male with a cytogenetically visible 2q32.2-q33.1 deletion that included
Two studies have estimated the frequency of SAS in large cohorts of individuals with undiagnosed intellectual disability / developmental delay to be 0.24%-0.3% [
• Most individuals are nonverbal communicators and use gestures, signs, or augmentative and alternative communication (AAC) devices as their primary way to communicate [
• For individuals with a heterozygous pathogenic variant within
• In a single study analyzing the long-term history of 49 individuals age 12 years or older with SAS, difficulties with speech were persistent, with 69% of individuals having ten or fewer words of total speech [
• Most individuals are nonverbal communicators and use gestures, signs, or augmentative and alternative communication (AAC) devices as their primary way to communicate [
• For individuals with a heterozygous pathogenic variant within
• In a single study analyzing the long-term history of 49 individuals age 12 years or older with SAS, difficulties with speech were persistent, with 69% of individuals having ten or fewer words of total speech [
• More than half of the cohort was able to read single words and type letters on a keyboard independently;
• For 79% of adults (n=24), the highest level of education was high school, and only one individual was employed;
• Most individuals required some degree of assistance for activities of daily living and needed supervision to remain home on their own.
• More than half of the cohort was able to read single words and type letters on a keyboard independently;
• For 79% of adults (n=24), the highest level of education was high school, and only one individual was employed;
• Most individuals required some degree of assistance for activities of daily living and needed supervision to remain home on their own.
• Most individuals are nonverbal communicators and use gestures, signs, or augmentative and alternative communication (AAC) devices as their primary way to communicate [
• For individuals with a heterozygous pathogenic variant within
• In a single study analyzing the long-term history of 49 individuals age 12 years or older with SAS, difficulties with speech were persistent, with 69% of individuals having ten or fewer words of total speech [
• More than half of the cohort was able to read single words and type letters on a keyboard independently;
• For 79% of adults (n=24), the highest level of education was high school, and only one individual was employed;
• Most individuals required some degree of assistance for activities of daily living and needed supervision to remain home on their own.
• Hypotonia, particularly during infancy (59%)
• Clinical seizures (20%)
• EEG abnormalities are frequent but may be without clinically recognizable seizures [
• Less common neurologic issues include gait abnormalities / ataxia (17%), hypertonicity and/or spasticity (4%), and hyperreflexia (3%).
• Deep-set eyes
• Long, smooth philtrum
• Thin vermilion of the upper lip
• Abnormal chin morphology
• Palatal abnormalities documented in 76% of individuals include cleft palate (45%), high-arched palate, velopharyngeal insufficiency, and bifid uvula (3%) [
• Micrognathia, diagnosed in 42% of individuals, has rarely required surgical correction.
• Mandibular hypoplasia and asymmetric jaw have also been documented radiographically [
• Abnormal shape or size or the upper central incisors (67%)
• Dental crowding, hypodontia, and delayed teeth eruption (76%)
• Pulp stones
• Malformed crowns and/or diastema
• Fused incisors
• Abnormal shape or size or the upper central incisors (67%)
• Dental crowding, hypodontia, and delayed teeth eruption (76%)
• Pulp stones
• Malformed crowns and/or diastema
• Fused incisors
• Sialorrhea
• Bruxism
• Malocclusion
• Frequent trauma to maxillary anterior teeth
• Sialorrhea
• Bruxism
• Malocclusion
• Frequent trauma to maxillary anterior teeth
• Delayed development of the mandibular second bicuspids (83%)
• Delayed development of the roots of the permanent teeth (78%)
• Rotated (56%) or malformed (44%) teeth
• Taurodontism (44%)
• Delayed development of the mandibular second bicuspids (83%)
• Delayed development of the roots of the permanent teeth (78%)
• Rotated (56%) or malformed (44%) teeth
• Taurodontism (44%)
• Abnormal shape or size or the upper central incisors (67%)
• Dental crowding, hypodontia, and delayed teeth eruption (76%)
• Pulp stones
• Malformed crowns and/or diastema
• Fused incisors
• Sialorrhea
• Bruxism
• Malocclusion
• Frequent trauma to maxillary anterior teeth
• Delayed development of the mandibular second bicuspids (83%)
• Delayed development of the roots of the permanent teeth (78%)
• Rotated (56%) or malformed (44%) teeth
• Taurodontism (44%)
• Bone mineral density is reported to be low (z scores two or more standard deviations below the mean on DXA scan) in 26% of affected individuals.
• Detailed skeletal radiographic characterization in a cohort of individuals with SAS revealed frequent abnormalities such as skeletal demineralization (94%), calvaria digitiform impressions (57%), vertebral compression fractures (35%), metaphyseal long bone striations (68%), and small epiphyses (63%), among others [
• Biochemically, markers of bone formation and resorption are often elevated in individuals with SAS; 62% of affected individuals have elevated alkaline phosphatase levels, often with low vitamin D and high phosphate levels. However, high alkaline phosphatase levels do not seem to predict the presence of low bone density [
• Bone mineral density is reported to be low (z scores two or more standard deviations below the mean on DXA scan) in 26% of affected individuals.
• Detailed skeletal radiographic characterization in a cohort of individuals with SAS revealed frequent abnormalities such as skeletal demineralization (94%), calvaria digitiform impressions (57%), vertebral compression fractures (35%), metaphyseal long bone striations (68%), and small epiphyses (63%), among others [
• Biochemically, markers of bone formation and resorption are often elevated in individuals with SAS; 62% of affected individuals have elevated alkaline phosphatase levels, often with low vitamin D and high phosphate levels. However, high alkaline phosphatase levels do not seem to predict the presence of low bone density [
• Pectus deformities
• Kyphosis/lordosis
• Scoliosis
• Small hands/feet
• Arachnodactyly
• Broad thumbs or halluces
• Clinodactyly
• Finger contractures
• Tibial bowing
• Pectus deformities
• Kyphosis/lordosis
• Scoliosis
• Small hands/feet
• Arachnodactyly
• Broad thumbs or halluces
• Clinodactyly
• Finger contractures
• Tibial bowing
• Bone mineral density is reported to be low (z scores two or more standard deviations below the mean on DXA scan) in 26% of affected individuals.
• Detailed skeletal radiographic characterization in a cohort of individuals with SAS revealed frequent abnormalities such as skeletal demineralization (94%), calvaria digitiform impressions (57%), vertebral compression fractures (35%), metaphyseal long bone striations (68%), and small epiphyses (63%), among others [
• Biochemically, markers of bone formation and resorption are often elevated in individuals with SAS; 62% of affected individuals have elevated alkaline phosphatase levels, often with low vitamin D and high phosphate levels. However, high alkaline phosphatase levels do not seem to predict the presence of low bone density [
• Pectus deformities
• Kyphosis/lordosis
• Scoliosis
• Small hands/feet
• Arachnodactyly
• Broad thumbs or halluces
• Clinodactyly
• Finger contractures
• Tibial bowing
• Null pathogenic variants located after amino acid 350 (the start of the CUT1 domain)
• The recurrent missense
• The
• Intragenic deletions
• Null pathogenic variants located after amino acid 350 (the start of the CUT1 domain)
• The recurrent missense
• The
• Intragenic deletions
• Null pathogenic variants located after amino acid 350 (the start of the CUT1 domain)
• The recurrent missense
• The
• Intragenic deletions
• Genitourinary anomalies
• Cardiac defects
• In some individuals with large deletions including
• Aortic dilatation has been described in individuals with large deletions encompassing
• In some individuals with large deletions including
• Aortic dilatation has been described in individuals with large deletions encompassing
• Ectodermal changes (other than dental)
• Growth restriction (65% of individuals with large deletions vs 31% of individuals with intragenic pathogenic variants) [
• In some individuals with large deletions including
• Aortic dilatation has been described in individuals with large deletions encompassing
## Clinical Description
To date, more than 500 individuals have been identified with a pathogenic variant in
Complete information was not available for some individuals.
Most individuals are nonverbal communicators and use gestures, signs, or augmentative and alternative communication (AAC) devices as their primary way to communicate [
For individuals with a heterozygous pathogenic variant within
In a single study analyzing the long-term history of 49 individuals age 12 years or older with SAS, difficulties with speech were persistent, with 69% of individuals having ten or fewer words of total speech [
More than half of the cohort was able to read single words and type letters on a keyboard independently;
For 79% of adults (n=24), the highest level of education was high school, and only one individual was employed;
Most individuals required some degree of assistance for activities of daily living and needed supervision to remain home on their own.
Developmental regression and/or cognitive decline has been described once in an adult female with an 8.6-Mb deletion of 2q32.2-q33.1 who progressed from mild to severe intellectual disability and from poor to absent speech between ages six and 12 years [
Hypotonia, particularly during infancy (59%)
Clinical seizures (20%)
EEG abnormalities are frequent but may be without clinically recognizable seizures [
Less common neurologic issues include gait abnormalities / ataxia (17%), hypertonicity and/or spasticity (4%), and hyperreflexia (3%).
Deep-set eyes
Long, smooth philtrum
Thin vermilion of the upper lip
Abnormal chin morphology
In those with larger 2q33.1 deletions, additional features can include a prominent forehead, high anterior hairline, triangular appearance of the lower face, low-set ears, and/or long face (see
Palatal abnormalities documented in 76% of individuals include cleft palate (45%), high-arched palate, velopharyngeal insufficiency, and bifid uvula (3%) [
Micrognathia, diagnosed in 42% of individuals, has rarely required surgical correction.
Mandibular hypoplasia and asymmetric jaw have also been documented radiographically [
Abnormal shape or size or the upper central incisors (67%)
Dental crowding, hypodontia, and delayed teeth eruption (76%)
Pulp stones
Malformed crowns and/or diastema
Fused incisors
Sialorrhea
Bruxism
Malocclusion
Frequent trauma to maxillary anterior teeth
Delayed development of the mandibular second bicuspids (83%)
Delayed development of the roots of the permanent teeth (78%)
Rotated (56%) or malformed (44%) teeth
Taurodontism (44%)
Bone mineral density is reported to be low (z scores two or more standard deviations below the mean on DXA scan) in 26% of affected individuals.
Detailed skeletal radiographic characterization in a cohort of individuals with SAS revealed frequent abnormalities such as skeletal demineralization (94%), calvaria digitiform impressions (57%), vertebral compression fractures (35%), metaphyseal long bone striations (68%), and small epiphyses (63%), among others [
Biochemically, markers of bone formation and resorption are often elevated in individuals with SAS; 62% of affected individuals have elevated alkaline phosphatase levels, often with low vitamin D and high phosphate levels. However, high alkaline phosphatase levels do not seem to predict the presence of low bone density [
Pectus deformities
Kyphosis/lordosis
Scoliosis
Small hands/feet
Arachnodactyly
Broad thumbs or halluces
Clinodactyly
Finger contractures
Tibial bowing
• Most individuals are nonverbal communicators and use gestures, signs, or augmentative and alternative communication (AAC) devices as their primary way to communicate [
• For individuals with a heterozygous pathogenic variant within
• In a single study analyzing the long-term history of 49 individuals age 12 years or older with SAS, difficulties with speech were persistent, with 69% of individuals having ten or fewer words of total speech [
• Most individuals are nonverbal communicators and use gestures, signs, or augmentative and alternative communication (AAC) devices as their primary way to communicate [
• For individuals with a heterozygous pathogenic variant within
• In a single study analyzing the long-term history of 49 individuals age 12 years or older with SAS, difficulties with speech were persistent, with 69% of individuals having ten or fewer words of total speech [
• More than half of the cohort was able to read single words and type letters on a keyboard independently;
• For 79% of adults (n=24), the highest level of education was high school, and only one individual was employed;
• Most individuals required some degree of assistance for activities of daily living and needed supervision to remain home on their own.
• More than half of the cohort was able to read single words and type letters on a keyboard independently;
• For 79% of adults (n=24), the highest level of education was high school, and only one individual was employed;
• Most individuals required some degree of assistance for activities of daily living and needed supervision to remain home on their own.
• Most individuals are nonverbal communicators and use gestures, signs, or augmentative and alternative communication (AAC) devices as their primary way to communicate [
• For individuals with a heterozygous pathogenic variant within
• In a single study analyzing the long-term history of 49 individuals age 12 years or older with SAS, difficulties with speech were persistent, with 69% of individuals having ten or fewer words of total speech [
• More than half of the cohort was able to read single words and type letters on a keyboard independently;
• For 79% of adults (n=24), the highest level of education was high school, and only one individual was employed;
• Most individuals required some degree of assistance for activities of daily living and needed supervision to remain home on their own.
• Hypotonia, particularly during infancy (59%)
• Clinical seizures (20%)
• EEG abnormalities are frequent but may be without clinically recognizable seizures [
• Less common neurologic issues include gait abnormalities / ataxia (17%), hypertonicity and/or spasticity (4%), and hyperreflexia (3%).
• Deep-set eyes
• Long, smooth philtrum
• Thin vermilion of the upper lip
• Abnormal chin morphology
• Palatal abnormalities documented in 76% of individuals include cleft palate (45%), high-arched palate, velopharyngeal insufficiency, and bifid uvula (3%) [
• Micrognathia, diagnosed in 42% of individuals, has rarely required surgical correction.
• Mandibular hypoplasia and asymmetric jaw have also been documented radiographically [
• Abnormal shape or size or the upper central incisors (67%)
• Dental crowding, hypodontia, and delayed teeth eruption (76%)
• Pulp stones
• Malformed crowns and/or diastema
• Fused incisors
• Abnormal shape or size or the upper central incisors (67%)
• Dental crowding, hypodontia, and delayed teeth eruption (76%)
• Pulp stones
• Malformed crowns and/or diastema
• Fused incisors
• Sialorrhea
• Bruxism
• Malocclusion
• Frequent trauma to maxillary anterior teeth
• Sialorrhea
• Bruxism
• Malocclusion
• Frequent trauma to maxillary anterior teeth
• Delayed development of the mandibular second bicuspids (83%)
• Delayed development of the roots of the permanent teeth (78%)
• Rotated (56%) or malformed (44%) teeth
• Taurodontism (44%)
• Delayed development of the mandibular second bicuspids (83%)
• Delayed development of the roots of the permanent teeth (78%)
• Rotated (56%) or malformed (44%) teeth
• Taurodontism (44%)
• Abnormal shape or size or the upper central incisors (67%)
• Dental crowding, hypodontia, and delayed teeth eruption (76%)
• Pulp stones
• Malformed crowns and/or diastema
• Fused incisors
• Sialorrhea
• Bruxism
• Malocclusion
• Frequent trauma to maxillary anterior teeth
• Delayed development of the mandibular second bicuspids (83%)
• Delayed development of the roots of the permanent teeth (78%)
• Rotated (56%) or malformed (44%) teeth
• Taurodontism (44%)
• Bone mineral density is reported to be low (z scores two or more standard deviations below the mean on DXA scan) in 26% of affected individuals.
• Detailed skeletal radiographic characterization in a cohort of individuals with SAS revealed frequent abnormalities such as skeletal demineralization (94%), calvaria digitiform impressions (57%), vertebral compression fractures (35%), metaphyseal long bone striations (68%), and small epiphyses (63%), among others [
• Biochemically, markers of bone formation and resorption are often elevated in individuals with SAS; 62% of affected individuals have elevated alkaline phosphatase levels, often with low vitamin D and high phosphate levels. However, high alkaline phosphatase levels do not seem to predict the presence of low bone density [
• Bone mineral density is reported to be low (z scores two or more standard deviations below the mean on DXA scan) in 26% of affected individuals.
• Detailed skeletal radiographic characterization in a cohort of individuals with SAS revealed frequent abnormalities such as skeletal demineralization (94%), calvaria digitiform impressions (57%), vertebral compression fractures (35%), metaphyseal long bone striations (68%), and small epiphyses (63%), among others [
• Biochemically, markers of bone formation and resorption are often elevated in individuals with SAS; 62% of affected individuals have elevated alkaline phosphatase levels, often with low vitamin D and high phosphate levels. However, high alkaline phosphatase levels do not seem to predict the presence of low bone density [
• Pectus deformities
• Kyphosis/lordosis
• Scoliosis
• Small hands/feet
• Arachnodactyly
• Broad thumbs or halluces
• Clinodactyly
• Finger contractures
• Tibial bowing
• Pectus deformities
• Kyphosis/lordosis
• Scoliosis
• Small hands/feet
• Arachnodactyly
• Broad thumbs or halluces
• Clinodactyly
• Finger contractures
• Tibial bowing
• Bone mineral density is reported to be low (z scores two or more standard deviations below the mean on DXA scan) in 26% of affected individuals.
• Detailed skeletal radiographic characterization in a cohort of individuals with SAS revealed frequent abnormalities such as skeletal demineralization (94%), calvaria digitiform impressions (57%), vertebral compression fractures (35%), metaphyseal long bone striations (68%), and small epiphyses (63%), among others [
• Biochemically, markers of bone formation and resorption are often elevated in individuals with SAS; 62% of affected individuals have elevated alkaline phosphatase levels, often with low vitamin D and high phosphate levels. However, high alkaline phosphatase levels do not seem to predict the presence of low bone density [
• Pectus deformities
• Kyphosis/lordosis
• Scoliosis
• Small hands/feet
• Arachnodactyly
• Broad thumbs or halluces
• Clinodactyly
• Finger contractures
• Tibial bowing
## Genotype-Phenotype Correlations
Null pathogenic variants located after amino acid 350 (the start of the CUT1 domain)
The recurrent missense
The
Intragenic deletions
Genitourinary anomalies
Cardiac defects
In some individuals with large deletions including
Aortic dilatation has been described in individuals with large deletions encompassing
Ectodermal changes (other than dental)
Growth restriction (65% of individuals with large deletions vs 31% of individuals with intragenic pathogenic variants) [
• Null pathogenic variants located after amino acid 350 (the start of the CUT1 domain)
• The recurrent missense
• The
• Intragenic deletions
• Null pathogenic variants located after amino acid 350 (the start of the CUT1 domain)
• The recurrent missense
• The
• Intragenic deletions
• Null pathogenic variants located after amino acid 350 (the start of the CUT1 domain)
• The recurrent missense
• The
• Intragenic deletions
• Genitourinary anomalies
• Cardiac defects
• In some individuals with large deletions including
• Aortic dilatation has been described in individuals with large deletions encompassing
• In some individuals with large deletions including
• Aortic dilatation has been described in individuals with large deletions encompassing
• Ectodermal changes (other than dental)
• Growth restriction (65% of individuals with large deletions vs 31% of individuals with intragenic pathogenic variants) [
• In some individuals with large deletions including
• Aortic dilatation has been described in individuals with large deletions encompassing
## Nomenclature
The term "Glass syndrome" was suggested after a report of a male with a cytogenetically visible 2q32.2-q33.1 deletion that included
## Prevalence
Two studies have estimated the frequency of SAS in large cohorts of individuals with undiagnosed intellectual disability / developmental delay to be 0.24%-0.3% [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
In early infancy
Disorders to Consider in the Differential Diagnosis of
AD = autosomal dominant; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; del = deletion; ID = intellectual disability; MOI = mode of inheritance; PV = pathogenic variant
Consistent features associated with larger 2q33.1 deletions include prominent forehead or high anterior hairline, thin vermilion of the upper lip, low-set ears, and long face. Consistent features associated with pathogenic missense, nonsense, and frameshift variants include long and flat philtrum and thin vermilion of the upper lip [
Angelman syndrome is caused by disruption of the maternally imprinted
## Management
No consensus clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with SAS, the evaluations summarized in
To evaluate for poor growth
SAS-specific growth charts are available.
Consider head MRI to evaluate for brain malformations if clinical seizures are present.
Baseline EEG, preferably incl sleep stages to evaluate for ESES
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Referral to dentist
Consider dental radiographs if/when affected person can cooperate.
To incl eval of aspiration risk & nutritional status
Consider a videofluoroscopic swallowing study.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Gross motor & fine motor skills
Scoliosis, kyphosis, tibial bowing, joint contractures
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
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; DXA = dual-energy x-ray absorptiometry; ESES = electrical status epilepticus in sleep; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; PTH = parathyroid hormone
Brain MRI abnormalities were found in 67.7% of affected individuals, although this did not correlate with the frequency of seizures [
EEG abnormalities are often documented, even with no clinical seizures. However, electrical status epilepticus in sleep has been reported [
Elevations in alkaline phosphatase have been documented in more than 60% of affected individuals and are due to the bone-specific fraction. These elevations, however, do not seem to predict the presence of low bone density [
In addition to structural defects, individuals with deletions involving
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for SAS. 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
Standard treatment ideally by craniofacial team
Surgical correction of cleft palate
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Optimize physical activity & calcium / vitamin D levels.
Denosumab & bisphosphonates have been used, w/no direct comparison between the different options.
Denosumab was reported to be used in 1 affected person.
Pamidronate & zoledronic acid infusions have also been used.
Oral alendronate was documented to improve bone mineral content in 1 person.
Long-term response to these treatments is unknown.
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
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 by 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
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 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
Eval of nutritional status & safety of oral intake
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures or changes in tone.
Annually if BMD z score is below −1
Every 2 yrs if BMD z score is above −1
Measure alkaline phosphatase.
Consider obtaining vitamin D levels &, if vitamin D supplementation is being considered, serum calcium levels.
Annually if elevated
Every 2 yrs if normal
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
See
Search
• To evaluate for poor growth
• SAS-specific growth charts are available.
• Consider head MRI to evaluate for brain malformations if clinical seizures are present.
• Baseline EEG, preferably incl sleep stages to evaluate for ESES
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Referral to dentist
• Consider dental radiographs if/when affected person can cooperate.
• To incl eval of aspiration risk & nutritional status
• Consider a videofluoroscopic swallowing study.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Gross motor & fine motor skills
• Scoliosis, kyphosis, tibial bowing, joint contractures
• 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
• Standard treatment ideally by craniofacial team
• Surgical correction of cleft palate
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Optimize physical activity & calcium / vitamin D levels.
• Denosumab & bisphosphonates have been used, w/no direct comparison between the different options.
• Denosumab was reported to be used in 1 affected person.
• Pamidronate & zoledronic acid infusions have also been used.
• Oral alendronate was documented to improve bone mineral content in 1 person.
• Long-term response to these treatments is unknown.
• 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
• 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• Consider use of durable medical equipment as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
• 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 or changes in tone.
• Annually if BMD z score is below −1
• Every 2 yrs if BMD z score is above −1
• Measure alkaline phosphatase.
• Consider obtaining vitamin D levels &, if vitamin D supplementation is being considered, serum calcium levels.
• Annually if elevated
• Every 2 yrs if normal
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SAS, the evaluations summarized in
To evaluate for poor growth
SAS-specific growth charts are available.
Consider head MRI to evaluate for brain malformations if clinical seizures are present.
Baseline EEG, preferably incl sleep stages to evaluate for ESES
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Referral to dentist
Consider dental radiographs if/when affected person can cooperate.
To incl eval of aspiration risk & nutritional status
Consider a videofluoroscopic swallowing study.
Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
Gross motor & fine motor skills
Scoliosis, kyphosis, tibial bowing, joint contractures
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
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; DXA = dual-energy x-ray absorptiometry; ESES = electrical status epilepticus in sleep; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; PTH = parathyroid hormone
Brain MRI abnormalities were found in 67.7% of affected individuals, although this did not correlate with the frequency of seizures [
EEG abnormalities are often documented, even with no clinical seizures. However, electrical status epilepticus in sleep has been reported [
Elevations in alkaline phosphatase have been documented in more than 60% of affected individuals and are due to the bone-specific fraction. These elevations, however, do not seem to predict the presence of low bone density [
In addition to structural defects, individuals with deletions involving
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To evaluate for poor growth
• SAS-specific growth charts are available.
• Consider head MRI to evaluate for brain malformations if clinical seizures are present.
• Baseline EEG, preferably incl sleep stages to evaluate for ESES
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Referral to dentist
• Consider dental radiographs if/when affected person can cooperate.
• To incl eval of aspiration risk & nutritional status
• Consider a videofluoroscopic swallowing study.
• Consider eval for gastrostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Gross motor & fine motor skills
• Scoliosis, kyphosis, tibial bowing, joint contractures
• 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 SAS. 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
Standard treatment ideally by craniofacial team
Surgical correction of cleft palate
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Optimize physical activity & calcium / vitamin D levels.
Denosumab & bisphosphonates have been used, w/no direct comparison between the different options.
Denosumab was reported to be used in 1 affected person.
Pamidronate & zoledronic acid infusions have also been used.
Oral alendronate was documented to improve bone mineral content in 1 person.
Long-term response to these treatments is unknown.
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
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 by 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
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 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.
• Standard treatment ideally by craniofacial team
• Surgical correction of cleft palate
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Optimize physical activity & calcium / vitamin D levels.
• Denosumab & bisphosphonates have been used, w/no direct comparison between the different options.
• Denosumab was reported to be used in 1 affected person.
• Pamidronate & zoledronic acid infusions have also been used.
• Oral alendronate was documented to improve bone mineral content in 1 person.
• Long-term response to these treatments is unknown.
• 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
• 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
• 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 by 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 and to reduce the risk for later-onset orthopedic complications (e.g., contractures, scoliosis, hip dislocation).
Consider use of durable medical equipment 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 as needed (e.g., wheelchairs, walkers, bath chairs, orthotics, adaptive strollers).
## 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
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 or changes in tone.
Annually if BMD z score is below −1
Every 2 yrs if BMD z score is above −1
Measure alkaline phosphatase.
Consider obtaining vitamin D levels &, if vitamin D supplementation is being considered, serum calcium levels.
Annually if elevated
Every 2 yrs if normal
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; BMD = bone mineral density; DXA = dual-energy x-ray absorptiometry; 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 or changes in tone.
• Annually if BMD z score is below −1
• Every 2 yrs if BMD z score is above −1
• Measure alkaline phosphatase.
• Consider obtaining vitamin D levels &, if vitamin D supplementation is being considered, serum calcium levels.
• Annually if elevated
• Every 2 yrs if normal
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
To date, almost all probands with SAS reported in the literature have the disorder as the result of a
In approximately 1% of individuals, SAS is the result of a genetic alteration inherited from a mosaic parent.
Sib recurrence due to presumed parental germline mosaicism was reported in two families in which the genetic alteration identified in the affected sibs was not detected in parental leukocyte DNA (in one family, a
Low-level parental somatic mosaicism for a
Recommendations for the evaluation of parents of a proband with SAS include genetic testing capable of detecting the SAS-related genetic alteration identified in the proband. If the proband has a 2q33.1 deletion or duplication encompassing
If the genetic alteration identified in the proband is not identified in either parent, neither parent has a balanced translocation or other predisposing chromosomal anomaly, 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 [
Almost all affected individuals reported in the literature to date have had a
Each child of an individual with a
To date, individuals with SAS are not known to reproduce.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/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.
Once the SAS-related genetic alteration has been identified in an affected family member, molecular genetic 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.
• To date, almost all probands with SAS reported in the literature have the disorder as the result of a
• In approximately 1% of individuals, SAS is the result of a genetic alteration inherited from a mosaic parent.
• Sib recurrence due to presumed parental germline mosaicism was reported in two families in which the genetic alteration identified in the affected sibs was not detected in parental leukocyte DNA (in one family, a
• Low-level parental somatic mosaicism for a
• Sib recurrence due to presumed parental germline mosaicism was reported in two families in which the genetic alteration identified in the affected sibs was not detected in parental leukocyte DNA (in one family, a
• Low-level parental somatic mosaicism for a
• Recommendations for the evaluation of parents of a proband with SAS include genetic testing capable of detecting the SAS-related genetic alteration identified in the proband. If the proband has a 2q33.1 deletion or duplication encompassing
• If the genetic alteration identified in the proband is not identified in either parent, neither parent has a balanced translocation or other predisposing chromosomal anomaly, 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 [
• Sib recurrence due to presumed parental germline mosaicism was reported in two families in which the genetic alteration identified in the affected sibs was not detected in parental leukocyte DNA (in one family, a
• Low-level parental somatic mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• Almost all affected individuals reported in the literature to date have had a
• Each child of an individual with a
• To date, individuals with SAS are not known to reproduce.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/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.
## Mode of Inheritance
## Risk to Family Members
To date, almost all probands with SAS reported in the literature have the disorder as the result of a
In approximately 1% of individuals, SAS is the result of a genetic alteration inherited from a mosaic parent.
Sib recurrence due to presumed parental germline mosaicism was reported in two families in which the genetic alteration identified in the affected sibs was not detected in parental leukocyte DNA (in one family, a
Low-level parental somatic mosaicism for a
Recommendations for the evaluation of parents of a proband with SAS include genetic testing capable of detecting the SAS-related genetic alteration identified in the proband. If the proband has a 2q33.1 deletion or duplication encompassing
If the genetic alteration identified in the proband is not identified in either parent, neither parent has a balanced translocation or other predisposing chromosomal anomaly, 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 [
Almost all affected individuals reported in the literature to date have had a
Each child of an individual with a
To date, individuals with SAS are not known to reproduce.
• To date, almost all probands with SAS reported in the literature have the disorder as the result of a
• In approximately 1% of individuals, SAS is the result of a genetic alteration inherited from a mosaic parent.
• Sib recurrence due to presumed parental germline mosaicism was reported in two families in which the genetic alteration identified in the affected sibs was not detected in parental leukocyte DNA (in one family, a
• Low-level parental somatic mosaicism for a
• Sib recurrence due to presumed parental germline mosaicism was reported in two families in which the genetic alteration identified in the affected sibs was not detected in parental leukocyte DNA (in one family, a
• Low-level parental somatic mosaicism for a
• Recommendations for the evaluation of parents of a proband with SAS include genetic testing capable of detecting the SAS-related genetic alteration identified in the proband. If the proband has a 2q33.1 deletion or duplication encompassing
• If the genetic alteration identified in the proband is not identified in either parent, neither parent has a balanced translocation or other predisposing chromosomal anomaly, 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 [
• Sib recurrence due to presumed parental germline mosaicism was reported in two families in which the genetic alteration identified in the affected sibs was not detected in parental leukocyte DNA (in one family, a
• Low-level parental somatic mosaicism for a
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism [
• Almost all affected individuals reported in the literature to date have had a
• Each child of an individual with a
• To date, individuals with SAS are not known to reproduce.
## 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/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.
## Prenatal Testing and Preimplantation Genetic Testing
Once the SAS-related genetic alteration has been identified in an affected family member, molecular genetic 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
Australia
United Kingdom
•
• Australia
•
•
•
•
•
•
•
•
•
• United Kingdom
•
## Molecular Genetics
SATB2-Associated Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SATB2-Associated Syndrome (
SATB2 has several cellular/molecular functions. First, SATB2 has been identified as a transcription factor, containing CUT domains and a homeodomain for DNA binding [
Second, SATB2 has been ascribed as a chromatin remodeler with pioneer factor function [
In mice,
Variants listed in the table have been provided by the authors.
SATB2 Portal (
## Chapter Notes
The
Dr Yuri Zarate (
Contact Dr Yuri Zarate to inquire about review of
We would like to acknowledge the continued support of the families we follow with SAS from around the world.
Katherine Bosanko, MS (2024-present)Jennifer Fish, PhD (2016-present)Julie Kaylor, MS; Arkansas Children's Hospital (2016-2024)Yuri A Zarate, MD (2016-present)
20 June 2024 (ma) Comprehensive update posted live
12 October 2017 (ma) Review posted live
19 December 2016 (yaz) Original submission
• 20 June 2024 (ma) Comprehensive update posted live
• 12 October 2017 (ma) Review posted live
• 19 December 2016 (yaz) Original submission
## Author Notes
The
Dr Yuri Zarate (
Contact Dr Yuri Zarate to inquire about review of
## Acknowledgments
We would like to acknowledge the continued support of the families we follow with SAS from around the world.
## Author History
Katherine Bosanko, MS (2024-present)Jennifer Fish, PhD (2016-present)Julie Kaylor, MS; Arkansas Children's Hospital (2016-2024)Yuri A Zarate, MD (2016-present)
## Revision History
20 June 2024 (ma) Comprehensive update posted live
12 October 2017 (ma) Review posted live
19 December 2016 (yaz) Original submission
• 20 June 2024 (ma) Comprehensive update posted live
• 12 October 2017 (ma) Review posted live
• 19 December 2016 (yaz) Original submission
## References
## Literature Cited
Facial features of individuals with
|
[] |
12/10/2017
|
20/6/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
saul-wilson
|
saul-wilson
|
[
"Microcephalic Osteodysplastic Dysplasia",
"Microcephalic Osteodysplastic Dysplasia",
"Conserved oligomeric Golgi complex subunit 4",
"COG4",
"Saul-Wilson Syndrome"
] |
Saul-Wilson Syndrome
|
Carlos Ferreira
|
Summary Saul-Wilson syndrome (SWS) is a skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges of fingers and toes, and often clubfoot. Early development (primarily speech and motor) is delayed; cognition is normal. Other findings can include hearing loss (conductive, sensorineural, and mixed), lamellar cataracts, and/or rod-cone retinal dystrophy. To date, 16 affected individuals have been reported. The diagnosis of SWS is established in a proband with marked short stature, typical facial and skeletal features, and a heterozygous pathogenic variant in SWS is an autosomal dominant disorder typically caused by a
|
## Diagnosis
Formal diagnostic criteria for Saul-Wilson syndrome have not been established.
Saul-Wilson syndrome
Skeletal
Profound short stature (typically of prenatal onset)
Clubfoot
Short distal phalanges of fingers and toes (See
Distinctive craniofacial features (See
Progeroid facial appearance (more striking during infancy)
Sparse hair and sparse eyebrows
Prominent forehead with prominent scalp veins
Enlargement and delayed closure of the anterior fontanelle (earliest known closure 21 months; still open at age 3 years in one child)
Narrow nasal bridge with convex nasal ridge
Prominent columella (developing in late childhood)
Thin vermilion of the upper lip
Mild micrognathia
Eyes
Blue sclerae (during the first few months of life)
Lamellar cataracts
Rod-cone dystrophy
Hearing loss (conductive, sensorineural, and mixed)
Early developmental delay (primarily speech) with normal cognition
Elevated hepatic transaminases
Intermittent neutropenia
Long bones
Short long bones
Overtubulation with thin diaphyses and flared metaphyses
Lucency of proximal femora
Coxa valga
Megaepiphyses
Hand
Small hands with short metacarpals and short phalanges
Accessory ossification centers of the proximal metacarpals
Cone-shaped epiphyses of the phalanges
Ivory epiphyses of the distal phalanges (in late childhood)
Spine
Hypoplasia of the odontoid process of C2
Hypoplasia of T12 or L1
Platyspondyly (vertebral bodies become taller with age)
Irregularities of the endplates of the vertebral bodies (in later life)
The diagnosis of Saul-Wilson syndrome
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 requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because Saul-Wilson syndrome is rare, individuals with the distinctive findings described in
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Saul-Wilson 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.
Since Saul-Wilson syndrome occurs through a gain-of-function mechanism and large intragenic deletions or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
• Skeletal
• Profound short stature (typically of prenatal onset)
• Clubfoot
• Short distal phalanges of fingers and toes (See
• Profound short stature (typically of prenatal onset)
• Clubfoot
• Short distal phalanges of fingers and toes (See
• Distinctive craniofacial features (See
• Progeroid facial appearance (more striking during infancy)
• Sparse hair and sparse eyebrows
• Prominent forehead with prominent scalp veins
• Enlargement and delayed closure of the anterior fontanelle (earliest known closure 21 months; still open at age 3 years in one child)
• Narrow nasal bridge with convex nasal ridge
• Prominent columella (developing in late childhood)
• Thin vermilion of the upper lip
• Mild micrognathia
• Progeroid facial appearance (more striking during infancy)
• Sparse hair and sparse eyebrows
• Prominent forehead with prominent scalp veins
• Enlargement and delayed closure of the anterior fontanelle (earliest known closure 21 months; still open at age 3 years in one child)
• Narrow nasal bridge with convex nasal ridge
• Prominent columella (developing in late childhood)
• Thin vermilion of the upper lip
• Mild micrognathia
• Eyes
• Blue sclerae (during the first few months of life)
• Lamellar cataracts
• Rod-cone dystrophy
• Blue sclerae (during the first few months of life)
• Lamellar cataracts
• Rod-cone dystrophy
• Hearing loss (conductive, sensorineural, and mixed)
• Early developmental delay (primarily speech) with normal cognition
• Profound short stature (typically of prenatal onset)
• Clubfoot
• Short distal phalanges of fingers and toes (See
• Progeroid facial appearance (more striking during infancy)
• Sparse hair and sparse eyebrows
• Prominent forehead with prominent scalp veins
• Enlargement and delayed closure of the anterior fontanelle (earliest known closure 21 months; still open at age 3 years in one child)
• Narrow nasal bridge with convex nasal ridge
• Prominent columella (developing in late childhood)
• Thin vermilion of the upper lip
• Mild micrognathia
• Blue sclerae (during the first few months of life)
• Lamellar cataracts
• Rod-cone dystrophy
• Elevated hepatic transaminases
• Intermittent neutropenia
• Long bones
• Short long bones
• Overtubulation with thin diaphyses and flared metaphyses
• Lucency of proximal femora
• Coxa valga
• Megaepiphyses
• Short long bones
• Overtubulation with thin diaphyses and flared metaphyses
• Lucency of proximal femora
• Coxa valga
• Megaepiphyses
• Hand
• Small hands with short metacarpals and short phalanges
• Accessory ossification centers of the proximal metacarpals
• Cone-shaped epiphyses of the phalanges
• Ivory epiphyses of the distal phalanges (in late childhood)
• Small hands with short metacarpals and short phalanges
• Accessory ossification centers of the proximal metacarpals
• Cone-shaped epiphyses of the phalanges
• Ivory epiphyses of the distal phalanges (in late childhood)
• Spine
• Hypoplasia of the odontoid process of C2
• Hypoplasia of T12 or L1
• Platyspondyly (vertebral bodies become taller with age)
• Irregularities of the endplates of the vertebral bodies (in later life)
• Hypoplasia of the odontoid process of C2
• Hypoplasia of T12 or L1
• Platyspondyly (vertebral bodies become taller with age)
• Irregularities of the endplates of the vertebral bodies (in later life)
• Short long bones
• Overtubulation with thin diaphyses and flared metaphyses
• Lucency of proximal femora
• Coxa valga
• Megaepiphyses
• Small hands with short metacarpals and short phalanges
• Accessory ossification centers of the proximal metacarpals
• Cone-shaped epiphyses of the phalanges
• Ivory epiphyses of the distal phalanges (in late childhood)
• Hypoplasia of the odontoid process of C2
• Hypoplasia of T12 or L1
• Platyspondyly (vertebral bodies become taller with age)
• Irregularities of the endplates of the vertebral bodies (in later life)
## Suggestive Findings
Saul-Wilson syndrome
Skeletal
Profound short stature (typically of prenatal onset)
Clubfoot
Short distal phalanges of fingers and toes (See
Distinctive craniofacial features (See
Progeroid facial appearance (more striking during infancy)
Sparse hair and sparse eyebrows
Prominent forehead with prominent scalp veins
Enlargement and delayed closure of the anterior fontanelle (earliest known closure 21 months; still open at age 3 years in one child)
Narrow nasal bridge with convex nasal ridge
Prominent columella (developing in late childhood)
Thin vermilion of the upper lip
Mild micrognathia
Eyes
Blue sclerae (during the first few months of life)
Lamellar cataracts
Rod-cone dystrophy
Hearing loss (conductive, sensorineural, and mixed)
Early developmental delay (primarily speech) with normal cognition
Elevated hepatic transaminases
Intermittent neutropenia
Long bones
Short long bones
Overtubulation with thin diaphyses and flared metaphyses
Lucency of proximal femora
Coxa valga
Megaepiphyses
Hand
Small hands with short metacarpals and short phalanges
Accessory ossification centers of the proximal metacarpals
Cone-shaped epiphyses of the phalanges
Ivory epiphyses of the distal phalanges (in late childhood)
Spine
Hypoplasia of the odontoid process of C2
Hypoplasia of T12 or L1
Platyspondyly (vertebral bodies become taller with age)
Irregularities of the endplates of the vertebral bodies (in later life)
• Skeletal
• Profound short stature (typically of prenatal onset)
• Clubfoot
• Short distal phalanges of fingers and toes (See
• Profound short stature (typically of prenatal onset)
• Clubfoot
• Short distal phalanges of fingers and toes (See
• Distinctive craniofacial features (See
• Progeroid facial appearance (more striking during infancy)
• Sparse hair and sparse eyebrows
• Prominent forehead with prominent scalp veins
• Enlargement and delayed closure of the anterior fontanelle (earliest known closure 21 months; still open at age 3 years in one child)
• Narrow nasal bridge with convex nasal ridge
• Prominent columella (developing in late childhood)
• Thin vermilion of the upper lip
• Mild micrognathia
• Progeroid facial appearance (more striking during infancy)
• Sparse hair and sparse eyebrows
• Prominent forehead with prominent scalp veins
• Enlargement and delayed closure of the anterior fontanelle (earliest known closure 21 months; still open at age 3 years in one child)
• Narrow nasal bridge with convex nasal ridge
• Prominent columella (developing in late childhood)
• Thin vermilion of the upper lip
• Mild micrognathia
• Eyes
• Blue sclerae (during the first few months of life)
• Lamellar cataracts
• Rod-cone dystrophy
• Blue sclerae (during the first few months of life)
• Lamellar cataracts
• Rod-cone dystrophy
• Hearing loss (conductive, sensorineural, and mixed)
• Early developmental delay (primarily speech) with normal cognition
• Profound short stature (typically of prenatal onset)
• Clubfoot
• Short distal phalanges of fingers and toes (See
• Progeroid facial appearance (more striking during infancy)
• Sparse hair and sparse eyebrows
• Prominent forehead with prominent scalp veins
• Enlargement and delayed closure of the anterior fontanelle (earliest known closure 21 months; still open at age 3 years in one child)
• Narrow nasal bridge with convex nasal ridge
• Prominent columella (developing in late childhood)
• Thin vermilion of the upper lip
• Mild micrognathia
• Blue sclerae (during the first few months of life)
• Lamellar cataracts
• Rod-cone dystrophy
• Elevated hepatic transaminases
• Intermittent neutropenia
• Long bones
• Short long bones
• Overtubulation with thin diaphyses and flared metaphyses
• Lucency of proximal femora
• Coxa valga
• Megaepiphyses
• Short long bones
• Overtubulation with thin diaphyses and flared metaphyses
• Lucency of proximal femora
• Coxa valga
• Megaepiphyses
• Hand
• Small hands with short metacarpals and short phalanges
• Accessory ossification centers of the proximal metacarpals
• Cone-shaped epiphyses of the phalanges
• Ivory epiphyses of the distal phalanges (in late childhood)
• Small hands with short metacarpals and short phalanges
• Accessory ossification centers of the proximal metacarpals
• Cone-shaped epiphyses of the phalanges
• Ivory epiphyses of the distal phalanges (in late childhood)
• Spine
• Hypoplasia of the odontoid process of C2
• Hypoplasia of T12 or L1
• Platyspondyly (vertebral bodies become taller with age)
• Irregularities of the endplates of the vertebral bodies (in later life)
• Hypoplasia of the odontoid process of C2
• Hypoplasia of T12 or L1
• Platyspondyly (vertebral bodies become taller with age)
• Irregularities of the endplates of the vertebral bodies (in later life)
• Short long bones
• Overtubulation with thin diaphyses and flared metaphyses
• Lucency of proximal femora
• Coxa valga
• Megaepiphyses
• Small hands with short metacarpals and short phalanges
• Accessory ossification centers of the proximal metacarpals
• Cone-shaped epiphyses of the phalanges
• Ivory epiphyses of the distal phalanges (in late childhood)
• Hypoplasia of the odontoid process of C2
• Hypoplasia of T12 or L1
• Platyspondyly (vertebral bodies become taller with age)
• Irregularities of the endplates of the vertebral bodies (in later life)
## Establishing the Diagnosis
The diagnosis of Saul-Wilson syndrome
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 requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Because Saul-Wilson syndrome is rare, individuals with the distinctive findings described in
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Saul-Wilson 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.
Since Saul-Wilson syndrome occurs through a gain-of-function mechanism and large intragenic deletions or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
## Option 1: Single-Gene Testing
## Option 2: Genomic Testing
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Saul-Wilson 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.
Since Saul-Wilson syndrome occurs through a gain-of-function mechanism and large intragenic deletions or duplication has not been reported, testing for intragenic deletions or duplication is unlikely to identify a disease-causing variant.
## Clinical Characteristics
Saul-Wilson syndrome is a skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges of fingers and toes, and often clubfoot. Early development (primarily speech) is delayed; cognition is normal. Other findings can include hearing loss (conductive, sensorineural, and mixed), lamellar cataracts, and/or rod-cone retinal dystrophy.
A total of 16 individuals with Saul-Wilson syndrome have been reported to date. Saul-Wilson syndrome was first described in a small-for-gestational-age infant with bulging fontanelles, clubfoot, blue sclerae, and blunted fingertips; over time, growth was delayed and the child developed bilateral cataracts, and hearing loss as the result of frequent otitis media [
Individuals with Saul-Wilson syndrome show impaired postnatal growth, and several also had intrauterine growth restriction (IUGR).
Mean length, weight, and head circumference at birth:
Length. 44.1 cm (range: 38.0-49.0)
Weight. 2.09 kg (range: 1.45-2.80)
Head circumference. 31.7 cm (range: 29.0-34.0)
Z scores at birth:
Length. -2.3 (1.5 SD; range: -0.4 to -5.1)
Weight. -2.4 (0.7 SD; range: -1.2 to -3.8)
Head circumference: -2.0 (0.9 SD; range: -0.8 to -3.9)
Z scores decline sharply over the first few months of life. At last examination:
Stature. -6.3 (1.8 SD; range: -3.5 to -9.8)
Weight. -4.0 (1.2 SD; range: -1.1 to -5.8)
Head circumference. -1.7 (1.7 SD; range: 0.8 to -5.0)
Mean height, weight, and head circumference at skeletal maturity:
Height. 107.6 cm
Weight. 30.5 kg
Head circumference. 50.2 cm
Z scores at skeletal maturity:
Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
Growth charts for clinical use are currently under development.
Despite absolute microcephaly, head circumferences exceed the height by more than 2 SD, with consequent relative macrocephaly.
Speech delay (8/11) and motor delay (12/14) are common, probably related to the presence of hearing loss and skeletal deformities, respectively; cognitive development does not appear to be affected.
The majority of affected individuals develop lamellar cataracts during the first few years of life (10/13), and several developed retinal involvement (6/9). Retinal pigmentary changes can be seen in the periphery as early as the toddler years. During adolescence and early adulthood, a rod-cone dystrophy (5/9) becomes evident with constricted visual fields and night blindness.
Macular cystic changes were also described (2/4). One individual had myelinated retinal nerve fibers [
Shortening of the distal phalanges of fingers and toes is appreciated on physical examination (12/14). This finding, apparent at birth, did not progress over time. The majority of individuals (10/14) had clubfoot, and in some cases residual deformity even after multiple attempts at surgical repair [
Bone fragility has been suggested, as several individuals (4/14) developed fractures with minimal or no known trauma [
Osteoarticular pain was reported by all three adults. Two had confirmed degenerative joint disease, leading to joint replacement surgeries in one individual in her 20s [
The combination of megaepiphyses with coxa valga, leading to acetabulum-femoral epiphyseal incongruence, may contribute to premature osteoarthropathy of the hip.
No genotype-phenotype correlation is possible because all affected individuals have the same amino acid substitution.
Penetrance is thought to be 100%.
Sixteen individuals have been reported to date. Three additional individuals are known to have the diagnosis of Saul-Wilson syndrome [Author, personal observation]. There is no known geographic predilection.
• Length. 44.1 cm (range: 38.0-49.0)
• Weight. 2.09 kg (range: 1.45-2.80)
• Head circumference. 31.7 cm (range: 29.0-34.0)
• Length. -2.3 (1.5 SD; range: -0.4 to -5.1)
• Weight. -2.4 (0.7 SD; range: -1.2 to -3.8)
• Head circumference: -2.0 (0.9 SD; range: -0.8 to -3.9)
• Stature. -6.3 (1.8 SD; range: -3.5 to -9.8)
• Weight. -4.0 (1.2 SD; range: -1.1 to -5.8)
• Head circumference. -1.7 (1.7 SD; range: 0.8 to -5.0)
• Mean height, weight, and head circumference at skeletal maturity:
• Height. 107.6 cm
• Weight. 30.5 kg
• Head circumference. 50.2 cm
• Height. 107.6 cm
• Weight. 30.5 kg
• Head circumference. 50.2 cm
• Z scores at skeletal maturity:
• Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
• Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
• Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
• Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
• Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
• Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
• Height. 107.6 cm
• Weight. 30.5 kg
• Head circumference. 50.2 cm
• Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
• Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
• Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
## Clinical Description
Saul-Wilson syndrome is a skeletal dysplasia characterized by profound short stature, distinctive craniofacial features, short distal phalanges of fingers and toes, and often clubfoot. Early development (primarily speech) is delayed; cognition is normal. Other findings can include hearing loss (conductive, sensorineural, and mixed), lamellar cataracts, and/or rod-cone retinal dystrophy.
A total of 16 individuals with Saul-Wilson syndrome have been reported to date. Saul-Wilson syndrome was first described in a small-for-gestational-age infant with bulging fontanelles, clubfoot, blue sclerae, and blunted fingertips; over time, growth was delayed and the child developed bilateral cataracts, and hearing loss as the result of frequent otitis media [
Individuals with Saul-Wilson syndrome show impaired postnatal growth, and several also had intrauterine growth restriction (IUGR).
Mean length, weight, and head circumference at birth:
Length. 44.1 cm (range: 38.0-49.0)
Weight. 2.09 kg (range: 1.45-2.80)
Head circumference. 31.7 cm (range: 29.0-34.0)
Z scores at birth:
Length. -2.3 (1.5 SD; range: -0.4 to -5.1)
Weight. -2.4 (0.7 SD; range: -1.2 to -3.8)
Head circumference: -2.0 (0.9 SD; range: -0.8 to -3.9)
Z scores decline sharply over the first few months of life. At last examination:
Stature. -6.3 (1.8 SD; range: -3.5 to -9.8)
Weight. -4.0 (1.2 SD; range: -1.1 to -5.8)
Head circumference. -1.7 (1.7 SD; range: 0.8 to -5.0)
Mean height, weight, and head circumference at skeletal maturity:
Height. 107.6 cm
Weight. 30.5 kg
Head circumference. 50.2 cm
Z scores at skeletal maturity:
Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
Growth charts for clinical use are currently under development.
Despite absolute microcephaly, head circumferences exceed the height by more than 2 SD, with consequent relative macrocephaly.
Speech delay (8/11) and motor delay (12/14) are common, probably related to the presence of hearing loss and skeletal deformities, respectively; cognitive development does not appear to be affected.
The majority of affected individuals develop lamellar cataracts during the first few years of life (10/13), and several developed retinal involvement (6/9). Retinal pigmentary changes can be seen in the periphery as early as the toddler years. During adolescence and early adulthood, a rod-cone dystrophy (5/9) becomes evident with constricted visual fields and night blindness.
Macular cystic changes were also described (2/4). One individual had myelinated retinal nerve fibers [
Shortening of the distal phalanges of fingers and toes is appreciated on physical examination (12/14). This finding, apparent at birth, did not progress over time. The majority of individuals (10/14) had clubfoot, and in some cases residual deformity even after multiple attempts at surgical repair [
Bone fragility has been suggested, as several individuals (4/14) developed fractures with minimal or no known trauma [
Osteoarticular pain was reported by all three adults. Two had confirmed degenerative joint disease, leading to joint replacement surgeries in one individual in her 20s [
The combination of megaepiphyses with coxa valga, leading to acetabulum-femoral epiphyseal incongruence, may contribute to premature osteoarthropathy of the hip.
• Length. 44.1 cm (range: 38.0-49.0)
• Weight. 2.09 kg (range: 1.45-2.80)
• Head circumference. 31.7 cm (range: 29.0-34.0)
• Length. -2.3 (1.5 SD; range: -0.4 to -5.1)
• Weight. -2.4 (0.7 SD; range: -1.2 to -3.8)
• Head circumference: -2.0 (0.9 SD; range: -0.8 to -3.9)
• Stature. -6.3 (1.8 SD; range: -3.5 to -9.8)
• Weight. -4.0 (1.2 SD; range: -1.1 to -5.8)
• Head circumference. -1.7 (1.7 SD; range: 0.8 to -5.0)
• Mean height, weight, and head circumference at skeletal maturity:
• Height. 107.6 cm
• Weight. 30.5 kg
• Head circumference. 50.2 cm
• Height. 107.6 cm
• Weight. 30.5 kg
• Head circumference. 50.2 cm
• Z scores at skeletal maturity:
• Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
• Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
• Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
• Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
• Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
• Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
• Height. 107.6 cm
• Weight. 30.5 kg
• Head circumference. 50.2 cm
• Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
• Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
• Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
## Growth
Individuals with Saul-Wilson syndrome show impaired postnatal growth, and several also had intrauterine growth restriction (IUGR).
Mean length, weight, and head circumference at birth:
Length. 44.1 cm (range: 38.0-49.0)
Weight. 2.09 kg (range: 1.45-2.80)
Head circumference. 31.7 cm (range: 29.0-34.0)
Z scores at birth:
Length. -2.3 (1.5 SD; range: -0.4 to -5.1)
Weight. -2.4 (0.7 SD; range: -1.2 to -3.8)
Head circumference: -2.0 (0.9 SD; range: -0.8 to -3.9)
Z scores decline sharply over the first few months of life. At last examination:
Stature. -6.3 (1.8 SD; range: -3.5 to -9.8)
Weight. -4.0 (1.2 SD; range: -1.1 to -5.8)
Head circumference. -1.7 (1.7 SD; range: 0.8 to -5.0)
Mean height, weight, and head circumference at skeletal maturity:
Height. 107.6 cm
Weight. 30.5 kg
Head circumference. 50.2 cm
Z scores at skeletal maturity:
Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
Growth charts for clinical use are currently under development.
Despite absolute microcephaly, head circumferences exceed the height by more than 2 SD, with consequent relative macrocephaly.
• Length. 44.1 cm (range: 38.0-49.0)
• Weight. 2.09 kg (range: 1.45-2.80)
• Head circumference. 31.7 cm (range: 29.0-34.0)
• Length. -2.3 (1.5 SD; range: -0.4 to -5.1)
• Weight. -2.4 (0.7 SD; range: -1.2 to -3.8)
• Head circumference: -2.0 (0.9 SD; range: -0.8 to -3.9)
• Stature. -6.3 (1.8 SD; range: -3.5 to -9.8)
• Weight. -4.0 (1.2 SD; range: -1.1 to -5.8)
• Head circumference. -1.7 (1.7 SD; range: 0.8 to -5.0)
• Mean height, weight, and head circumference at skeletal maturity:
• Height. 107.6 cm
• Weight. 30.5 kg
• Head circumference. 50.2 cm
• Height. 107.6 cm
• Weight. 30.5 kg
• Head circumference. 50.2 cm
• Z scores at skeletal maturity:
• Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
• Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
• Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
• Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
• Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
• Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
• Height. 107.6 cm
• Weight. 30.5 kg
• Head circumference. 50.2 cm
• Height. -8.9 (0.8 SD; range: -8.3 to -9.8)
• Weight. -4.3 (0.6 SD; range: -3.6 to -4.8)
• Head circumference. -3.9 (1.6 SD; range: -2.7 to -5.0)
## Development
Speech delay (8/11) and motor delay (12/14) are common, probably related to the presence of hearing loss and skeletal deformities, respectively; cognitive development does not appear to be affected.
## Ophthalmologic Features
The majority of affected individuals develop lamellar cataracts during the first few years of life (10/13), and several developed retinal involvement (6/9). Retinal pigmentary changes can be seen in the periphery as early as the toddler years. During adolescence and early adulthood, a rod-cone dystrophy (5/9) becomes evident with constricted visual fields and night blindness.
Macular cystic changes were also described (2/4). One individual had myelinated retinal nerve fibers [
## Skeletal Features
Shortening of the distal phalanges of fingers and toes is appreciated on physical examination (12/14). This finding, apparent at birth, did not progress over time. The majority of individuals (10/14) had clubfoot, and in some cases residual deformity even after multiple attempts at surgical repair [
Bone fragility has been suggested, as several individuals (4/14) developed fractures with minimal or no known trauma [
Osteoarticular pain was reported by all three adults. Two had confirmed degenerative joint disease, leading to joint replacement surgeries in one individual in her 20s [
The combination of megaepiphyses with coxa valga, leading to acetabulum-femoral epiphyseal incongruence, may contribute to premature osteoarthropathy of the hip.
## Other
## Genotype-Phenotype Correlations
No genotype-phenotype correlation is possible because all affected individuals have the same amino acid substitution.
## Penetrance
Penetrance is thought to be 100%.
## Prevalence
Sixteen individuals have been reported to date. Three additional individuals are known to have the diagnosis of Saul-Wilson syndrome [Author, personal observation]. There is no known geographic predilection.
## Genetically Related (Allelic) Disorders
Biallelic loss-of-function or hypomorphic variants in
## Differential Diagnosis
Disorders Interest in the Differential Diagnosis of Saul-Wilson Syndrome
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; SWS = Saul-Wilson syndrome
In most families, a proband with SRS represents a simplex case (a single affected family member) and has SRS as the result of an apparent
The majority of individuals diagnosed with osteogenesis imperfect (OI) have the disorder as the result of a pathogenic variant in
Intellectual disability is not typically observed in Saul-Wilson syndrome.
## Management
To establish the extent of disease and needs in an individual diagnosed with Saul-Wilson syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Saul-Wilson Syndrome
Mgmt of clubfoot
Assess osteoarticular pain.
Flexion-extension radiographs of lateral cervical spine
Flexion-extension MRI if instability & compression seen on radiographs or interpretation is limited (e.g., in young individuals w/delayed ossification of cervical vertebral bodies)
BCVA
Refractive error
Assessment of dark adaptation
Full-field ERG
Spectral-domain OCT
Community or online
Social work involvement for parental support.
BCVA = best-corrected Snellen visual acuity; BMD = bone mineral density; ERG = electroretinography; FTT = failure to thrive; HC = head circumference; HT = height; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy; SNHL= sensorineural hearing loss; SWS = Saul-Wilson syndrome; WT = weight
See
Treatment of Manifestations in Individuals with Saul-Wilson Syndrome
Night vision scopes or selected wavelength filters
Community vision services in teen yrs / young adulthood
Myringotomy tubes
Hearing aids
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments.
GCSF = granulocyte colony-stimulating factor; OT = occupational therapist; PT = physical therapist
See
In the US, publicly funded agencies at the state level provide services for the visually impaired or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living.
See
The following information represents typical management recommendations for individuals with developmental delay 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.
Recommended Surveillance for Individuals with Saul-Wilson Syndrome
Flexion-extension radiograph
Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
Those known to have rod-cone dystrophy: BVCA, refractive error, dark adaptation, & visual field testing
Those not known to have rod-cone dystrophy (See
All patients: cataracts
BCVA = best-corrected Snellen visual acuity; DXA = dual-energy x-ray absorptiometry; HC = head circumference; HT = height; SWS = Saul-Wilson syndrome; WT = weight
Participation in gymnastics and jumping on a trampoline should be avoided until atlanto-axial instability is excluded.
See
Pregnancy of an affected woman has not been documented to date, although regular menstrual cycles and a normal hormone profile in two adult females suggest no impairment of the ability to conceive [
Search
• Mgmt of clubfoot
• Assess osteoarticular pain.
• Flexion-extension radiographs of lateral cervical spine
• Flexion-extension MRI if instability & compression seen on radiographs or interpretation is limited (e.g., in young individuals w/delayed ossification of cervical vertebral bodies)
• BCVA
• Refractive error
• Assessment of dark adaptation
• Full-field ERG
• Spectral-domain OCT
• Community or online
• Social work involvement for parental support.
• Night vision scopes or selected wavelength filters
• Community vision services in teen yrs / young adulthood
• Myringotomy tubes
• Hearing aids
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments.
• 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.
• Flexion-extension radiograph
• Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
• Those known to have rod-cone dystrophy: BVCA, refractive error, dark adaptation, & visual field testing
• Those not known to have rod-cone dystrophy (See
• All patients: cataracts
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Saul-Wilson syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Saul-Wilson Syndrome
Mgmt of clubfoot
Assess osteoarticular pain.
Flexion-extension radiographs of lateral cervical spine
Flexion-extension MRI if instability & compression seen on radiographs or interpretation is limited (e.g., in young individuals w/delayed ossification of cervical vertebral bodies)
BCVA
Refractive error
Assessment of dark adaptation
Full-field ERG
Spectral-domain OCT
Community or online
Social work involvement for parental support.
BCVA = best-corrected Snellen visual acuity; BMD = bone mineral density; ERG = electroretinography; FTT = failure to thrive; HC = head circumference; HT = height; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy; SNHL= sensorineural hearing loss; SWS = Saul-Wilson syndrome; WT = weight
See
• Mgmt of clubfoot
• Assess osteoarticular pain.
• Flexion-extension radiographs of lateral cervical spine
• Flexion-extension MRI if instability & compression seen on radiographs or interpretation is limited (e.g., in young individuals w/delayed ossification of cervical vertebral bodies)
• BCVA
• Refractive error
• Assessment of dark adaptation
• Full-field ERG
• Spectral-domain OCT
• Community or online
• Social work involvement for parental support.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Saul-Wilson Syndrome
Night vision scopes or selected wavelength filters
Community vision services in teen yrs / young adulthood
Myringotomy tubes
Hearing aids
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments.
GCSF = granulocyte colony-stimulating factor; OT = occupational therapist; PT = physical therapist
See
In the US, publicly funded agencies at the state level provide services for the visually impaired or those with progressive eye disorders; services include vocational training, mobility training, and skills for independent living.
See
The following information represents typical management recommendations for individuals with developmental delay 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.
• Night vision scopes or selected wavelength filters
• Community vision services in teen yrs / young adulthood
• Myringotomy tubes
• Hearing aids
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments.
• 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 Management Issues
The following information represents typical management recommendations for individuals with developmental delay 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.
## Surveillance
Recommended Surveillance for Individuals with Saul-Wilson Syndrome
Flexion-extension radiograph
Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
Those known to have rod-cone dystrophy: BVCA, refractive error, dark adaptation, & visual field testing
Those not known to have rod-cone dystrophy (See
All patients: cataracts
BCVA = best-corrected Snellen visual acuity; DXA = dual-energy x-ray absorptiometry; HC = head circumference; HT = height; SWS = Saul-Wilson syndrome; WT = weight
• Flexion-extension radiograph
• Flexion-extension MRI if instability & compression on radiographs or limited interpretation on radiographs
• Those known to have rod-cone dystrophy: BVCA, refractive error, dark adaptation, & visual field testing
• Those not known to have rod-cone dystrophy (See
• All patients: cataracts
## Agents/Circumstances to Avoid
Participation in gymnastics and jumping on a trampoline should be avoided until atlanto-axial instability is excluded.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Pregnancy of an affected woman has not been documented to date, although regular menstrual cycles and a normal hormone profile in two adult females suggest no impairment of the ability to conceive [
## Therapies Under Investigation
Search
## Genetic Counseling
Saul-Wilson syndrome is an autosomal dominant disorder typically caused by a
No individual with Saul-Wilson syndrome reported to date has had an affected parent.
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
If a parent of the proband is affected and/or is known to have the
If the proband has a known SWS-related
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• No individual with Saul-Wilson syndrome reported to date has had an affected parent.
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• If a parent of the proband is affected and/or is known to have the
• If the proband has a known SWS-related
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Saul-Wilson syndrome is an autosomal dominant disorder typically caused by a
## Risk to Family Members
No individual with Saul-Wilson syndrome reported to date has had an affected parent.
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
If a parent of the proband is affected and/or is known to have the
If the proband has a known SWS-related
• No individual with Saul-Wilson syndrome reported to date has had an affected parent.
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• If a parent of the proband is affected and/or is known to have the
• If the proband has a known SWS-related
## 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
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
Saul-Wilson Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Saul-Wilson Syndrome (
COG4 is a subunit of the conserved oligomeric Golgi (COG) complex, a hetero-octameric protein complex that regulates vesicular trafficking between the Golgi apparatus and the endoplasmic reticulum (ER).
Notable
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
COG4 is a subunit of the conserved oligomeric Golgi (COG) complex, a hetero-octameric protein complex that regulates vesicular trafficking between the Golgi apparatus and the endoplasmic reticulum (ER).
Notable
Variants listed in the table have been provided by the author.
## Chapter Notes
20 February 2020 (bp) Review posted live
4 October 2019 (cf) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 20 February 2020 (bp) Review posted live
• 4 October 2019 (cf) Original submission
## Revision History
20 February 2020 (bp) Review posted live
4 October 2019 (cf) Original submission
Note: Pursuant to 17 USC Section 105 of the United States Copyright Act, the
• 20 February 2020 (bp) Review posted live
• 4 October 2019 (cf) Original submission
## References
## Literature Cited
A, C, and D. Note prominent forehead, scalp veins, and columella, as well as thin vermilion of the upper lip.
B. Note short distal phalanges of the fingers.
Images provided by the author.
A. Babygram obtained at age 11 months. Note coxa valga, overtubulation of the long bones, and lucencies of the proximal femora.
B. Lateral cervical spine radiograph obtained at age eight months highlighting hypoplasia of the odontoid process
C. Left hand radiograph obtained at age six years nine months showing short metacarpals and short phalanges, cone-shaped epiphyses of phalanges, pseudoepiphysis of the second metacarpal, and ivory epiphyses of the distal phalanges.
Images provided by the author.
|
[
"Y Chinen, T Kaneshi, T Kamiya, K Hata, G Nishimura, T Kaname. Progressive hip joint subluxation in Saul-Wilson syndrome.. Am J Med Genet A. 2015;167A:2834-8",
"CR Ferreira, ZJ Xia, A Clément, DA Parry, M Davids, F Taylan, P Sharma, CT Turgeon, B Blanco-Sánchez, BG Ng, CV Logan, LA Wolfe, BD Solomon, MT Cho, G Douglas, DR Carvalho, H Bratke, MG Haug, JB Phillips, J Wegner, M Tiemeyer, K Aoki, A Nordgren, A Hammarsjö, AL Duker, L Rohena, HB Hove, J Ek, D Adams, CJ Tifft, T Onyekweli, T Weixel, E Macnamara, K Radtke, Z Powis, D Earl, M Gabriel, AHS Russi, L Brick, M Kozenko, E Tham, KM Raymond, JA Phillips, GE Tiller, WG Wilson, R Hamid, MCV Malicdan, G Nishimura, G Grigelioniene, A Jackson, M Westerfield, MB Bober, WA Gahl, HH Freeze. A recurrent de novo heterozygous COG4 substitution leads to Saul-Wilson syndrome, disrupted vesicular trafficking, and altered proteoglycan glycosylation.. Am J Hum Genet. 2018;103:553-67",
"CR Ferreira, WM Zein, LA Huryn, A Merker, SI Berger, WG Wilson, GE Tiller, LA Wolfe, M Merideth, DR Carvalho, AL Duker, H Bratke, MG Haug, L Rohena, HB Hove, ZJ Xia, BG Ng, HH Freeze, M Gabriel, AHS Russi, L Brick, M Kozenko, DL Earl, E Tham, G Nishimura, JA Phillips, WA Gahl, R Hamid, AP Jackson, G Grigelioniene, MB Bober. Defining the clinical phenotype of Saul-Wilson syndrome.. Genet Med. 2020;22:857-66",
"JH Hersh, MR Joyce, J Spranger, EC Goatley, RS Lachman, S Bhatt, DL Rimoin. Microcephalic osteodysplastic dysplasia.. Am J Med Genet. 1994;51:194-9",
"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",
"RA Saul. Unknown cases.. Proc Greenwood Genet Ctr. 1982;1:102-5",
"RA Saul, WG Wilson. A new skeletal dysplasia in two unrelated boys.. Am J Med Genet. 1990;35:388-93",
"KK White, V Bompadre, MJ Goldberg, MB Bober, TJ Cho, JE Hoover-Fong, M Irving, WG Mackenzie, SE Kamps, C Raggio, GJ Redding, SS Spencer, R Savarirayan, MC Theroux. Best practices in peri-operative management of patients with skeletal dysplasias.. Am J Med Genet A. 2017;173:2584-95",
"BS Zemel, HJ Kalkwarf, V Gilsanz, JM Lappe, S Oberfield, JA Shepherd, MM Frederick, X Huang, M Lu, S Mahboubi, T Hangartner, KK Winer. Revised reference curves for bone mineral content and areal bone mineral density according to age and sex for black and non-black children: results of the bone mineral density in childhood study.. J Clin Endocrinol Metab. 2011;96:3160-9",
"BS Zemel, MB Leonard, A Kelly, JM Lappe, V Gilsanz, S Oberfield, S Mahboubi, JA Shepherd, TN Hangartner, MM Frederick, KK Winer, HJ Kalkwarf. Height adjustment in assessing dual energy x-ray absorptiometry measurements of bone mass and density in children.. J Clin Endocrinol Metab. 2010;95:1265-73"
] |
20/2/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sca-io
|
sca-io
|
[
"IOSCA",
"Mitochondrial DNA Depletion Syndrome 7",
"IOSCA",
"Mitochondrial DNA Depletion Syndrome 7",
"Twinkle mtDNA helicase",
"TWNK",
"Infantile-Onset Spinocerebellar Ataxia"
] |
Infantile-Onset Spinocerebellar Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Tuula Lönnqvist
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Summary Infantile-onset spinocerebellar ataxia (IOSCA) is a severe, progressive neurodegenerative disorder characterized by normal development until age one year, followed by onset of ataxia, muscle hypotonia, loss of deep-tendon reflexes, and athetosis. Ophthalmoplegia and sensorineural deafness develop by age seven years. By adolescence, affected individuals are profoundly deaf and no longer ambulatory; sensory axonal neuropathy, optic atrophy, autonomic nervous system dysfunction, and hypergonadotropic hypogonadism in females become evident. Epilepsy can develop into a serious and often fatal encephalopathy: myoclonic jerks or focal clonic seizures that progress to epilepsia partialis continua followed by status epilepticus with loss of consciousness. The diagnosis of IOSCA is established in a proband with typical clinical findings and identification of biallelic pathogenic variants in IOSCA 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 pathogenic variants in the family are known.
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## Diagnosis
Infantile-onset spinocerebellar ataxia (IOSCA) is a clinical spectrum that was originally described in individuals of Finnish descent; however, the phenotype has been expanded by the identification of affected individuals of non-Finnish descent whose features may deviate from the originally described "classic" phenotype
Clinical diagnostic criteria for IOSCA were published by
Infantile-onset spinocerebellar ataxia (IOSCA)
Spinocerebellar ataxia
Muscle hypotonia
Athetoid movements
Loss of deep-tendon reflexes
Hearing deficit
Ophthalmoplegia
Optic atrophy
Primary hypergonadotropic hypogonadism in females
Epileptic encephalopathy
Normal routine laboratory and metabolic screening tests
Normal muscle morphology and respiratory chain enzyme analyses
Absence of mitochondrial DNA (mtDNA) deletion and/or depletion in muscle; however:
A few affected individuals had mtDNA depletion in the liver [
Postmortem material has revealed complex I deficiency and mtDNA depletion in the brain [
Note: Muscle biopsy with histology and respiratory chain enzyme analysis are not required for the diagnosis of IOSCA.
The diagnosis of IOSCA
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 [
Identification of biallelic
Molecular genetic testing approaches can include
Targeted analysis for the founder pathogenic
Note: All individuals with the IOSCA founder variant in
In those who are not of known Finnish ancestry or in whom targeted testing for the Finnish founder variant identifies one or no pathogenic variant, sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Infantile-Onset Spinocerebellar Ataxia
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
In the exon / flanking intron regions sequenced; pathogenic variants in non-sequenced intron and regulatory regions are not detected.
Sequence analysis detects the Finnish founder variant and others, including
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.
Gene-targeted deletion/duplication analysis has not identified any deletions/duplications.
• Spinocerebellar ataxia
• Muscle hypotonia
• Athetoid movements
• Loss of deep-tendon reflexes
• Hearing deficit
• Ophthalmoplegia
• Optic atrophy
• Primary hypergonadotropic hypogonadism in females
• Epileptic encephalopathy
• Normal routine laboratory and metabolic screening tests
• Normal muscle morphology and respiratory chain enzyme analyses
• Absence of mitochondrial DNA (mtDNA) deletion and/or depletion in muscle; however:
• A few affected individuals had mtDNA depletion in the liver [
• Postmortem material has revealed complex I deficiency and mtDNA depletion in the brain [
• A few affected individuals had mtDNA depletion in the liver [
• Postmortem material has revealed complex I deficiency and mtDNA depletion in the brain [
• A few affected individuals had mtDNA depletion in the liver [
• Postmortem material has revealed complex I deficiency and mtDNA depletion in the brain [
• Targeted analysis for the founder pathogenic
• Note: All individuals with the IOSCA founder variant in
• In those who are not of known Finnish ancestry or in whom targeted testing for the Finnish founder variant identifies one or no pathogenic variant, sequence analysis of
## Suggestive Findings
Infantile-onset spinocerebellar ataxia (IOSCA)
Spinocerebellar ataxia
Muscle hypotonia
Athetoid movements
Loss of deep-tendon reflexes
Hearing deficit
Ophthalmoplegia
Optic atrophy
Primary hypergonadotropic hypogonadism in females
Epileptic encephalopathy
Normal routine laboratory and metabolic screening tests
Normal muscle morphology and respiratory chain enzyme analyses
Absence of mitochondrial DNA (mtDNA) deletion and/or depletion in muscle; however:
A few affected individuals had mtDNA depletion in the liver [
Postmortem material has revealed complex I deficiency and mtDNA depletion in the brain [
Note: Muscle biopsy with histology and respiratory chain enzyme analysis are not required for the diagnosis of IOSCA.
• Spinocerebellar ataxia
• Muscle hypotonia
• Athetoid movements
• Loss of deep-tendon reflexes
• Hearing deficit
• Ophthalmoplegia
• Optic atrophy
• Primary hypergonadotropic hypogonadism in females
• Epileptic encephalopathy
• Normal routine laboratory and metabolic screening tests
• Normal muscle morphology and respiratory chain enzyme analyses
• Absence of mitochondrial DNA (mtDNA) deletion and/or depletion in muscle; however:
• A few affected individuals had mtDNA depletion in the liver [
• Postmortem material has revealed complex I deficiency and mtDNA depletion in the brain [
• A few affected individuals had mtDNA depletion in the liver [
• Postmortem material has revealed complex I deficiency and mtDNA depletion in the brain [
• A few affected individuals had mtDNA depletion in the liver [
• Postmortem material has revealed complex I deficiency and mtDNA depletion in the brain [
## Establishing the Diagnosis
The diagnosis of IOSCA
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 [
Identification of biallelic
Molecular genetic testing approaches can include
Targeted analysis for the founder pathogenic
Note: All individuals with the IOSCA founder variant in
In those who are not of known Finnish ancestry or in whom targeted testing for the Finnish founder variant identifies one or no pathogenic variant, sequence analysis of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Infantile-Onset Spinocerebellar Ataxia
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
In the exon / flanking intron regions sequenced; pathogenic variants in non-sequenced intron and regulatory regions are not detected.
Sequence analysis detects the Finnish founder variant and others, including
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.
Gene-targeted deletion/duplication analysis has not identified any deletions/duplications.
• Targeted analysis for the founder pathogenic
• Note: All individuals with the IOSCA founder variant in
• In those who are not of known Finnish ancestry or in whom targeted testing for the Finnish founder variant identifies one or no pathogenic variant, sequence analysis of
## Clinical Characteristics
Infantile-onset spinocerebellar ataxia (IOSCA) was originally described in individuals of Finnish descent who had biallelic pathogenic founder variants in
By adolescence affected individuals are no longer ambulatory, being dependent on either a walker or wheelchair. The hearing deficit is severe (>100 dB) and communication relies on sign language. Progressive
The supratentorial brain (i.e., cerebral cortex, cerebral white matter, basal ganglia, and other deep brain nuclei) is well preserved until the onset of epilepsy. In 15 children, epilepsy developed into a serious encephalopathy, beginning at ages two and four years in those who were compound heterozygotes for the Finnish founder variant and another pathogenic variant, and between ages 15 and 34 years (mean age 24 years) in homozygotes for the Finnish founder variant. The seizures were myoclonic jerks or focal clonic seizures that progressed to epilepsia partialis continua and further to status epilepticus with loss of consciousness and tonic-clonic seizures. Death of nine of these 15 individuals was directly or indirectly related to epilepsy. The oldest individual (without epilepsy) who is homozygous for the Finnish founder variant is alive at age 50 years.
Spinocerebellar degeneration progresses gradually with increasing age. Serial brain MRI imaging reveals cerebellar, cortical, and brain stem atrophy with increased signal intensity in the cerebellar white matter on T
Individuals who are compound heterozygotes for
IOSCA was originally known as OHAHA (
The carrier frequency of the
• Individuals who are compound heterozygotes for
## Clinical Description
Infantile-onset spinocerebellar ataxia (IOSCA) was originally described in individuals of Finnish descent who had biallelic pathogenic founder variants in
By adolescence affected individuals are no longer ambulatory, being dependent on either a walker or wheelchair. The hearing deficit is severe (>100 dB) and communication relies on sign language. Progressive
The supratentorial brain (i.e., cerebral cortex, cerebral white matter, basal ganglia, and other deep brain nuclei) is well preserved until the onset of epilepsy. In 15 children, epilepsy developed into a serious encephalopathy, beginning at ages two and four years in those who were compound heterozygotes for the Finnish founder variant and another pathogenic variant, and between ages 15 and 34 years (mean age 24 years) in homozygotes for the Finnish founder variant. The seizures were myoclonic jerks or focal clonic seizures that progressed to epilepsia partialis continua and further to status epilepticus with loss of consciousness and tonic-clonic seizures. Death of nine of these 15 individuals was directly or indirectly related to epilepsy. The oldest individual (without epilepsy) who is homozygous for the Finnish founder variant is alive at age 50 years.
Spinocerebellar degeneration progresses gradually with increasing age. Serial brain MRI imaging reveals cerebellar, cortical, and brain stem atrophy with increased signal intensity in the cerebellar white matter on T
## Genotype-Phenotype Correlations
Individuals who are compound heterozygotes for
• Individuals who are compound heterozygotes for
## Nomenclature
IOSCA was originally known as OHAHA (
## Prevalence
The carrier frequency of the
## Genetically Related (Allelic) Disorders
Other Phenotypes Caused by Pathogenic Variants in
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance
Autosomal dominant progressive external ophthalmoplegia (adPEO) (OMIM
## Autosomal Dominant Progressive External Ophthalmoplegia
Autosomal dominant progressive external ophthalmoplegia (adPEO) (OMIM
## Novel
## Differential Diagnosis
Differential diagnosis for infantile-onset spinocerebellar ataxia (IOSCA) should include all early-onset cerebellar ataxias with sensory axonal neuropathy and epileptic encephalopathy.
The spinocerebellar degeneration in IOSCA is similar to that in
The syndromes associated with biallelic
Early encephalopathy, sensory axonal neuropathy, epilepsy, and signs of hepatopathy with mtDNA depletion in the liver are seen in individuals with
While IOSCA and ANS share clinical features, spinocerebellar degeneration starts earlier and progresses faster in IOSCA than in ANS [
Diagnosis of A-T relies on clinical findings including slurred speech, truncal ataxia, and oculomotor apraxia; family history; and neuroimaging. Testing that supports the diagnosis includes serum alphafetoprotein concentration (elevated in >95% of individuals with A-T), identification of a 7;14 chromosome translocation on routine karyotype of peripheral blood, the presence of immunodeficiency, and in vitro radiosensitivity assay. A-T is caused by biallelic pathogenic variants in
IOSCA is distinguished from A-T by: normal chromosome studies, normal immune function, loss of deep-tendon reflexes, early ophthalmoplegia, deafness, and absence of telangiectasias.
• Early encephalopathy, sensory axonal neuropathy, epilepsy, and signs of hepatopathy with mtDNA depletion in the liver are seen in individuals with
• While IOSCA and ANS share clinical features, spinocerebellar degeneration starts earlier and progresses faster in IOSCA than in ANS [
## Management
To establish the extent of disease and needs in an individual diagnosed with infantile-onset spinocerebellar ataxia (IOSCA), the following are recommended (if not already been completed as part of the evaluation that led to the diagnosis):
Neurologic examination to evaluate the grade of ataxia and neuropathy
Audiologic examination to evaluate the degree of hearing loss and need for hearing aids
Ophthalmologic examination to evaluate the grade of ophthalmoparesis and optic atrophy
Neurophysiologic examinations
ENMG (electroneuromyography)
SEP (somatosensory evoked potentials). Note: Changes in SEP occur early in the disease course and correlate with sensory system involvement.
VEP (visual evoked potentials)
Brain MRI
Consultation with a clinical geneticist and/or genetic counselor
Treatment is symptomatic:
Some affected individuals have benefited from lamotrigine, levetiracetam, topiramate, or lacosamide.
Benzodiazepines, especially midazolam infusion, when started early in status epilepticus, were occasionally effective.
Oxcarbazepine has some effect, but hyponatremia is a troublesome side effect.
Neurologic, audiologic, and ophthalmologic evaluation every six to 12 months
Neurophysiologic studies when clinically indicated
Brain MRI every three to five years
Neurologic examination annually
Audiologic and ophthalmologic examinations every one to two years
EEG and brain MRI at least during status epilepticus
Valproate is contraindicated in those with IOSCA, as it is in other disorders that potentially affect mitochondrial function in liver. Valproate caused significant elevation of liver enzymes (alanine aminotransferase: 232 units/L [normal: 10-35 U/L]; gamma-GT: 160 U/L [normal: 5-50 U/L]) and icterus with elevated bilirubin levels (total: 224 μmol/L [normal: 5-25 μmol/L]; conjugated: 160 μmol/L [normal:1-8 μmol/L]) in one affected individual, and similar elevation of liver transaminases in another. When valproate was discontinued, icterus resolved and liver enzymes normalized.
See
Search
• Neurologic examination to evaluate the grade of ataxia and neuropathy
• Audiologic examination to evaluate the degree of hearing loss and need for hearing aids
• Ophthalmologic examination to evaluate the grade of ophthalmoparesis and optic atrophy
• Neurophysiologic examinations
• ENMG (electroneuromyography)
• SEP (somatosensory evoked potentials). Note: Changes in SEP occur early in the disease course and correlate with sensory system involvement.
• VEP (visual evoked potentials)
• ENMG (electroneuromyography)
• SEP (somatosensory evoked potentials). Note: Changes in SEP occur early in the disease course and correlate with sensory system involvement.
• VEP (visual evoked potentials)
• Brain MRI
• Consultation with a clinical geneticist and/or genetic counselor
• ENMG (electroneuromyography)
• SEP (somatosensory evoked potentials). Note: Changes in SEP occur early in the disease course and correlate with sensory system involvement.
• VEP (visual evoked potentials)
• Some affected individuals have benefited from lamotrigine, levetiracetam, topiramate, or lacosamide.
• Benzodiazepines, especially midazolam infusion, when started early in status epilepticus, were occasionally effective.
• Oxcarbazepine has some effect, but hyponatremia is a troublesome side effect.
• Some affected individuals have benefited from lamotrigine, levetiracetam, topiramate, or lacosamide.
• Benzodiazepines, especially midazolam infusion, when started early in status epilepticus, were occasionally effective.
• Oxcarbazepine has some effect, but hyponatremia is a troublesome side effect.
• Some affected individuals have benefited from lamotrigine, levetiracetam, topiramate, or lacosamide.
• Benzodiazepines, especially midazolam infusion, when started early in status epilepticus, were occasionally effective.
• Oxcarbazepine has some effect, but hyponatremia is a troublesome side effect.
• Neurologic, audiologic, and ophthalmologic evaluation every six to 12 months
• Neurophysiologic studies when clinically indicated
• Brain MRI every three to five years
• Neurologic examination annually
• Audiologic and ophthalmologic examinations every one to two years
• EEG and brain MRI at least during status epilepticus
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with infantile-onset spinocerebellar ataxia (IOSCA), the following are recommended (if not already been completed as part of the evaluation that led to the diagnosis):
Neurologic examination to evaluate the grade of ataxia and neuropathy
Audiologic examination to evaluate the degree of hearing loss and need for hearing aids
Ophthalmologic examination to evaluate the grade of ophthalmoparesis and optic atrophy
Neurophysiologic examinations
ENMG (electroneuromyography)
SEP (somatosensory evoked potentials). Note: Changes in SEP occur early in the disease course and correlate with sensory system involvement.
VEP (visual evoked potentials)
Brain MRI
Consultation with a clinical geneticist and/or genetic counselor
• Neurologic examination to evaluate the grade of ataxia and neuropathy
• Audiologic examination to evaluate the degree of hearing loss and need for hearing aids
• Ophthalmologic examination to evaluate the grade of ophthalmoparesis and optic atrophy
• Neurophysiologic examinations
• ENMG (electroneuromyography)
• SEP (somatosensory evoked potentials). Note: Changes in SEP occur early in the disease course and correlate with sensory system involvement.
• VEP (visual evoked potentials)
• ENMG (electroneuromyography)
• SEP (somatosensory evoked potentials). Note: Changes in SEP occur early in the disease course and correlate with sensory system involvement.
• VEP (visual evoked potentials)
• Brain MRI
• Consultation with a clinical geneticist and/or genetic counselor
• ENMG (electroneuromyography)
• SEP (somatosensory evoked potentials). Note: Changes in SEP occur early in the disease course and correlate with sensory system involvement.
• VEP (visual evoked potentials)
## Treatment of Manifestations
Treatment is symptomatic:
Some affected individuals have benefited from lamotrigine, levetiracetam, topiramate, or lacosamide.
Benzodiazepines, especially midazolam infusion, when started early in status epilepticus, were occasionally effective.
Oxcarbazepine has some effect, but hyponatremia is a troublesome side effect.
• Some affected individuals have benefited from lamotrigine, levetiracetam, topiramate, or lacosamide.
• Benzodiazepines, especially midazolam infusion, when started early in status epilepticus, were occasionally effective.
• Oxcarbazepine has some effect, but hyponatremia is a troublesome side effect.
• Some affected individuals have benefited from lamotrigine, levetiracetam, topiramate, or lacosamide.
• Benzodiazepines, especially midazolam infusion, when started early in status epilepticus, were occasionally effective.
• Oxcarbazepine has some effect, but hyponatremia is a troublesome side effect.
• Some affected individuals have benefited from lamotrigine, levetiracetam, topiramate, or lacosamide.
• Benzodiazepines, especially midazolam infusion, when started early in status epilepticus, were occasionally effective.
• Oxcarbazepine has some effect, but hyponatremia is a troublesome side effect.
## Surveillance
Neurologic, audiologic, and ophthalmologic evaluation every six to 12 months
Neurophysiologic studies when clinically indicated
Brain MRI every three to five years
Neurologic examination annually
Audiologic and ophthalmologic examinations every one to two years
EEG and brain MRI at least during status epilepticus
• Neurologic, audiologic, and ophthalmologic evaluation every six to 12 months
• Neurophysiologic studies when clinically indicated
• Brain MRI every three to five years
• Neurologic examination annually
• Audiologic and ophthalmologic examinations every one to two years
• EEG and brain MRI at least during status epilepticus
## Agents/Circumstances to Avoid
Valproate is contraindicated in those with IOSCA, as it is in other disorders that potentially affect mitochondrial function in liver. Valproate caused significant elevation of liver enzymes (alanine aminotransferase: 232 units/L [normal: 10-35 U/L]; gamma-GT: 160 U/L [normal: 5-50 U/L]) and icterus with elevated bilirubin levels (total: 224 μmol/L [normal: 5-25 μmol/L]; conjugated: 160 μmol/L [normal:1-8 μmol/L]) in one affected individual, and similar elevation of liver transaminases in another. When valproate was discontinued, icterus resolved and liver enzymes normalized.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Infantile-onset spinocerebellar ataxia (IOSCA) 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.
Females with IOSCA have hypergonadotropic hypogonadism, indicative of ovarian failure.
Males with IOSCA are too severely disabled to reproduce [
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
• 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.
• Females with IOSCA have hypergonadotropic hypogonadism, indicative of ovarian failure.
• Males with IOSCA are too severely disabled to reproduce [
• 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
Infantile-onset spinocerebellar ataxia (IOSCA) 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.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Females with IOSCA have hypergonadotropic hypogonadism, indicative of ovarian failure.
Males with IOSCA are too severely disabled to reproduce [
• 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.
• Females with IOSCA have hypergonadotropic hypogonadism, indicative of ovarian failure.
• Males with IOSCA are too severely disabled to reproduce [
## 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
## Resources
United Kingdom
Ilkantie 4
PL 51
Helsinki 00400
Finland
Finland
Sanford Research
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• United Kingdom
•
•
• Ilkantie 4
• PL 51
• Helsinki 00400
• Finland
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• Finland
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• Sanford Research
•
## Molecular Genetics
Infantile-Onset Spinocerebellar Ataxia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Infantile-Onset Spinocerebellar Ataxia (
Infantile-onset spinocerebellar ataxia (IOSCA) is caused by pathogenic variants in
Transcript variant
For a detailed summary of gene, transcript, and protein isoforms, see
To date, 24 individuals with IOSCA have been identified [
21 homozygotes: c.[1523A>G];[1523A>G]
Two compound heterozygotes: c.[1523A>G];[952G>A] [
One compound heterozygote: c.[1523A>G];[1287C>T] [
Variants listed in the table have been provided by the author.
Designates that no variant that changes (or is predicted to change) the protein sequence was found; see
As a mtDNA-specific helicase, twinkle catalyzes ATP-dependent unwinding of duplex DNA with 5'→3' polarity [
In addition to being essential for mtDNA integrity, twinkle regulates mtDNA copy number, as shown by analyzing overexpression of wild type twinkle in mice and human osteosarcoma cell lines [
Phylogenetic analyses showed that twinkle is widespread in the eukaryotic radiation and suggested that it may also function as a primase [
The primase/helicase linker region of twinkle is essential for hexamer formation, which is required for the ATP-hydrolyzing activity and DNA unwinding. Supposedly, the linker region interacts with amino acids in the helicase domain of the adjacent monomer to form functional multimers [
The following describes the behavior and function of the twinkle protein isoform with the p.Tyr508Cys pathogenic variant.
Small amounts of normal
• 21 homozygotes: c.[1523A>G];[1523A>G]
• Two compound heterozygotes: c.[1523A>G];[952G>A] [
• One compound heterozygote: c.[1523A>G];[1287C>T] [
• As a mtDNA-specific helicase, twinkle catalyzes ATP-dependent unwinding of duplex DNA with 5'→3' polarity [
• In addition to being essential for mtDNA integrity, twinkle regulates mtDNA copy number, as shown by analyzing overexpression of wild type twinkle in mice and human osteosarcoma cell lines [
• Phylogenetic analyses showed that twinkle is widespread in the eukaryotic radiation and suggested that it may also function as a primase [
• The primase/helicase linker region of twinkle is essential for hexamer formation, which is required for the ATP-hydrolyzing activity and DNA unwinding. Supposedly, the linker region interacts with amino acids in the helicase domain of the adjacent monomer to form functional multimers [
## Molecular Pathogenesis
Infantile-onset spinocerebellar ataxia (IOSCA) is caused by pathogenic variants in
Transcript variant
For a detailed summary of gene, transcript, and protein isoforms, see
To date, 24 individuals with IOSCA have been identified [
21 homozygotes: c.[1523A>G];[1523A>G]
Two compound heterozygotes: c.[1523A>G];[952G>A] [
One compound heterozygote: c.[1523A>G];[1287C>T] [
Variants listed in the table have been provided by the author.
Designates that no variant that changes (or is predicted to change) the protein sequence was found; see
As a mtDNA-specific helicase, twinkle catalyzes ATP-dependent unwinding of duplex DNA with 5'→3' polarity [
In addition to being essential for mtDNA integrity, twinkle regulates mtDNA copy number, as shown by analyzing overexpression of wild type twinkle in mice and human osteosarcoma cell lines [
Phylogenetic analyses showed that twinkle is widespread in the eukaryotic radiation and suggested that it may also function as a primase [
The primase/helicase linker region of twinkle is essential for hexamer formation, which is required for the ATP-hydrolyzing activity and DNA unwinding. Supposedly, the linker region interacts with amino acids in the helicase domain of the adjacent monomer to form functional multimers [
The following describes the behavior and function of the twinkle protein isoform with the p.Tyr508Cys pathogenic variant.
Small amounts of normal
• 21 homozygotes: c.[1523A>G];[1523A>G]
• Two compound heterozygotes: c.[1523A>G];[952G>A] [
• One compound heterozygote: c.[1523A>G];[1287C>T] [
• As a mtDNA-specific helicase, twinkle catalyzes ATP-dependent unwinding of duplex DNA with 5'→3' polarity [
• In addition to being essential for mtDNA integrity, twinkle regulates mtDNA copy number, as shown by analyzing overexpression of wild type twinkle in mice and human osteosarcoma cell lines [
• Phylogenetic analyses showed that twinkle is widespread in the eukaryotic radiation and suggested that it may also function as a primase [
• The primase/helicase linker region of twinkle is essential for hexamer formation, which is required for the ATP-hydrolyzing activity and DNA unwinding. Supposedly, the linker region interacts with amino acids in the helicase domain of the adjacent monomer to form functional multimers [
## Chapter Notes
Tuula Lönnqvist, MD, PhD (2009-present)Kaisu Nikali, MD, PhD; University College London (2009-2018)
30 May 2024 (ma) Chapter retired: outdated; qualified authors not available for update
19 April 2018 (ma) Comprehensive update posted live
15 January 2015 (me) Comprehensive update posted live
22 July 2010 (me) Comprehensive update posted live
27 January 2009 (me) Review posted live
17 September 2008 (kn) Original submission
• 30 May 2024 (ma) Chapter retired: outdated; qualified authors not available for update
• 19 April 2018 (ma) Comprehensive update posted live
• 15 January 2015 (me) Comprehensive update posted live
• 22 July 2010 (me) Comprehensive update posted live
• 27 January 2009 (me) Review posted live
• 17 September 2008 (kn) Original submission
## Author History
Tuula Lönnqvist, MD, PhD (2009-present)Kaisu Nikali, MD, PhD; University College London (2009-2018)
## Revision History
30 May 2024 (ma) Chapter retired: outdated; qualified authors not available for update
19 April 2018 (ma) Comprehensive update posted live
15 January 2015 (me) Comprehensive update posted live
22 July 2010 (me) Comprehensive update posted live
27 January 2009 (me) Review posted live
17 September 2008 (kn) Original submission
• 30 May 2024 (ma) Chapter retired: outdated; qualified authors not available for update
• 19 April 2018 (ma) Comprehensive update posted live
• 15 January 2015 (me) Comprehensive update posted live
• 22 July 2010 (me) Comprehensive update posted live
• 27 January 2009 (me) Review posted live
• 17 September 2008 (kn) Original submission
## References
## Literature Cited
|
[] |
27/1/2009
|
19/4/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sca1
|
sca1
|
[
"SCA1",
"SCA1",
"Ataxin-1",
"ATXN1",
"Spinocerebellar Ataxia Type 1"
] |
Spinocerebellar Ataxia Type 1
|
Puneet Opal, Tetsuo Ashizawa
|
Summary Spinocerebellar ataxia type 1 (SCA1) is characterized by progressive cerebellar ataxia, dysarthria, and eventual deterioration of bulbar functions. Early in the disease, affected individuals may have gait disturbance, slurred speech, difficulty with balance, brisk deep tendon reflexes, hypermetric saccades, nystagmus, and mild dysphagia. Later signs include slowing of saccadic velocity, development of upgaze palsy, dysmetria, dysdiadochokinesia, and hypotonia. In advanced stages, muscle atrophy, decreased deep tendon reflexes, loss of proprioception, cognitive impairment (e.g., frontal executive dysfunction, impaired verbal memory), chorea, dystonia, and bulbar dysfunction are seen. Onset is typically in the third or fourth decade, although childhood onset and late-adult onset have been reported. Those with onset after age 60 years may manifest a pure cerebellar phenotype. Interval from onset to death varies from ten to 30 years; individuals with juvenile onset show more rapid progression and more severe disease. Anticipation is observed. An axonal sensory neuropathy detected by electrophysiologic testing is common; brain imaging typically shows cerebellar and brain stem atrophy. The diagnosis of SCA1 is established in a proband with characteristic clinical findings and an abnormal CAG repeat expansion in SCA1 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the expanded allele. Anticipation has been observed in SCA1; expansions are more likely to occur when the pathogenic
|
## Diagnosis
The phenotypic manifestations of spinocerebellar ataxia type 1 (SCA1) are not specific, and no formal clinical diagnostic criteria exist.
SCA1
Progressive cerebellar ataxia
Dysarthria
Eventual deterioration of bulbar functions
The diagnosis of SCA1
39-44 CAG repeat alleles must be uninterrupted by CAT repeats to be considered abnormal and are likely to be associated with symptoms [
46-70 uninterrupted CAG repeats with CAT interruptions and additional CAGs (e.g., a measured 62-CAG repeat allele with 51 uninterrupted CAGs) have been reported [
Complex alleles may occur. One individual with symptomatic SCA1 with a 58-CAG repeat sequence interrupted by two CAT repeats has been reported [
The European Molecular Genetics Quality Network (EMQN) has published best practice guidelines for the genetic testing of the spinocerebellar ataxias including SCA1 [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 1
See
See
Typically, the number of CAG repeats is determined by standard PCR and fragment length analysis.
Distinguishing normal, mutable normal, and pathogenic alleles with 39-44 CAG repeats requires additional evaluation for the presence of CAT trinucleotides that interrupt the CAG repeat tract. Methods may vary (e.g.,
In some individuals with infantile- or childhood-onset SCA1, direct amplification of the
Expansion of the number of CAG trinucleotide repeats in
• Progressive cerebellar ataxia
• Dysarthria
• Eventual deterioration of bulbar functions
•
•
• 39-44 CAG repeat alleles must be uninterrupted by CAT repeats to be considered abnormal and are likely to be associated with symptoms [
• 46-70 uninterrupted CAG repeats with CAT interruptions and additional CAGs (e.g., a measured 62-CAG repeat allele with 51 uninterrupted CAGs) have been reported [
• Complex alleles may occur. One individual with symptomatic SCA1 with a 58-CAG repeat sequence interrupted by two CAT repeats has been reported [
• 39-44 CAG repeat alleles must be uninterrupted by CAT repeats to be considered abnormal and are likely to be associated with symptoms [
• 46-70 uninterrupted CAG repeats with CAT interruptions and additional CAGs (e.g., a measured 62-CAG repeat allele with 51 uninterrupted CAGs) have been reported [
• Complex alleles may occur. One individual with symptomatic SCA1 with a 58-CAG repeat sequence interrupted by two CAT repeats has been reported [
• 39-44 CAG repeat alleles must be uninterrupted by CAT repeats to be considered abnormal and are likely to be associated with symptoms [
• 46-70 uninterrupted CAG repeats with CAT interruptions and additional CAGs (e.g., a measured 62-CAG repeat allele with 51 uninterrupted CAGs) have been reported [
• Complex alleles may occur. One individual with symptomatic SCA1 with a 58-CAG repeat sequence interrupted by two CAT repeats has been reported [
• For an introduction to multigene panels click
## Suggestive Findings
SCA1
Progressive cerebellar ataxia
Dysarthria
Eventual deterioration of bulbar functions
• Progressive cerebellar ataxia
• Dysarthria
• Eventual deterioration of bulbar functions
## Establishing the Diagnosis
The diagnosis of SCA1
39-44 CAG repeat alleles must be uninterrupted by CAT repeats to be considered abnormal and are likely to be associated with symptoms [
46-70 uninterrupted CAG repeats with CAT interruptions and additional CAGs (e.g., a measured 62-CAG repeat allele with 51 uninterrupted CAGs) have been reported [
Complex alleles may occur. One individual with symptomatic SCA1 with a 58-CAG repeat sequence interrupted by two CAT repeats has been reported [
The European Molecular Genetics Quality Network (EMQN) has published best practice guidelines for the genetic testing of the spinocerebellar ataxias including SCA1 [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 1
See
See
Typically, the number of CAG repeats is determined by standard PCR and fragment length analysis.
Distinguishing normal, mutable normal, and pathogenic alleles with 39-44 CAG repeats requires additional evaluation for the presence of CAT trinucleotides that interrupt the CAG repeat tract. Methods may vary (e.g.,
In some individuals with infantile- or childhood-onset SCA1, direct amplification of the
Expansion of the number of CAG trinucleotide repeats in
•
•
• 39-44 CAG repeat alleles must be uninterrupted by CAT repeats to be considered abnormal and are likely to be associated with symptoms [
• 46-70 uninterrupted CAG repeats with CAT interruptions and additional CAGs (e.g., a measured 62-CAG repeat allele with 51 uninterrupted CAGs) have been reported [
• Complex alleles may occur. One individual with symptomatic SCA1 with a 58-CAG repeat sequence interrupted by two CAT repeats has been reported [
• 39-44 CAG repeat alleles must be uninterrupted by CAT repeats to be considered abnormal and are likely to be associated with symptoms [
• 46-70 uninterrupted CAG repeats with CAT interruptions and additional CAGs (e.g., a measured 62-CAG repeat allele with 51 uninterrupted CAGs) have been reported [
• Complex alleles may occur. One individual with symptomatic SCA1 with a 58-CAG repeat sequence interrupted by two CAT repeats has been reported [
• 39-44 CAG repeat alleles must be uninterrupted by CAT repeats to be considered abnormal and are likely to be associated with symptoms [
• 46-70 uninterrupted CAG repeats with CAT interruptions and additional CAGs (e.g., a measured 62-CAG repeat allele with 51 uninterrupted CAGs) have been reported [
• Complex alleles may occur. One individual with symptomatic SCA1 with a 58-CAG repeat sequence interrupted by two CAT repeats has been reported [
• For an introduction to multigene panels click
## Clinical Characteristics
Spinocerebellar ataxia type 1 (SCA1) is characterized by ataxia, dysarthria, and eventual deterioration of bulbar functions [
Spinocerebellar Ataxia Type 1: Frequency of Select Features
In early stages of SCA1, most if not all individuals show ocular manifestations [
Non-ataxia signs measured by the Inventory of Non-Ataxia Signs (INAS) increase in number with time and correlate with the CAG repeat size until the increase reaches a plateau [
Individuals with SCA1 who have gait ataxia as the initial manifestation (comprising two thirds of affected individuals [
Large-scale natural history studies of some of the common SCAs (including SCA1) using validated neurologic rating scales and timed measures of motor function have been in progress in many countries. The annual increase in the Scale for Assessment and Rating of Ataxia (SARA) score (which quantifies various aspects of appendicular and limb ataxia – a score of 40 indicates maximum dysfunction [
Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation are abnormal in most individuals with SCA1. Oculomotor recordings reveal eye movement abnormalities in a quantitative fashion.
Voxel-based morphometry show volume loss in the cerebellum and brain stem involving both gray and white matter [
Regional damage to white matter in individuals with SCA1 has been repeatedly demonstrated by diffusion tensor imaging [
While positron emission tomography studies have demonstrated hypometabolism in presymptomatic individuals with an
Minor motor dysfunction and loss of cerebellar and brain stem gray matter by quantitative imaging studies have been documented in presymptomatic persons known to have an
Systematic studies have shown that SCA1 neuropathology can involve components of the cerebello-thalamocortical loop, the basal ganglia-thalamocortical loop, the visual system, the nuclei of the auditory system, the somatosensory system at many levels, the vestibular nuclei, both infranuclear and supranuclear oculomotor neurons, several brain stem nuclei, the midbrain dopaminergic system, and the basal forebrain and midbrain cholinergic systems [
The largest expansions of the CAG repeat tract are found in individuals with infantile- or juvenile-onset SCA1, who typically experience more rapid disease progression and are most commonly the offspring of affected males.
Some clinical signs (facio-lingual atrophy, dysphagia, skeletal muscle atrophy, and possibly ophthalmoparesis) are more common with larger repeat size, independent of disease duration.
Individuals who have biallelic pathogenic
Penetrance is considered to be greater than 95% but is age dependent. Onset after age 60 years has occasionally been reported [
Anticipation (an increase in the severity and earlier onset of the phenotype in progressive generations) has been observed in SCA1 [
The nomenclature for the autosomal dominant hereditary ataxias has varied over the years. Terms no longer used to refer to SCA1 include Marie's ataxia, atypical Friedreich's ataxia, and olivopontocerebellar atrophy.
Approximately one to two individuals in 100,000 develop SCA1.
Worldwide, SCA1 represents approximately 6% of individuals with autosomal dominant cerebellar ataxia; this figure varies considerably based on geographic location and ethnic background. For example, SCA1 has not been identified as a cause of autosomal dominant ataxia in Koreans [
## Clinical Description
Spinocerebellar ataxia type 1 (SCA1) is characterized by ataxia, dysarthria, and eventual deterioration of bulbar functions [
Spinocerebellar Ataxia Type 1: Frequency of Select Features
In early stages of SCA1, most if not all individuals show ocular manifestations [
Non-ataxia signs measured by the Inventory of Non-Ataxia Signs (INAS) increase in number with time and correlate with the CAG repeat size until the increase reaches a plateau [
Individuals with SCA1 who have gait ataxia as the initial manifestation (comprising two thirds of affected individuals [
Large-scale natural history studies of some of the common SCAs (including SCA1) using validated neurologic rating scales and timed measures of motor function have been in progress in many countries. The annual increase in the Scale for Assessment and Rating of Ataxia (SARA) score (which quantifies various aspects of appendicular and limb ataxia – a score of 40 indicates maximum dysfunction [
Visual evoked potentials and motor evoked potentials following transcranial magnetic stimulation are abnormal in most individuals with SCA1. Oculomotor recordings reveal eye movement abnormalities in a quantitative fashion.
Voxel-based morphometry show volume loss in the cerebellum and brain stem involving both gray and white matter [
Regional damage to white matter in individuals with SCA1 has been repeatedly demonstrated by diffusion tensor imaging [
While positron emission tomography studies have demonstrated hypometabolism in presymptomatic individuals with an
Minor motor dysfunction and loss of cerebellar and brain stem gray matter by quantitative imaging studies have been documented in presymptomatic persons known to have an
Systematic studies have shown that SCA1 neuropathology can involve components of the cerebello-thalamocortical loop, the basal ganglia-thalamocortical loop, the visual system, the nuclei of the auditory system, the somatosensory system at many levels, the vestibular nuclei, both infranuclear and supranuclear oculomotor neurons, several brain stem nuclei, the midbrain dopaminergic system, and the basal forebrain and midbrain cholinergic systems [
## Genotype-Phenotype Correlations
The largest expansions of the CAG repeat tract are found in individuals with infantile- or juvenile-onset SCA1, who typically experience more rapid disease progression and are most commonly the offspring of affected males.
Some clinical signs (facio-lingual atrophy, dysphagia, skeletal muscle atrophy, and possibly ophthalmoparesis) are more common with larger repeat size, independent of disease duration.
Individuals who have biallelic pathogenic
## Penetrance
Penetrance is considered to be greater than 95% but is age dependent. Onset after age 60 years has occasionally been reported [
## Anticipation
Anticipation (an increase in the severity and earlier onset of the phenotype in progressive generations) has been observed in SCA1 [
## Nomenclature
The nomenclature for the autosomal dominant hereditary ataxias has varied over the years. Terms no longer used to refer to SCA1 include Marie's ataxia, atypical Friedreich's ataxia, and olivopontocerebellar atrophy.
## Prevalence
Approximately one to two individuals in 100,000 develop SCA1.
Worldwide, SCA1 represents approximately 6% of individuals with autosomal dominant cerebellar ataxia; this figure varies considerably based on geographic location and ethnic background. For example, SCA1 has not been identified as a cause of autosomal dominant ataxia in Koreans [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurologic disorders that defy easy differentiation on the basis of clinical criteria alone. See Hereditary Ataxia Overview,
Rarely, SCA1 may present with features of hereditary spastic paraparesis [
## Management
To establish the extent of disease and needs in an individual with molecularly confirmed spinocerebellar ataxia type 1 (SCA1), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 1
Video esophagram in those w/dysphagia
Oral feeding assessment by speech or feeding therapist
Community or
Social work support;
Home nursing referral.
MOI = mode of inheritance; SCA1 = spinocerebellar ataxia type 1
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no known therapy to delay or halt the progression of SCA1.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by a neurologist with consultation from physiatrists, physical and occupational therapists, and other specialists as needed (see
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 1
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, & coordinative training should be prioritized over muscle strengthening) to maintain mobility & function
OT to optimize ADL
Inpatient rehab w/OT & PT may improve ataxia & functional abilities.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Modify food consistency to ↓ aspiration risk.
Consider feeding device for those w/recurrent aspiration.
Caloric support may be needed in those w/weight loss.
Vitamin supplementation to meet dietary needs
Standard pharmacotherapy for pain control
Referral to pain mgmt specialist as needed
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 1
Neurologic assessment for progression of ataxia, UMN or LMN signs, & history of falls
Monitor ataxia progression w/standardized scale (SARA).
Physiatry & OT/PT assessment of mobility & self-help skills as they relate to ataxia, spasticity, & weakness
LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SARA = Scale for Assessment and Rating of Ataxia; UMN = upper motor neuron
Affected individuals should avoid alcohol as well as medications known to be neurotoxic such as those that cause neuropathy (e.g., isoniazid, large-dose vitamin B
Circumstances that could lead to physical harm, such as operating machinery or climbing to great heights, should also be avoided.
See
Riluzole has been shown to provide some symptomatic relief of ataxia in a mixed group of individuals including persons with SCA1 [
Intrathecal injection of 3,000 mesenchymal stem cells in SCA1 transgenic mice mitigated the cerebellar neuronal disorganization, atrophy of dendrites, and motor disturbances [
Search
Tremor-controlling drugs do not work well for cerebellar tremors.
• Video esophagram in those w/dysphagia
• Oral feeding assessment by speech or feeding therapist
• Community or
• Social work support;
• Home nursing referral.
• 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, & coordinative training should be prioritized over muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• Inpatient rehab w/OT & PT may improve ataxia & functional abilities.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Modify food consistency to ↓ aspiration risk.
• Consider feeding device for those w/recurrent aspiration.
• Caloric support may be needed in those w/weight loss.
• Vitamin supplementation to meet dietary needs
• Standard pharmacotherapy for pain control
• Referral to pain mgmt specialist as needed
• Neurologic assessment for progression of ataxia, UMN or LMN signs, & history of falls
• Monitor ataxia progression w/standardized scale (SARA).
• Physiatry & OT/PT assessment of mobility & self-help skills as they relate to ataxia, spasticity, & weakness
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual with molecularly confirmed spinocerebellar ataxia type 1 (SCA1), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 1
Video esophagram in those w/dysphagia
Oral feeding assessment by speech or feeding therapist
Community or
Social work support;
Home nursing referral.
MOI = mode of inheritance; SCA1 = spinocerebellar ataxia type 1
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Video esophagram in those w/dysphagia
• Oral feeding assessment by speech or feeding therapist
• Community or
• Social work support;
• Home nursing referral.
## Treatment of Manifestations
There is no known therapy to delay or halt the progression of SCA1.
Supportive care to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by a neurologist with consultation from physiatrists, physical and occupational therapists, and other specialists as needed (see
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 1
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, & coordinative training should be prioritized over muscle strengthening) to maintain mobility & function
OT to optimize ADL
Inpatient rehab w/OT & PT may improve ataxia & functional abilities.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Modify food consistency to ↓ aspiration risk.
Consider feeding device for those w/recurrent aspiration.
Caloric support may be needed in those w/weight loss.
Vitamin supplementation to meet dietary needs
Standard pharmacotherapy for pain control
Referral to pain mgmt specialist as needed
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist
• 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, & coordinative training should be prioritized over muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• Inpatient rehab w/OT & PT may improve ataxia & functional abilities.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Modify food consistency to ↓ aspiration risk.
• Consider feeding device for those w/recurrent aspiration.
• Caloric support may be needed in those w/weight loss.
• Vitamin supplementation to meet dietary needs
• Standard pharmacotherapy for pain control
• Referral to pain mgmt specialist as needed
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations in
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 1
Neurologic assessment for progression of ataxia, UMN or LMN signs, & history of falls
Monitor ataxia progression w/standardized scale (SARA).
Physiatry & OT/PT assessment of mobility & self-help skills as they relate to ataxia, spasticity, & weakness
LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SARA = Scale for Assessment and Rating of Ataxia; UMN = upper motor neuron
• Neurologic assessment for progression of ataxia, UMN or LMN signs, & history of falls
• Monitor ataxia progression w/standardized scale (SARA).
• Physiatry & OT/PT assessment of mobility & self-help skills as they relate to ataxia, spasticity, & weakness
## Agents/Circumstances to Avoid
Affected individuals should avoid alcohol as well as medications known to be neurotoxic such as those that cause neuropathy (e.g., isoniazid, large-dose vitamin B
Circumstances that could lead to physical harm, such as operating machinery or climbing to great heights, should also be avoided.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Riluzole has been shown to provide some symptomatic relief of ataxia in a mixed group of individuals including persons with SCA1 [
Intrathecal injection of 3,000 mesenchymal stem cells in SCA1 transgenic mice mitigated the cerebellar neuronal disorganization, atrophy of dendrites, and motor disturbances [
Search
## Other
Tremor-controlling drugs do not work well for cerebellar tremors.
## Genetic Counseling
Spinocerebellar ataxia type 1 (SCA1) is inherited in an autosomal dominant manner.
Most individuals diagnosed with SCA1 have an affected parent.
A proband with SCA1 who appears to be the only affected family member may have inherited an expanded allele from a parent with an intermediate expansion. A parent with 36-38 CAG repeats that are not interrupted by CAT trinucleotide repeats is not likely to display any manifestations of SCA1 but does have a "mutable normal" (intermediate) allele that can expand on transmission to offspring (see
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.
The family history of some individuals diagnosed with SCA1 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has an abnormal CAG trinucleotide expansion in
If a parent has an abnormal CAG trinucleotide expansion in
Note: If a parent has a mutable normal (intermediate) allele (i.e., 36-38 CAG repeats without CAT interruptions), the parent is not likely to display any manifestations of SCA1, but the allele can expand on transmission to offspring (see
Anticipation (an increase in the severity and earlier onset of the phenotype in progressive generations) has been observed in SCA1. Expansions are more likely to occur when the pathogenic
Each child of an individual with SCA1 has a 50% chance of inheriting an abnormal CAG trinucleotide expansion in
Expanded CAG repeat tracts are unstable: during transmission to offspring they may contract by a few trinucleotides, though they are more likely to expand. Larger intergenerational expansions tend to occur more frequently on paternal than on maternal transmission.
Predictive testing for at-risk relatives is possible once an abnormal CAG repeat expansion in
Such testing should be performed in the context of formal genetic counseling and is not useful in reliably predicting age of onset, severity, type of manifestations, or rate of progression in asymptomatic individuals.
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 SCA1, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before 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 an abnormal CAG trinucleotide expansion in
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 SCA1 have an affected parent.
• A proband with SCA1 who appears to be the only affected family member may have inherited an expanded allele from a parent with an intermediate expansion. A parent with 36-38 CAG repeats that are not interrupted by CAT trinucleotide repeats is not likely to display any manifestations of SCA1 but does have a "mutable normal" (intermediate) allele that can expand on transmission to offspring (see
• 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.
• The family history of some individuals diagnosed with SCA1 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has an abnormal CAG trinucleotide expansion in
• If a parent has an abnormal CAG trinucleotide expansion in
• Note: If a parent has a mutable normal (intermediate) allele (i.e., 36-38 CAG repeats without CAT interruptions), the parent is not likely to display any manifestations of SCA1, but the allele can expand on transmission to offspring (see
• Anticipation (an increase in the severity and earlier onset of the phenotype in progressive generations) has been observed in SCA1. Expansions are more likely to occur when the pathogenic
• Each child of an individual with SCA1 has a 50% chance of inheriting an abnormal CAG trinucleotide expansion in
• Expanded CAG repeat tracts are unstable: during transmission to offspring they may contract by a few trinucleotides, though they are more likely to expand. Larger intergenerational expansions tend to occur more frequently on paternal than on maternal transmission.
• Predictive testing for at-risk relatives is possible once an abnormal CAG repeat expansion in
• Such testing should be performed in the context of formal genetic counseling and is not useful in reliably predicting age of onset, severity, type of manifestations, or rate of progression in asymptomatic individuals.
• 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 is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before 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
Spinocerebellar ataxia type 1 (SCA1) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with SCA1 have an affected parent.
A proband with SCA1 who appears to be the only affected family member may have inherited an expanded allele from a parent with an intermediate expansion. A parent with 36-38 CAG repeats that are not interrupted by CAT trinucleotide repeats is not likely to display any manifestations of SCA1 but does have a "mutable normal" (intermediate) allele that can expand on transmission to offspring (see
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.
The family history of some individuals diagnosed with SCA1 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has an abnormal CAG trinucleotide expansion in
If a parent has an abnormal CAG trinucleotide expansion in
Note: If a parent has a mutable normal (intermediate) allele (i.e., 36-38 CAG repeats without CAT interruptions), the parent is not likely to display any manifestations of SCA1, but the allele can expand on transmission to offspring (see
Anticipation (an increase in the severity and earlier onset of the phenotype in progressive generations) has been observed in SCA1. Expansions are more likely to occur when the pathogenic
Each child of an individual with SCA1 has a 50% chance of inheriting an abnormal CAG trinucleotide expansion in
Expanded CAG repeat tracts are unstable: during transmission to offspring they may contract by a few trinucleotides, though they are more likely to expand. Larger intergenerational expansions tend to occur more frequently on paternal than on maternal transmission.
• Most individuals diagnosed with SCA1 have an affected parent.
• A proband with SCA1 who appears to be the only affected family member may have inherited an expanded allele from a parent with an intermediate expansion. A parent with 36-38 CAG repeats that are not interrupted by CAT trinucleotide repeats is not likely to display any manifestations of SCA1 but does have a "mutable normal" (intermediate) allele that can expand on transmission to offspring (see
• 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.
• The family history of some individuals diagnosed with SCA1 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent has an abnormal CAG trinucleotide expansion in
• If a parent has an abnormal CAG trinucleotide expansion in
• Note: If a parent has a mutable normal (intermediate) allele (i.e., 36-38 CAG repeats without CAT interruptions), the parent is not likely to display any manifestations of SCA1, but the allele can expand on transmission to offspring (see
• Anticipation (an increase in the severity and earlier onset of the phenotype in progressive generations) has been observed in SCA1. Expansions are more likely to occur when the pathogenic
• Each child of an individual with SCA1 has a 50% chance of inheriting an abnormal CAG trinucleotide expansion in
• Expanded CAG repeat tracts are unstable: during transmission to offspring they may contract by a few trinucleotides, though they are more likely to expand. Larger intergenerational expansions tend to occur more frequently on paternal than on maternal transmission.
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once an abnormal CAG repeat expansion in
Such testing should be performed in the context of formal genetic counseling and is not useful in reliably predicting age of onset, severity, type of manifestations, or rate of progression in asymptomatic individuals.
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 SCA1, it is appropriate to consider testing of symptomatic individuals regardless of age.
The optimal time for determination of genetic risk is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before 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 an abnormal CAG repeat expansion in
• Such testing should be performed in the context of formal genetic counseling and is not useful in reliably predicting age of onset, severity, type of manifestations, or rate of progression in asymptomatic individuals.
• 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 is before pregnancy. Similarly, decisions regarding testing to determine the genetic status of at-risk asymptomatic family members are best made before 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 an abnormal CAG trinucleotide expansion in
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
Via Sara 12
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Spain
Sanford Research
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## Molecular Genetics
Spinocerebellar Ataxia Type 1: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 1 (
It is believed that the expanded polyglutamine tract resulting from the CAG expansion results in misfolding of ataxin-1, resulting in insoluble aggregates. The abnormal protein accumulates in the nucleus as a single aggregate, often referred to as a nuclear inclusion (NI). NIs affect portions of the cell's protein refolding and degradation machinery (chaperones, ubiquitin, and proteasomal subunits); it is thought that impaired protein clearance underlies the pathogenesis of SCA1. At least three lines of evidence support this hypothesis:
Neuronal degeneration is accelerated when ubiquitination is impaired in SCA1 transgenic mice [
Overexpression of specific chaperones suppresses neurodegeneration in fly and mouse models of polyglutamine disorders [
Polyglutamine-expanded ataxin-1 decreases the activity of the proteasome in cell culture [
The accumulated toxic species is likely to be oligomers [
An analysis of the genomic expression profile in SCA1 transgenic mice showed consistently altered levels of mRNA from five genes forming a biologic cohort centered on glutamate signaling pathways in Purkinje cells [
Normal
Mutable normal (intermediate) alleles have 36-38 CAG repeats without CAT interruptions. Mutable normal alleles have not been associated with symptoms but can expand into the abnormal range on transmission to offspring.
Somatic and meiotic instability has been observed for the
• Neuronal degeneration is accelerated when ubiquitination is impaired in SCA1 transgenic mice [
• Overexpression of specific chaperones suppresses neurodegeneration in fly and mouse models of polyglutamine disorders [
• Polyglutamine-expanded ataxin-1 decreases the activity of the proteasome in cell culture [
• Normal
• Mutable normal (intermediate) alleles have 36-38 CAG repeats without CAT interruptions. Mutable normal alleles have not been associated with symptoms but can expand into the abnormal range on transmission to offspring.
• Somatic and meiotic instability has been observed for the
## Molecular Pathogenesis
It is believed that the expanded polyglutamine tract resulting from the CAG expansion results in misfolding of ataxin-1, resulting in insoluble aggregates. The abnormal protein accumulates in the nucleus as a single aggregate, often referred to as a nuclear inclusion (NI). NIs affect portions of the cell's protein refolding and degradation machinery (chaperones, ubiquitin, and proteasomal subunits); it is thought that impaired protein clearance underlies the pathogenesis of SCA1. At least three lines of evidence support this hypothesis:
Neuronal degeneration is accelerated when ubiquitination is impaired in SCA1 transgenic mice [
Overexpression of specific chaperones suppresses neurodegeneration in fly and mouse models of polyglutamine disorders [
Polyglutamine-expanded ataxin-1 decreases the activity of the proteasome in cell culture [
The accumulated toxic species is likely to be oligomers [
An analysis of the genomic expression profile in SCA1 transgenic mice showed consistently altered levels of mRNA from five genes forming a biologic cohort centered on glutamate signaling pathways in Purkinje cells [
Normal
Mutable normal (intermediate) alleles have 36-38 CAG repeats without CAT interruptions. Mutable normal alleles have not been associated with symptoms but can expand into the abnormal range on transmission to offspring.
Somatic and meiotic instability has been observed for the
• Neuronal degeneration is accelerated when ubiquitination is impaired in SCA1 transgenic mice [
• Overexpression of specific chaperones suppresses neurodegeneration in fly and mouse models of polyglutamine disorders [
• Polyglutamine-expanded ataxin-1 decreases the activity of the proteasome in cell culture [
• Normal
• Mutable normal (intermediate) alleles have 36-38 CAG repeats without CAT interruptions. Mutable normal alleles have not been associated with symptoms but can expand into the abnormal range on transmission to offspring.
• Somatic and meiotic instability has been observed for the
## Chapter Notes
Tetsuo Ashizawa, MD (2005-present)Vicki L Brandt; Baylor College of Medicine (1998-2005)Xi Lin, MD, PhD; University of Texas Medical Branch (2005-2011)Puneet Opal, MD, PhD (2017-present)SH Subramony, MD; University of Florida (2011-2017)Huda Y Zoghbi, MD; Baylor College of Medicine (1998-2005)
2 February 2023 (sw) Comprehensive update posted live
22 June 2017 (ma) Comprehensive update posted live
3 July 2014 (me) Comprehensive update posted live
20 October 2011 (me) Comprehensive update posted live
1 November 2007 (me) Comprehensive update posted live
18 July 2005 (me) Comprehensive update posted live
18 June 2003 (ca) Comprehensive update posted live
29 January 2001 (me) Comprehensive update posted live
1 October 1998 (pb) Review posted live
26 June 1998 (hz) Original submission
•
•
• 2 February 2023 (sw) Comprehensive update posted live
• 22 June 2017 (ma) Comprehensive update posted live
• 3 July 2014 (me) Comprehensive update posted live
• 20 October 2011 (me) Comprehensive update posted live
• 1 November 2007 (me) Comprehensive update posted live
• 18 July 2005 (me) Comprehensive update posted live
• 18 June 2003 (ca) Comprehensive update posted live
• 29 January 2001 (me) Comprehensive update posted live
• 1 October 1998 (pb) Review posted live
• 26 June 1998 (hz) Original submission
## Author Notes
•
•
## Author History
Tetsuo Ashizawa, MD (2005-present)Vicki L Brandt; Baylor College of Medicine (1998-2005)Xi Lin, MD, PhD; University of Texas Medical Branch (2005-2011)Puneet Opal, MD, PhD (2017-present)SH Subramony, MD; University of Florida (2011-2017)Huda Y Zoghbi, MD; Baylor College of Medicine (1998-2005)
## Revision History
2 February 2023 (sw) Comprehensive update posted live
22 June 2017 (ma) Comprehensive update posted live
3 July 2014 (me) Comprehensive update posted live
20 October 2011 (me) Comprehensive update posted live
1 November 2007 (me) Comprehensive update posted live
18 July 2005 (me) Comprehensive update posted live
18 June 2003 (ca) Comprehensive update posted live
29 January 2001 (me) Comprehensive update posted live
1 October 1998 (pb) Review posted live
26 June 1998 (hz) Original submission
• 2 February 2023 (sw) Comprehensive update posted live
• 22 June 2017 (ma) Comprehensive update posted live
• 3 July 2014 (me) Comprehensive update posted live
• 20 October 2011 (me) Comprehensive update posted live
• 1 November 2007 (me) Comprehensive update posted live
• 18 July 2005 (me) Comprehensive update posted live
• 18 June 2003 (ca) Comprehensive update posted live
• 29 January 2001 (me) Comprehensive update posted live
• 1 October 1998 (pb) Review posted live
• 26 June 1998 (hz) Original submission
## References
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
Sequeiros J, Martindale J, Seneca S. EMQN Best Practice Guidelines for molecular genetic testing of the SCAs. European Molecular Quality Genetics Network. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Sequeiros J, Martindale J, Seneca S. EMQN Best Practice Guidelines for molecular genetic testing of the SCAs. European Molecular Quality Genetics Network. Available
## Published Guidelines / Consensus Statements
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
Sequeiros J, Martindale J, Seneca S. EMQN Best Practice Guidelines for molecular genetic testing of the SCAs. European Molecular Quality Genetics Network. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• Sequeiros J, Martindale J, Seneca S. EMQN Best Practice Guidelines for molecular genetic testing of the SCAs. European Molecular Quality Genetics Network. Available
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"FA Platonov, K Tyryshkin, DG Tikhonov, TS Neustroyeva, TM Sivtseva, NV Yakovleva, VP Nikolaev, OG Sidorova, SK Kononova, LG Goldfarb, NM Renwick. Genetic fitness and selection intensity in a population affected with high-incidence spinocerebellar ataxia type 1.. Neurogenetics. 2016;17:179-85",
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"Y Robitaille, I Lopes-Cendes, M Becher, G Rouleau, AW Clark. The neuropathology of CAG repeat diseases: review and update of genetic and molecular features.. Brain Pathol. 1997;7:901-26",
"S Romano, G Coarelli, C Marcotulli, L Leonardi, F Piccolo, M Spadaro, M Frontali, M Ferraldeschi, MC Vulpiani, F Ponzelli, M Salvetti, F Orzi, A Petrucci, N Vanacore, C Casali, G Ristori. Riluzole in patients with hereditary cerebellar ataxia: a randomised, double-blind, placebo-controlled trial.. Lancet Neurol. 2015;14:985-91",
"U Rüb, L Schöls, H Paulson, G Auburger, P Kermer, JC Jen, K Seidel, HW Korf, T Deller. Clinical features, neurogenetics and neuropathology of the polyglutamine spinocerebellar ataxias type 1, 2, 3, 6 and 7.. Prog Neurobiol 2013;104:38-66",
"H Sasaki, T Fukazawa, T Yanagihara, T Hamada, K Shima, A Matsumoto, K Hashimoto, N Ito, A Wakisaka, K Tashiro. Clinical features and natural history of spinocerebellar ataxia type 1.. Acta Neurol Scand. 1996;93:64-71",
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"A Venkatraman, YS Hu, A Didonna, M Cvetanovic, A Krbanjevic, P Bilesimo, P Opal. The histone deacetylase HDAC3 is essential for Purkinje cell function, potentially complicating the use of HDAC inhibitors in SCA1.. Hum Mol Genet. 2014;23:3733-45",
"NR Whaley, S Fujioka, ZK Wszolek. Autosomal dominant cerebellar ataxia type I: a review of the phenotypic and genotypic characteristics.. Orphanet J Rare Dis. 2011;6:33",
"M Yamada, T Sato, S Tsuji, H. Takahashi. CAG repeat disorder models and human neuropathology: similarities and differences.. Acta Neuropathol. 2008;115:71-86",
"CY Yang, RY Lai, N Amokrane, CY Lin, KP Figueroa, SM Pulst, S Perlman, G Wilmot, CM Gomez, JD Schmahmann, H Paulson, VG Shakkottai, LS Rosenthal, SH Ying, T Zesiewicz, K Bushara, M Geschwind, G Xia, SH Subramony, T Ashizawa, MS Troche, SH Kuo. Dysphagia in spinocerebellar ataxias type 1, 2, 3 and 6.. J Neurol Sci. 2020;415",
"HY Zoghbi, MS Pollack, LA Lyons, RE Ferrell, SP Daiger, AL Beaudet. Spinocerebellar ataxia: variable age of onset and linkage to human leukocyte antigen in a large kindred.. Ann Neurol. 1988;23:580-4"
] |
1/10/1998
|
2/2/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sca10
|
sca10
|
[
"SCA10",
"SCA10",
"Ataxin-10",
"ATXN10",
"Spinocerebellar Ataxia Type 10"
] |
Spinocerebellar Ataxia Type 10
|
Tohru Matsuura, Tetsuo Ashizawa
|
Summary Spinocerebellar ataxia type 10 (SCA10) is characterized by slowly progressive cerebellar ataxia that usually starts as poor balance and unsteady gait, followed by upper-limb ataxia, scanning dysarthria, and dysphagia. Abnormal tracking eye movements are common. Recurrent seizures after the onset of gait ataxia have been reported with variable frequencies among different families. Some individuals have cognitive dysfunction, behavioral disturbances, mood disorders, mild pyramidal signs, and peripheral neuropathy. Age of onset ranges from 12 to 48 years. Diagnosis of SCA10 is established in a proband by identification of a heterozygous ATTCT pentanucleotide-repeat expansion in SCA10 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the repeat expansion. The risk of developing the SCA10 phenotype in individuals with expanded alleles in the intermediate range (280-850) is uncertain because of the apparently reduced penetrance. Anticipation has been observed in some families with paternal (but not maternal) transmission of the pentanucleotide repeat expansion. Prenatal testing for pregnancies at increased risk is possible if the diagnosis has been established by molecular genetic testing in an affected family member.
|
## Diagnosis
Spinocerebellar ataxia type 10 (SCA10)
Slowly progressive cerebellar ataxia starting as poor balance and unsteady gait
Scanning dysarthria, dysphagia, and upper-limb ataxia following the gait ataxia
Family history consistent with autosomal dominant inheritance and Native American or East Asian ancestry
Generalized motor seizures and/or complex partial seizures
Note: Ataxia and its impact on quality of life is mild compared to SCA3 [
Other suggestive findings:
The diagnosis of SCA10
82% of unaffected individuals are compound heterozygotes for ATTCT repeat sizes in this range.
18% of unaffected individuals are homozygous for ATTCT repeat sizes in this range.
280 ATTCT repeats; standard nomenclature
Alleles of 360 and 370 ATTCT repeats; standard nomenclature
Overlap of full- and reduced-penetrance alleles in 800-850 ATTCT repeat range needs to be clarified by further studies. 850 ATTCT repeats; standard nomenclature
An individual with Sioux ancestry without a family history of ataxia or seizure had an expansion allele of 1,400 pure ATTCT repeats; standard nomenclature
Molecular genetic testing approaches can include
Analysis by PCR detects normal alleles. The presence of compound heterozygous
If PCR analysis shows only one allele, an alternate PCR test – the ATTCT-repeat-primed PCR [
Southern blot analysis of genomic DNA is necessary to determine the size of expanded alleles and to differentiate reduced-penetrance from full-penetrance alleles [
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 10
See
See
Southern blot analysis of both genomic DNA and amplicons from ATTCT-repeat primed PCR has been shown to be a reliable method to detect and characterize the ATTCT repeat insertion (see
Insertion of a variable number of ATTCT repeats in
• Slowly progressive cerebellar ataxia starting as poor balance and unsteady gait
• Scanning dysarthria, dysphagia, and upper-limb ataxia following the gait ataxia
• Family history consistent with autosomal dominant inheritance and Native American or East Asian ancestry
• Generalized motor seizures and/or complex partial seizures
• 82% of unaffected individuals are compound heterozygotes for ATTCT repeat sizes in this range.
• 18% of unaffected individuals are homozygous for ATTCT repeat sizes in this range.
• 82% of unaffected individuals are compound heterozygotes for ATTCT repeat sizes in this range.
• 18% of unaffected individuals are homozygous for ATTCT repeat sizes in this range.
• 280 ATTCT repeats; standard nomenclature
• Alleles of 360 and 370 ATTCT repeats; standard nomenclature
• Overlap of full- and reduced-penetrance alleles in 800-850 ATTCT repeat range needs to be clarified by further studies. 850 ATTCT repeats; standard nomenclature
• An individual with Sioux ancestry without a family history of ataxia or seizure had an expansion allele of 1,400 pure ATTCT repeats; standard nomenclature
• 280 ATTCT repeats; standard nomenclature
• Alleles of 360 and 370 ATTCT repeats; standard nomenclature
• Overlap of full- and reduced-penetrance alleles in 800-850 ATTCT repeat range needs to be clarified by further studies. 850 ATTCT repeats; standard nomenclature
• An individual with Sioux ancestry without a family history of ataxia or seizure had an expansion allele of 1,400 pure ATTCT repeats; standard nomenclature
• 82% of unaffected individuals are compound heterozygotes for ATTCT repeat sizes in this range.
• 18% of unaffected individuals are homozygous for ATTCT repeat sizes in this range.
• 280 ATTCT repeats; standard nomenclature
• Alleles of 360 and 370 ATTCT repeats; standard nomenclature
• Overlap of full- and reduced-penetrance alleles in 800-850 ATTCT repeat range needs to be clarified by further studies. 850 ATTCT repeats; standard nomenclature
• An individual with Sioux ancestry without a family history of ataxia or seizure had an expansion allele of 1,400 pure ATTCT repeats; standard nomenclature
• Analysis by PCR detects normal alleles. The presence of compound heterozygous
• If PCR analysis shows only one allele, an alternate PCR test – the ATTCT-repeat-primed PCR [
• Southern blot analysis of genomic DNA is necessary to determine the size of expanded alleles and to differentiate reduced-penetrance from full-penetrance alleles [
## Suggestive Findings
Spinocerebellar ataxia type 10 (SCA10)
Slowly progressive cerebellar ataxia starting as poor balance and unsteady gait
Scanning dysarthria, dysphagia, and upper-limb ataxia following the gait ataxia
Family history consistent with autosomal dominant inheritance and Native American or East Asian ancestry
Generalized motor seizures and/or complex partial seizures
Note: Ataxia and its impact on quality of life is mild compared to SCA3 [
Other suggestive findings:
• Slowly progressive cerebellar ataxia starting as poor balance and unsteady gait
• Scanning dysarthria, dysphagia, and upper-limb ataxia following the gait ataxia
• Family history consistent with autosomal dominant inheritance and Native American or East Asian ancestry
• Generalized motor seizures and/or complex partial seizures
## Establishing the Diagnosis
The diagnosis of SCA10
82% of unaffected individuals are compound heterozygotes for ATTCT repeat sizes in this range.
18% of unaffected individuals are homozygous for ATTCT repeat sizes in this range.
280 ATTCT repeats; standard nomenclature
Alleles of 360 and 370 ATTCT repeats; standard nomenclature
Overlap of full- and reduced-penetrance alleles in 800-850 ATTCT repeat range needs to be clarified by further studies. 850 ATTCT repeats; standard nomenclature
An individual with Sioux ancestry without a family history of ataxia or seizure had an expansion allele of 1,400 pure ATTCT repeats; standard nomenclature
Molecular genetic testing approaches can include
Analysis by PCR detects normal alleles. The presence of compound heterozygous
If PCR analysis shows only one allele, an alternate PCR test – the ATTCT-repeat-primed PCR [
Southern blot analysis of genomic DNA is necessary to determine the size of expanded alleles and to differentiate reduced-penetrance from full-penetrance alleles [
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 10
See
See
Southern blot analysis of both genomic DNA and amplicons from ATTCT-repeat primed PCR has been shown to be a reliable method to detect and characterize the ATTCT repeat insertion (see
Insertion of a variable number of ATTCT repeats in
• 82% of unaffected individuals are compound heterozygotes for ATTCT repeat sizes in this range.
• 18% of unaffected individuals are homozygous for ATTCT repeat sizes in this range.
• 82% of unaffected individuals are compound heterozygotes for ATTCT repeat sizes in this range.
• 18% of unaffected individuals are homozygous for ATTCT repeat sizes in this range.
• 280 ATTCT repeats; standard nomenclature
• Alleles of 360 and 370 ATTCT repeats; standard nomenclature
• Overlap of full- and reduced-penetrance alleles in 800-850 ATTCT repeat range needs to be clarified by further studies. 850 ATTCT repeats; standard nomenclature
• An individual with Sioux ancestry without a family history of ataxia or seizure had an expansion allele of 1,400 pure ATTCT repeats; standard nomenclature
• 280 ATTCT repeats; standard nomenclature
• Alleles of 360 and 370 ATTCT repeats; standard nomenclature
• Overlap of full- and reduced-penetrance alleles in 800-850 ATTCT repeat range needs to be clarified by further studies. 850 ATTCT repeats; standard nomenclature
• An individual with Sioux ancestry without a family history of ataxia or seizure had an expansion allele of 1,400 pure ATTCT repeats; standard nomenclature
• 82% of unaffected individuals are compound heterozygotes for ATTCT repeat sizes in this range.
• 18% of unaffected individuals are homozygous for ATTCT repeat sizes in this range.
• 280 ATTCT repeats; standard nomenclature
• Alleles of 360 and 370 ATTCT repeats; standard nomenclature
• Overlap of full- and reduced-penetrance alleles in 800-850 ATTCT repeat range needs to be clarified by further studies. 850 ATTCT repeats; standard nomenclature
• An individual with Sioux ancestry without a family history of ataxia or seizure had an expansion allele of 1,400 pure ATTCT repeats; standard nomenclature
• Analysis by PCR detects normal alleles. The presence of compound heterozygous
• If PCR analysis shows only one allele, an alternate PCR test – the ATTCT-repeat-primed PCR [
• Southern blot analysis of genomic DNA is necessary to determine the size of expanded alleles and to differentiate reduced-penetrance from full-penetrance alleles [
## Clinical Characteristics
The clinical findings of spinocerebellar ataxia type 10 (SCA10) are relatively homogeneous. Ataxia causes progressive disability, and seizures may become life threatening if status epilepticus emerges. Reported age of onset ranges from 12 to 83 years [
The gait ataxia gradually worsens, leading to an increasing number of falls and necessitating use of a cane, walker, and eventually wheelchair. In the advanced stage, the affected individual is unable to stand or sit without support.
Upper-limb coordination begins to deteriorate within a few years after the onset of gait ataxia. Handwriting and other fine motor tasks, such as buttoning, are the first to be impaired, followed by increasing difficulties in daily activities such as feeding, dressing, and personal hygiene.
Scanning dysarthria, a type of slurred speech typically seen in cerebellar ataxia, appears within a few years after the onset of gait ataxia. Scanning speech is the result of impaired coordination of the movements of the vocal cords, tongue, palate, cheeks, and lips. Impaired coordination of the diaphragm and other respiratory muscles contributes to the speech impairment.
Poor coordination of tongue, throat, and mouth muscles causes dysphagia in later stages of the disease, often leading to life-threatening aspiration pneumonia.
Most individuals develop abnormal tracking eye movements: fragmented ocular pursuit, ocular dysmetria, and occasionally ocular flutter. Impaired ocular movements are attributable to cerebellar dysfunction. Some individuals with relatively severe ataxia show coarse gaze-induced nystagmus. Saccade velocity is normal.
Ataxia may be induced by small amounts of alcohol [
Intention tremor was identified only in women from one of the 16 families with SCA10 reported in a Brazilian series [
Recurrent seizures have been reported in 20%-100% of affected individuals [
Without treatment, generalized motor seizures may occur daily and complex partial seizures may occur up to several times a day. Poorly treated seizures may result in life-threatening status epilepticus and/or death [
Seizures were found to occur in six of 91 Brazilians (6.6%) with SCA10 from the Parana/Santa Catarina region, and those with seizures had earlier age at onset [
Mild pyramidal signs (either hyperreflexia, Babinski sign, or both), behavioral disturbances (including psychosis, paranoid schizophrenia), dystonia, parkinsonism, peripheral neuropathy, central auditory processing, and sleep disorders have been variably seen [
Extraneural abnormalities including hepatic failure, anemia, and/or thrombocytopenia have been recorded in one family [
Low IQ, behavioral disturbances, and extraneural abnormalities have not been found in Brazilians with SCA10, although mild or equivocal pyramidal tract signs and rare sensory polyneuropathy were noted [
A comparison of clinical data and genotypes in individuals with SCA10 revealed an inverse correlation between expansion size and age of onset (p = 0.018) [
The presence of the
Though not as yet assessed quantitatively, the severity of the disease in individuals with SCA10 does not appear to correlate with expansion size. Longitudinal clinical data are needed to examine whether repeat size correlates with disease progression.
Penetrance is usually complete. However, apparent reduced penetrance has been reported [
Anticipation is usually associated with progressively larger ATTCT repeat expansions in successive generations. The expanded repeat alleles are mostly unstable with paternal transmission but remarkably stable with maternal transmission [
Anticipation was first noted in one large family with SCA10 [
Interrupted repeat expansions show anticipation but are accompanied by a paradoxic contraction in intergenerational repeat size [
The exact prevalence of SCA10 is unknown.
In a cohort of families from Mexico who had inherited ataxia, SCA10 was determined to be the second most common inherited ataxia, after
SCA10 has also been identified in Asian populations including Japanese [
## Clinical Description
The clinical findings of spinocerebellar ataxia type 10 (SCA10) are relatively homogeneous. Ataxia causes progressive disability, and seizures may become life threatening if status epilepticus emerges. Reported age of onset ranges from 12 to 83 years [
The gait ataxia gradually worsens, leading to an increasing number of falls and necessitating use of a cane, walker, and eventually wheelchair. In the advanced stage, the affected individual is unable to stand or sit without support.
Upper-limb coordination begins to deteriorate within a few years after the onset of gait ataxia. Handwriting and other fine motor tasks, such as buttoning, are the first to be impaired, followed by increasing difficulties in daily activities such as feeding, dressing, and personal hygiene.
Scanning dysarthria, a type of slurred speech typically seen in cerebellar ataxia, appears within a few years after the onset of gait ataxia. Scanning speech is the result of impaired coordination of the movements of the vocal cords, tongue, palate, cheeks, and lips. Impaired coordination of the diaphragm and other respiratory muscles contributes to the speech impairment.
Poor coordination of tongue, throat, and mouth muscles causes dysphagia in later stages of the disease, often leading to life-threatening aspiration pneumonia.
Most individuals develop abnormal tracking eye movements: fragmented ocular pursuit, ocular dysmetria, and occasionally ocular flutter. Impaired ocular movements are attributable to cerebellar dysfunction. Some individuals with relatively severe ataxia show coarse gaze-induced nystagmus. Saccade velocity is normal.
Ataxia may be induced by small amounts of alcohol [
Intention tremor was identified only in women from one of the 16 families with SCA10 reported in a Brazilian series [
Recurrent seizures have been reported in 20%-100% of affected individuals [
Without treatment, generalized motor seizures may occur daily and complex partial seizures may occur up to several times a day. Poorly treated seizures may result in life-threatening status epilepticus and/or death [
Seizures were found to occur in six of 91 Brazilians (6.6%) with SCA10 from the Parana/Santa Catarina region, and those with seizures had earlier age at onset [
Mild pyramidal signs (either hyperreflexia, Babinski sign, or both), behavioral disturbances (including psychosis, paranoid schizophrenia), dystonia, parkinsonism, peripheral neuropathy, central auditory processing, and sleep disorders have been variably seen [
Extraneural abnormalities including hepatic failure, anemia, and/or thrombocytopenia have been recorded in one family [
Low IQ, behavioral disturbances, and extraneural abnormalities have not been found in Brazilians with SCA10, although mild or equivocal pyramidal tract signs and rare sensory polyneuropathy were noted [
## Genotype-Phenotype Correlations
A comparison of clinical data and genotypes in individuals with SCA10 revealed an inverse correlation between expansion size and age of onset (p = 0.018) [
The presence of the
Though not as yet assessed quantitatively, the severity of the disease in individuals with SCA10 does not appear to correlate with expansion size. Longitudinal clinical data are needed to examine whether repeat size correlates with disease progression.
## Penetrance
Penetrance is usually complete. However, apparent reduced penetrance has been reported [
## Anticipation
Anticipation is usually associated with progressively larger ATTCT repeat expansions in successive generations. The expanded repeat alleles are mostly unstable with paternal transmission but remarkably stable with maternal transmission [
Anticipation was first noted in one large family with SCA10 [
Interrupted repeat expansions show anticipation but are accompanied by a paradoxic contraction in intergenerational repeat size [
## Prevalence
The exact prevalence of SCA10 is unknown.
In a cohort of families from Mexico who had inherited ataxia, SCA10 was determined to be the second most common inherited ataxia, after
SCA10 has also been identified in Asian populations including Japanese [
## Genetically Related (Allelic) Disorders
No other phenotypes with the pentanucleotide expansion of
## Differential Diagnosis
Significant overlap exists in the clinical presentation of the SCAs (see
Although the combination of "pure" cerebellar ataxia (lacking other motor or cranial nerve involvement) and seizures is typical for SCA10 and has seldom been seen in other autosomal dominant cerebellar ataxias, it is possible that in some families, SCA10 could be a pure cerebellar ataxia without seizures.
See
Hereditary Ataxia Disorders of Interest in the Differential Diagnosis of Spinocerebellar Ataxia Type 10
Seizures
Conspicuous neurologic signs (e.g., extrapyramidal signs) not seen in SCA10
Seizures may accompany relatively "pure" cerebellar ataxia.
Identified primarily in persons of Filipino & French ancestry
Seizures may accompany relatively "pure" cerebellar ataxia.
Axial myoclonus
Identified primarily in persons of European & Japanese ancestry (most persons w/SCA10 are of Latin American / Amerindian ancestry)
Seizures
Conspicuous neurologic signs (e.g., extrapyramidal signs; not seen in SCA10)
AD = autosomal dominant; AR = autosomal recessive; DRPLA = dentatorubral-pallidoluysian atrophy; FXTAS = fragile X-associated tremor/ataxia syndrome; MOI = mode of inheritance; SCA = spinocerebellar ataxia; XL = X-linked
• Seizures
• Conspicuous neurologic signs (e.g., extrapyramidal signs) not seen in SCA10
• Seizures may accompany relatively "pure" cerebellar ataxia.
• Identified primarily in persons of Filipino & French ancestry
• Seizures may accompany relatively "pure" cerebellar ataxia.
• Axial myoclonus
• Identified primarily in persons of European & Japanese ancestry (most persons w/SCA10 are of Latin American / Amerindian ancestry)
• Seizures
• Conspicuous neurologic signs (e.g., extrapyramidal signs; not seen in SCA10)
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 10 (SCA10), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SCA10
Atypical dysarthria or communication problems
Frequent choking or severe dysphagia to assess aspiration risks
Treatment of Manifestations in Individuals with SCA10
Uncontrolled seizures may lead to potentially fatal status epilepticus.
Occasional breakthrough seizures may occur.
Canes & walkers
Modification of home w/grab bars, raised toilet seats, & ramps to accommodate motorized chairs
Speech therapy
Communication devices (e.g., writing pads, computer-based devices)
Recommended Surveillance for Individuals with SCA10
Alcohol and drugs known to adversely affect cerebellar functions should be avoided.
Falls should be avoided because resulting injuries may greatly compromise motor function and the ability to perform activities of daily living.
Any activities that are potentially dangerous to individuals with ataxia or epilepsy should be avoided, depending on the severity of the manifestations.
See
At-risk individuals should be aware of the possibility of inducing ataxia during pregnancy or puerperium [
Epilepsy should be managed during pregnancy according to the American Academy of Neurology
Clinical trials of troriluzol (BHV-4157), a prodrug of riluzole, have included individuals with SCA10.
Search
Although taltirelin hydrate is widely used for symptomatic treatment of ataxia in Japan, it has never been used for individuals with SCA10.
Tremor-controlling drugs, such as beta-blockers and primidone, are ineffective for cerebellar tremors.
• Atypical dysarthria or communication problems
• Frequent choking or severe dysphagia to assess aspiration risks
• Uncontrolled seizures may lead to potentially fatal status epilepticus.
• Occasional breakthrough seizures may occur.
• Canes & walkers
• Modification of home w/grab bars, raised toilet seats, & ramps to accommodate motorized chairs
• Speech therapy
• Communication devices (e.g., writing pads, computer-based devices)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 10 (SCA10), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SCA10
Atypical dysarthria or communication problems
Frequent choking or severe dysphagia to assess aspiration risks
• Atypical dysarthria or communication problems
• Frequent choking or severe dysphagia to assess aspiration risks
## Treatment of Manifestations
Treatment of Manifestations in Individuals with SCA10
Uncontrolled seizures may lead to potentially fatal status epilepticus.
Occasional breakthrough seizures may occur.
Canes & walkers
Modification of home w/grab bars, raised toilet seats, & ramps to accommodate motorized chairs
Speech therapy
Communication devices (e.g., writing pads, computer-based devices)
• Uncontrolled seizures may lead to potentially fatal status epilepticus.
• Occasional breakthrough seizures may occur.
• Canes & walkers
• Modification of home w/grab bars, raised toilet seats, & ramps to accommodate motorized chairs
• Speech therapy
• Communication devices (e.g., writing pads, computer-based devices)
## Surveillance
Recommended Surveillance for Individuals with SCA10
## Agents/Circumstances to Avoid
Alcohol and drugs known to adversely affect cerebellar functions should be avoided.
Falls should be avoided because resulting injuries may greatly compromise motor function and the ability to perform activities of daily living.
Any activities that are potentially dangerous to individuals with ataxia or epilepsy should be avoided, depending on the severity of the manifestations.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
At-risk individuals should be aware of the possibility of inducing ataxia during pregnancy or puerperium [
Epilepsy should be managed during pregnancy according to the American Academy of Neurology
## Therapies Under Investigation
Clinical trials of troriluzol (BHV-4157), a prodrug of riluzole, have included individuals with SCA10.
Search
## Other
Although taltirelin hydrate is widely used for symptomatic treatment of ataxia in Japan, it has never been used for individuals with SCA10.
Tremor-controlling drugs, such as beta-blockers and primidone, are ineffective for cerebellar tremors.
## Genetic Counseling
Spinocerebellar ataxia type 10 (SCA10) is inherited in an autosomal dominant manner.
To date, all reported individuals diagnosed with SCA10 inherited an expanded
Recommendations for the evaluation of apparently asymptomatic parents of a proband include neurologic evaluation and molecular genetic testing.
The family history 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 late onset of the disease in the transmitting parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If one of the parents of a proband is known to have a full-penetrance allele, the risk to the sibs is 50%.
In general, the age of onset and progression of SCA10 in sibs who inherit an expansion are variable and cannot be reliably predicted by the family history or molecular genetic testing.
The presence of the
Interrupted repeat expansions are also known to be associated with anticipation but are accompanied by a paradoxic contraction in intergenerational repeat size [
If one of the parents of a proband is known to have a reduced-penetrance allele but is clinically unaffected, the risk to the sibs of a proband may be anywhere between zero and 50% (see
If an expanded
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 an ATTCT repeat expansion in
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 SCA10, it is appropriate to consider testing of symptomatic individuals regardless of age.
Once an ATTCT repeat expansion in
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care centers would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• To date, all reported individuals diagnosed with SCA10 inherited an expanded
• Recommendations for the evaluation of apparently asymptomatic parents of a proband include neurologic evaluation and molecular genetic testing.
• The family history 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 late onset of the disease in the transmitting parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If one of the parents of a proband is known to have a full-penetrance allele, the risk to the sibs is 50%.
• In general, the age of onset and progression of SCA10 in sibs who inherit an expansion are variable and cannot be reliably predicted by the family history or molecular genetic testing.
• The presence of the
• Interrupted repeat expansions are also known to be associated with anticipation but are accompanied by a paradoxic contraction in intergenerational repeat size [
• In general, the age of onset and progression of SCA10 in sibs who inherit an expansion are variable and cannot be reliably predicted by the family history or molecular genetic testing.
• The presence of the
• Interrupted repeat expansions are also known to be associated with anticipation but are accompanied by a paradoxic contraction in intergenerational repeat size [
• If one of the parents of a proband is known to have a reduced-penetrance allele but is clinically unaffected, the risk to the sibs of a proband may be anywhere between zero and 50% (see
• If an expanded
• In general, the age of onset and progression of SCA10 in sibs who inherit an expansion are variable and cannot be reliably predicted by the family history or molecular genetic testing.
• The presence of the
• Interrupted repeat expansions are also known to be associated with anticipation but are accompanied by a paradoxic contraction in intergenerational repeat size [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 an ATTCT repeat expansion in
• 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.
## Mode of Inheritance
Spinocerebellar ataxia type 10 (SCA10) is inherited in an autosomal dominant manner.
## Risk to Family Members
To date, all reported individuals diagnosed with SCA10 inherited an expanded
Recommendations for the evaluation of apparently asymptomatic parents of a proband include neurologic evaluation and molecular genetic testing.
The family history 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 late onset of the disease in the transmitting parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If one of the parents of a proband is known to have a full-penetrance allele, the risk to the sibs is 50%.
In general, the age of onset and progression of SCA10 in sibs who inherit an expansion are variable and cannot be reliably predicted by the family history or molecular genetic testing.
The presence of the
Interrupted repeat expansions are also known to be associated with anticipation but are accompanied by a paradoxic contraction in intergenerational repeat size [
If one of the parents of a proband is known to have a reduced-penetrance allele but is clinically unaffected, the risk to the sibs of a proband may be anywhere between zero and 50% (see
If an expanded
• To date, all reported individuals diagnosed with SCA10 inherited an expanded
• Recommendations for the evaluation of apparently asymptomatic parents of a proband include neurologic evaluation and molecular genetic testing.
• The family history 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 late onset of the disease in the transmitting parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If one of the parents of a proband is known to have a full-penetrance allele, the risk to the sibs is 50%.
• In general, the age of onset and progression of SCA10 in sibs who inherit an expansion are variable and cannot be reliably predicted by the family history or molecular genetic testing.
• The presence of the
• Interrupted repeat expansions are also known to be associated with anticipation but are accompanied by a paradoxic contraction in intergenerational repeat size [
• In general, the age of onset and progression of SCA10 in sibs who inherit an expansion are variable and cannot be reliably predicted by the family history or molecular genetic testing.
• The presence of the
• Interrupted repeat expansions are also known to be associated with anticipation but are accompanied by a paradoxic contraction in intergenerational repeat size [
• If one of the parents of a proband is known to have a reduced-penetrance allele but is clinically unaffected, the risk to the sibs of a proband may be anywhere between zero and 50% (see
• If an expanded
• In general, the age of onset and progression of SCA10 in sibs who inherit an expansion are variable and cannot be reliably predicted by the family history or molecular genetic testing.
• The presence of the
• Interrupted repeat expansions are also known to be associated with anticipation but are accompanied by a paradoxic contraction in intergenerational repeat size [
## 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 an ATTCT repeat expansion in
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 SCA10, 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 an ATTCT repeat expansion in
• 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.
## Prenatal Testing and Preimplantation Genetic Testing
Once an ATTCT repeat expansion in
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal and preimplantation genetic testing. While most health care centers 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
Spain
•
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
• Spain
•
## Molecular Genetics
Spinocerebellar Ataxia Type 10: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 10 (
There is evidence to suggest that expanded non-coding intron 9 ATTCT repeats do not interfere with the transcription and post-transcriptional processing of
Genetically altered mice heterozygous for ataxin-10 deficiency exhibit no disease phenotype, while homozygous deficiency of ataxin-10 is embryonically lethal [
Expanded alleles are unstable in somatic tissues, appearing as "smeared" expanded alleles with multiple distinct expansion alleles on PCR and Southern blot analyses.
The expanded ATTCT repeat shows repeat-size instability when it is transmitted from generation to generation [
During paternal transmission, the expanded ATTCT repeats are highly unstable.
During maternal transmission, the expanded ATTCT repeats undergo no change or changes of a smaller magnitude.
Notable
Variants listed in the table have been provided by the authors.
Sequence analysis of
About 70% of large normal alleles (≥17 repeats), which comprise about 7% of normal alleles, have ATTGT-TTTCT or TTTCT interruptions at the second-to-last repeat [
The sequence of one allele of 280 ATTCT repeats with apparent reduced penetrance showed a complex pattern of interruptions, including multiple repetitive ATGCT repeats at the 5' end of the expansion and ATTCTAT septanucleotide repeats at the 3' end.
Limited sequencing of fully expanded ATTCT repeat alleles showed interruptions by multiple ATTTTCTs and ATATTCTs or uninterrupted ATTCTs, depending on the family from which the mutated allele was obtained [
• During paternal transmission, the expanded ATTCT repeats are highly unstable.
• During maternal transmission, the expanded ATTCT repeats undergo no change or changes of a smaller magnitude.
## Molecular Pathogenesis
There is evidence to suggest that expanded non-coding intron 9 ATTCT repeats do not interfere with the transcription and post-transcriptional processing of
Genetically altered mice heterozygous for ataxin-10 deficiency exhibit no disease phenotype, while homozygous deficiency of ataxin-10 is embryonically lethal [
Expanded alleles are unstable in somatic tissues, appearing as "smeared" expanded alleles with multiple distinct expansion alleles on PCR and Southern blot analyses.
The expanded ATTCT repeat shows repeat-size instability when it is transmitted from generation to generation [
During paternal transmission, the expanded ATTCT repeats are highly unstable.
During maternal transmission, the expanded ATTCT repeats undergo no change or changes of a smaller magnitude.
Notable
Variants listed in the table have been provided by the authors.
Sequence analysis of
About 70% of large normal alleles (≥17 repeats), which comprise about 7% of normal alleles, have ATTGT-TTTCT or TTTCT interruptions at the second-to-last repeat [
The sequence of one allele of 280 ATTCT repeats with apparent reduced penetrance showed a complex pattern of interruptions, including multiple repetitive ATGCT repeats at the 5' end of the expansion and ATTCTAT septanucleotide repeats at the 3' end.
Limited sequencing of fully expanded ATTCT repeat alleles showed interruptions by multiple ATTTTCTs and ATATTCTs or uninterrupted ATTCTs, depending on the family from which the mutated allele was obtained [
• During paternal transmission, the expanded ATTCT repeats are highly unstable.
• During maternal transmission, the expanded ATTCT repeats undergo no change or changes of a smaller magnitude.
## Chapter Notes
This work was supported by grants from NIH NS041547 (TA), National Ataxia Foundation, National Organization for Rare Disorders and Grants-in Aid from the Ministry of Education, Culture, Sports, Science, and Technology as well as the Ministry of Health, Labor, and Welfare of Japan (TM).
19 September 2019 (sw) Comprehensive update posted live
20 September 2012 (me) Comprehensive update posted live
9 March 2010 (me) Comprehensive update posted live
13 July 2006 (me) Comprehensive update posted live
13 May 2004 (me) Comprehensive update posted live
23 April 2002 (me) Review posted live
14 December 2001 (tm) Original submission
• 19 September 2019 (sw) Comprehensive update posted live
• 20 September 2012 (me) Comprehensive update posted live
• 9 March 2010 (me) Comprehensive update posted live
• 13 July 2006 (me) Comprehensive update posted live
• 13 May 2004 (me) Comprehensive update posted live
• 23 April 2002 (me) Review posted live
• 14 December 2001 (tm) Original submission
## Acknowledgments
This work was supported by grants from NIH NS041547 (TA), National Ataxia Foundation, National Organization for Rare Disorders and Grants-in Aid from the Ministry of Education, Culture, Sports, Science, and Technology as well as the Ministry of Health, Labor, and Welfare of Japan (TM).
## Revision History
19 September 2019 (sw) Comprehensive update posted live
20 September 2012 (me) Comprehensive update posted live
9 March 2010 (me) Comprehensive update posted live
13 July 2006 (me) Comprehensive update posted live
13 May 2004 (me) Comprehensive update posted live
23 April 2002 (me) Review posted live
14 December 2001 (tm) Original submission
• 19 September 2019 (sw) Comprehensive update posted live
• 20 September 2012 (me) Comprehensive update posted live
• 9 March 2010 (me) Comprehensive update posted live
• 13 July 2006 (me) Comprehensive update posted live
• 13 May 2004 (me) Comprehensive update posted live
• 23 April 2002 (me) Review posted live
• 14 December 2001 (tm) Original submission
## References
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available
## Published Guidelines / Consensus Statements
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset disorders. Available
## Literature Cited
|
[] |
23/4/2002
|
19/9/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sca11
|
sca11
|
[
"SCA11",
"SCA11",
"Tau-tubulin kinase 2",
"TTBK2",
"Spinocerebellar Ataxia Type 11"
] |
Spinocerebellar Ataxia Type 11
|
Zhongbo Chen, Arina Puzriakova, Henry Houlden
|
Summary Spinocerebellar ataxia type 11 (SCA11) is characterized by progressive cerebellar ataxia and abnormal eye signs (jerky pursuit, horizontal and vertical nystagmus). Pyramidal features are seen on occasion. Peripheral neuropathy and dystonia are rare. Six families have been reported to date, one each from the UK, Pakistan, France, Germany, Denmark, and China. Age of onset ranged from early childhood to the mid-40s. Life span is thought to be normal. The diagnosis of spinocerebellar ataxia type 11 (SCA11) is established in a proband with a heterozygous pathogenic variant in SCA11 is inherited in an autosomal dominant manner. The proportion of SCA11 caused by
|
## Diagnosis
Spinocerebellar ataxia type 11 (SCA11)
Progressive cerebellar ataxia
Abnormal eye signs (jerky pursuit, horizontal and vertical nystagmus)
Dysarthria
Pyramidal features (mild-to-moderate lower-extremity hyperreflexia; in very rare cases, a positive Babinski sign or other pyramidal features)
Swallowing difficulties
Rare findings in SCA11:
Peripheral neuropathy
Dystonia
The diagnosis of spinocerebellar ataxia type 11 (SCA11)
Because the phenotype of SCA11 is indistinguishable from many other inherited disorders with ataxia, recommended molecular genetic testing approaches include use of a
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 Spinocerebellar Ataxia Type 11
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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Progressive cerebellar ataxia
• Abnormal eye signs (jerky pursuit, horizontal and vertical nystagmus)
• Dysarthria
• Pyramidal features (mild-to-moderate lower-extremity hyperreflexia; in very rare cases, a positive Babinski sign or other pyramidal features)
• Swallowing difficulties
• Peripheral neuropathy
• Dystonia
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Spinocerebellar ataxia type 11 (SCA11)
Progressive cerebellar ataxia
Abnormal eye signs (jerky pursuit, horizontal and vertical nystagmus)
Dysarthria
Pyramidal features (mild-to-moderate lower-extremity hyperreflexia; in very rare cases, a positive Babinski sign or other pyramidal features)
Swallowing difficulties
Rare findings in SCA11:
Peripheral neuropathy
Dystonia
• Progressive cerebellar ataxia
• Abnormal eye signs (jerky pursuit, horizontal and vertical nystagmus)
• Dysarthria
• Pyramidal features (mild-to-moderate lower-extremity hyperreflexia; in very rare cases, a positive Babinski sign or other pyramidal features)
• Swallowing difficulties
• Peripheral neuropathy
• Dystonia
## Establishing the Diagnosis
The diagnosis of spinocerebellar ataxia type 11 (SCA11)
Because the phenotype of SCA11 is indistinguishable from many other inherited disorders with ataxia, recommended molecular genetic testing approaches include use of a
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 Spinocerebellar Ataxia Type 11
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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
To date, 28 individuals from six families have been identified with a pathogenic variant in
Clinical Features of Spinocerebellar Ataxia Type 11
Most prominent in the British family
Lower > upper limbs
Laterocollis
"No-no" head tremor
No other pyramidal signs apart from hyperreflexia were observed in the 28 individuals apart from one individual with upgoing plantar reflexes. This individual from Devon presented with both extrapyramidal and pyramidal signs including spastic gait, hyperreflexia with upgoing plantar reflexes, "no-no" head tremor, and upper-limb tremor with laterocollis [
No genotype-phenotype correlations have been identified.
The
Prevalence is unknown but SCA11 is a rare cause of pure spinocerebellar ataxia. It accounts for less than 1% of autosomal dominant ataxia in Europe [
The six families described with SCA11 are from Devon (UK), Pakistan, France, Germany, Denmark, and China.
• Most prominent in the British family
• Lower > upper limbs
• Laterocollis
• "No-no" head tremor
## Clinical Description
To date, 28 individuals from six families have been identified with a pathogenic variant in
Clinical Features of Spinocerebellar Ataxia Type 11
Most prominent in the British family
Lower > upper limbs
Laterocollis
"No-no" head tremor
No other pyramidal signs apart from hyperreflexia were observed in the 28 individuals apart from one individual with upgoing plantar reflexes. This individual from Devon presented with both extrapyramidal and pyramidal signs including spastic gait, hyperreflexia with upgoing plantar reflexes, "no-no" head tremor, and upper-limb tremor with laterocollis [
• Most prominent in the British family
• Lower > upper limbs
• Laterocollis
• "No-no" head tremor
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
The
## Prevalence
Prevalence is unknown but SCA11 is a rare cause of pure spinocerebellar ataxia. It accounts for less than 1% of autosomal dominant ataxia in Europe [
The six families described with SCA11 are from Devon (UK), Pakistan, France, Germany, Denmark, and China.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
According to AE Harding's classification, spinocerebellar ataxia type 11 (SCA11) is included in the pure autosomal dominant cerebellar ataxias (ADCA III) [
Significant overlap is observed between SCA11 and SCA5,
Hereditary Ataxia Disorders of Interest in the Differential Diagnosis of Spinocerebellar Ataxia Type 11
AD = autosomal dominant; MOI = mode of inheritance; SCA = spinocerebellar ataxia
The locus for SCA20 lies within the pericentromeric region of chromosome 11; the gene is unknown. A 260-kb duplication of 11q12.2-11q12.3 has been proposed as the probable cause of SCA20 in the index family.
See the
## Management
Management is supportive; a multidisciplinary approach is recommended.
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 11 (SCA11), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 11
OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
Management is supportive; no disease-modifying treatments are known to date.
Treatment of Manifestations in Individuals with SCA11
PT eval/treatment
OT eval/treatment
OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with SCA11
OT = occupational therapy; PT = physical therapy
See
Search
• PT eval/treatment
• OT eval/treatment
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 11 (SCA11), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 11
OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia
## Treatment of Manifestations
Management is supportive; no disease-modifying treatments are known to date.
Treatment of Manifestations in Individuals with SCA11
PT eval/treatment
OT eval/treatment
OT = occupational therapy; PT = physical therapy
• PT eval/treatment
• OT eval/treatment
## Surveillance
Recommended Surveillance for Individuals with SCA11
OT = occupational therapy; PT = physical therapy
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Spinocerebellar ataxia type 11 (SCA11) is inherited in an autosomal dominant manner.
Twenty-seven of 28 of individuals diagnosed with SCA11 have an affected parent.
A proband with SCA11 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 SCA11 may appear to be negative because of failure to recognize the disorder in family members with a milder phenotypic presentation, 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 appropriate molecular genetic testing has been performed on the parents of the proband.
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%. Age of onset may vary within a family.
If the proband has a known SCA11-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 theoretic possibility of parental germline mosaicism [
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 SCA11, 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.
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.
• Twenty-seven of 28 of individuals diagnosed with SCA11 have an affected parent.
• A proband with SCA11 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 SCA11 may appear to be negative because of failure to recognize the disorder in family members with a milder phenotypic presentation, 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 appropriate molecular genetic testing has been performed on the parents of the proband.
• 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%. Age of onset may vary within a family.
• If the proband has a known SCA11-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 theoretic possibility of parental germline mosaicism [
• 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
Spinocerebellar ataxia type 11 (SCA11) is inherited in an autosomal dominant manner.
## Risk to Family Members
Twenty-seven of 28 of individuals diagnosed with SCA11 have an affected parent.
A proband with SCA11 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 SCA11 may appear to be negative because of failure to recognize the disorder in family members with a milder phenotypic presentation, 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 appropriate molecular genetic testing has been performed on the parents of the proband.
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%. Age of onset may vary within a family.
If the proband has a known SCA11-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 theoretic possibility of parental germline mosaicism [
If the parents have not been tested for the
• Twenty-seven of 28 of individuals diagnosed with SCA11 have an affected parent.
• A proband with SCA11 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 SCA11 may appear to be negative because of failure to recognize the disorder in family members with a milder phenotypic presentation, 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 appropriate molecular genetic testing has been performed on the parents of the proband.
• 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%. Age of onset may vary within a family.
• If the proband has a known SCA11-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 theoretic possibility of parental germline mosaicism [
• 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 SCA11, 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
• 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, 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
Spain
Sanford Research
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• United Kingdom
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• United Kingdom
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• Spain
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• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia Type 11: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 11 (
Non-ciliary functions of TTBK2 within the brain include phosphorylation of synaptic vesicle protein 2A (SV2A), which is important for synaptic vesicle trafficking and regulation of neurotransmitter release [
Loss of TTBK2 function affects normal phosphorylation of tau, which leads to tau deposition and impaired ciliogenesis. There is evidence that TTBK2 may interact with the inositol/IP3 pathway and stabilize cells (in particular, Purkinje cells) against calcium-induced cell death [
Further supporting the dominant-negative effect is the presence of other reported heterozygous frameshift variants clustered in exon 11, leading to truncation of the TTBK2 protein C-terminal to the kinase domain at amino acid 450 [
No gene-dosage alterations have been detected in
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## Molecular Pathogenesis
Non-ciliary functions of TTBK2 within the brain include phosphorylation of synaptic vesicle protein 2A (SV2A), which is important for synaptic vesicle trafficking and regulation of neurotransmitter release [
Loss of TTBK2 function affects normal phosphorylation of tau, which leads to tau deposition and impaired ciliogenesis. There is evidence that TTBK2 may interact with the inositol/IP3 pathway and stabilize cells (in particular, Purkinje cells) against calcium-induced cell death [
Further supporting the dominant-negative effect is the presence of other reported heterozygous frameshift variants clustered in exon 11, leading to truncation of the TTBK2 protein C-terminal to the kinase domain at amino acid 450 [
No gene-dosage alterations have been detected in
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
## References
## Literature Cited
## Chapter Notes
We are grateful to the Medical Research Council (MRC) for their support: HH holds an MRC clinician scientist fellowship. This work was also supported by the NIHR UCL/UCLH biomedical research centre (BRC). ZC was supported by a fellowship from the Leonard Wolfson Foundation. We thank the families involved and the organization Ataxia UK for their continued support and assistance with our work.
31 October 2019 (sw) Comprehensive update posted live
7 March 2013 (me) Comprehensive update posted live
22 July 2008 (me) Review posted live
9 June 2008 (hh) Original submission
• 31 October 2019 (sw) Comprehensive update posted live
• 7 March 2013 (me) Comprehensive update posted live
• 22 July 2008 (me) Review posted live
• 9 June 2008 (hh) Original submission
## Acknowledgments
We are grateful to the Medical Research Council (MRC) for their support: HH holds an MRC clinician scientist fellowship. This work was also supported by the NIHR UCL/UCLH biomedical research centre (BRC). ZC was supported by a fellowship from the Leonard Wolfson Foundation. We thank the families involved and the organization Ataxia UK for their continued support and assistance with our work.
## Revision History
31 October 2019 (sw) Comprehensive update posted live
7 March 2013 (me) Comprehensive update posted live
22 July 2008 (me) Review posted live
9 June 2008 (hh) Original submission
• 31 October 2019 (sw) Comprehensive update posted live
• 7 March 2013 (me) Comprehensive update posted live
• 22 July 2008 (me) Review posted live
• 9 June 2008 (hh) Original submission
|
[
"I Alesutan, M Sopjani, M Dërmaku-Sopjani, C Munoz, J Voelkl, F Lang. Upregulation of Na-coupled glucose transporter SGLT1 by Tau tubulin kinase 2.. Cell Physiol Biochem. 2012;30:458-65",
"P Bauer, G Stevanin, C Beetz, M Synofzik, T Schmitz-Hübsch, U Wüllner, E Berthier, E Ollagnon-Roman, O Riess, S Forlani, E Mundwiller, A Durr, L Schöls, A. Brice. Spinocerebellar ataxia type 11 (SCA11) is an uncommon cause of dominant ataxia among French and German kindreds.. J Neurol Neurosurg Psychiatry. 2010;81:1229-32",
"E Bowie, R Norris, KV Anderson, SC Goetz. Spinocerebellar ataxia type 11-associated alleles of Ttbk2 dominantly interfere with ciliogenesis and cilium stability.. PLoS Genet 2018;14",
"Y Deng, J Fu, Y Zhong, M Zhang, X Qi. First finding of familial spinal cerebellar ataxia 11 in China: clinical, imaging and genetic features.. Neurol Sci. 2020;41:155-60",
"U Edener, I Kurth, A Meiner, F Hoffmann, CA Hübner, V Bernard, G Gillessen-Kaesbach, C Zühlke. Missense exchanges in the TTBK2 gene mutated in SCA11.. J Neurol 2009;256:1856-9",
"SC Goetz, KF Liem, KV Anderson. The spinocerebellar ataxia-associated gene Tau tubulin kinase 2 controls the initiation of ciliogenesis.. Cell. 2012;151:847-58",
"H Houlden, J Johnson, C Gardner-Thorpe, T Lashley, D Hernandez, P Worth, AB Singleton, DA Hilton, J Holton, T Revesz, MB Davis, P Giunti, NW Wood. Mutations in TTBK2, encoding a kinase implicated in tau phosphorylation, segregate with spinocerebellar ataxia type 11.. Nat Genet 2007;39:1434-6",
"SG Lindquist, LB Møller, CI Dali, L Marner, E-J Kamsteeg, JE Nielsen, LE Hjermind. A novel TTBK2 de novo mutation in a Danish family with early-onset spinocerebellar ataxia.. Cerebellum 2017;16:268-71",
"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",
"LM Taylor, PJ McMillan, NF Liachko, TJ Strovas, B Ghetti, TD Bird, CD Keene, BC Kraemer. Pathological phosphorylation of tau and TDP-43 by TTBK1 and TTBK2 drives neurodegeneration.. Mol Neurodegener 2018;13:7",
"PF Worth, P Giunti, C Gardner-Thorpe, PH Dixon, MB Davis, NW Wood. Autosomal dominant cerebellar ataxia type III: linkage in a large British family to a 7.6-cM region on chromosome 15q14-21.3.. Am J Hum Genet 1999;65:420-6",
"Q Xu, X Li, J Wang, J Yi, L Lei, L Shen, H Jiang, K Xia, Q Pan, B Tang. Spinocerebellar ataxia type 11 in the Chinese Han population.. Neurol Sci. 2010;31:107-9",
"N Zhang, SL Gordon, MJ Fritsch, N Esoof, DG Campbell, R Gourlay, S Velupillai, T Macartney, M Peggie, DM van Aalten, MA Cousin, DR Alessi. Phosphorylation of synaptic vesicle protein 2A at Thr84 by casein kinase 1 family kinases controls the specific retrieval of synaptotagmin-1.. J Neurosci. 2015;35:2492-507"
] |
22/7/2008
|
31/10/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sca12
|
sca12
|
[
"SCA12",
"SCA12",
"SCA 12",
"Serine/threonine-protein phosphatase 2A 55 kDa regulatory subunit B beta isoform",
"PPP2R2B",
"Spinocerebellar Ataxia Type 12"
] |
Spinocerebellar Ataxia Type 12 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Russell L Margolis, Susan E Holmes, Achal K Srivastava, Mitali Mukherji, KK Sinha
|
Summary Spinocerebellar ataxia type 12 (SCA12) is characterized by onset of action tremor of the upper extremities in the fourth decade, slowly progressing to include ataxia and other cerebellar and cortical signs. Given the small number of individuals known to have SCA12, it is possible that other clinical manifestations have not yet been recognized. SCA12 is inherited in an autosomal dominant manner.
|
## Diagnosis
Clinical information on spinocerebellar ataxia type 12 (SCA12) derives from studies of the index pedigree, an American family of German descent [
The diagnosis of SCA12 should be considered in the following:
Individuals of Indian descent who:
Develop an action tremor of the upper extremities in mid-life;
Note: The action tremor of the arms and/or head in individuals with SCA12 may initially resemble essential tremor.
Later develop a wide range of findings, including mild cerebellar dysfunction, hyperreflexia, and parkinsonian features.
Individuals who are not Indian but have a similar clinical presentation that may also include:
A mild gait abnormality and more prominent parkinsonian features;
Psychiatric disorders and dementia in some of the oldest individuals.
Basal ganglia, thalamus, brain stem nuclei, and other subcortical brain regions are relatively spared.
The only known pathogenic
An allele with four CAG triplets, detected in an individual of German descent with ataxia and probably unrelated to SCA12, represents the smallest normal allele observed [
The largest normal allele has 32 CAG repeats; however, the range seems to become wider as more individuals are tested.
The most common repeat length in all samples studied to date is ten triplets [
Two Northern Germans with ataxia had CAG repeats of 40 and 41 triplets; it is unclear if their ataxia was related to the expansions [
A 28-year-old unaffected individual from India with no known family history of degenerative neurologic disorder had a CAG repeat of 45 triplets, a finding of uncertain significance [
An individual with typical Creutzfeld-Jacob disease (CJD) had an allele of 49 triplets at the SCA12 locus; the relationship between the CJD and the expansion is unknown [
A 46-year-old woman with SCA12 from Changsha in the Hunan region of China was reported to have 51 repeats. Disease onset was at age 34 years with mild progressive upper- and lower-limb ataxia, dysarthria, and dysphagia. MRI showed mild cerebellar cortical atrophy with little change over 12 years. International Cooperative Ataxia Rating Scale (ICARS) score was 6 at 12 years after symptom onset. An asymptomatic younger brother and an asymptomatic daughter had alleles of 52 repeats.
In an Italian kindred with SCA12, a sister of the proband who had 57 repeats was unaffected at age 70 years.
A 52-year-old woman from India with an allele of 62 CAG triplets did not show symptoms.
Summary of Molecular Genetic Testing Used in the Diagnosis of Spinocerebellar Ataxia Type 12
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Targeted analysis for pathogenic variants in
• Individuals of Indian descent who:
• Develop an action tremor of the upper extremities in mid-life;
• Note: The action tremor of the arms and/or head in individuals with SCA12 may initially resemble essential tremor.
• Later develop a wide range of findings, including mild cerebellar dysfunction, hyperreflexia, and parkinsonian features.
• Develop an action tremor of the upper extremities in mid-life;
• Note: The action tremor of the arms and/or head in individuals with SCA12 may initially resemble essential tremor.
• Later develop a wide range of findings, including mild cerebellar dysfunction, hyperreflexia, and parkinsonian features.
• Individuals who are not Indian but have a similar clinical presentation that may also include:
• A mild gait abnormality and more prominent parkinsonian features;
• Psychiatric disorders and dementia in some of the oldest individuals.
• A mild gait abnormality and more prominent parkinsonian features;
• Psychiatric disorders and dementia in some of the oldest individuals.
• Develop an action tremor of the upper extremities in mid-life;
• Note: The action tremor of the arms and/or head in individuals with SCA12 may initially resemble essential tremor.
• Later develop a wide range of findings, including mild cerebellar dysfunction, hyperreflexia, and parkinsonian features.
• A mild gait abnormality and more prominent parkinsonian features;
• Psychiatric disorders and dementia in some of the oldest individuals.
• An allele with four CAG triplets, detected in an individual of German descent with ataxia and probably unrelated to SCA12, represents the smallest normal allele observed [
• The largest normal allele has 32 CAG repeats; however, the range seems to become wider as more individuals are tested.
• The most common repeat length in all samples studied to date is ten triplets [
• Two Northern Germans with ataxia had CAG repeats of 40 and 41 triplets; it is unclear if their ataxia was related to the expansions [
• A 28-year-old unaffected individual from India with no known family history of degenerative neurologic disorder had a CAG repeat of 45 triplets, a finding of uncertain significance [
• An individual with typical Creutzfeld-Jacob disease (CJD) had an allele of 49 triplets at the SCA12 locus; the relationship between the CJD and the expansion is unknown [
• A 46-year-old woman with SCA12 from Changsha in the Hunan region of China was reported to have 51 repeats. Disease onset was at age 34 years with mild progressive upper- and lower-limb ataxia, dysarthria, and dysphagia. MRI showed mild cerebellar cortical atrophy with little change over 12 years. International Cooperative Ataxia Rating Scale (ICARS) score was 6 at 12 years after symptom onset. An asymptomatic younger brother and an asymptomatic daughter had alleles of 52 repeats.
• In an Italian kindred with SCA12, a sister of the proband who had 57 repeats was unaffected at age 70 years.
• A 52-year-old woman from India with an allele of 62 CAG triplets did not show symptoms.
## Clinical Diagnosis
Clinical information on spinocerebellar ataxia type 12 (SCA12) derives from studies of the index pedigree, an American family of German descent [
The diagnosis of SCA12 should be considered in the following:
Individuals of Indian descent who:
Develop an action tremor of the upper extremities in mid-life;
Note: The action tremor of the arms and/or head in individuals with SCA12 may initially resemble essential tremor.
Later develop a wide range of findings, including mild cerebellar dysfunction, hyperreflexia, and parkinsonian features.
Individuals who are not Indian but have a similar clinical presentation that may also include:
A mild gait abnormality and more prominent parkinsonian features;
Psychiatric disorders and dementia in some of the oldest individuals.
Basal ganglia, thalamus, brain stem nuclei, and other subcortical brain regions are relatively spared.
• Individuals of Indian descent who:
• Develop an action tremor of the upper extremities in mid-life;
• Note: The action tremor of the arms and/or head in individuals with SCA12 may initially resemble essential tremor.
• Later develop a wide range of findings, including mild cerebellar dysfunction, hyperreflexia, and parkinsonian features.
• Develop an action tremor of the upper extremities in mid-life;
• Note: The action tremor of the arms and/or head in individuals with SCA12 may initially resemble essential tremor.
• Later develop a wide range of findings, including mild cerebellar dysfunction, hyperreflexia, and parkinsonian features.
• Individuals who are not Indian but have a similar clinical presentation that may also include:
• A mild gait abnormality and more prominent parkinsonian features;
• Psychiatric disorders and dementia in some of the oldest individuals.
• A mild gait abnormality and more prominent parkinsonian features;
• Psychiatric disorders and dementia in some of the oldest individuals.
• Develop an action tremor of the upper extremities in mid-life;
• Note: The action tremor of the arms and/or head in individuals with SCA12 may initially resemble essential tremor.
• Later develop a wide range of findings, including mild cerebellar dysfunction, hyperreflexia, and parkinsonian features.
• A mild gait abnormality and more prominent parkinsonian features;
• Psychiatric disorders and dementia in some of the oldest individuals.
## Molecular Genetic Testing
The only known pathogenic
An allele with four CAG triplets, detected in an individual of German descent with ataxia and probably unrelated to SCA12, represents the smallest normal allele observed [
The largest normal allele has 32 CAG repeats; however, the range seems to become wider as more individuals are tested.
The most common repeat length in all samples studied to date is ten triplets [
Two Northern Germans with ataxia had CAG repeats of 40 and 41 triplets; it is unclear if their ataxia was related to the expansions [
A 28-year-old unaffected individual from India with no known family history of degenerative neurologic disorder had a CAG repeat of 45 triplets, a finding of uncertain significance [
An individual with typical Creutzfeld-Jacob disease (CJD) had an allele of 49 triplets at the SCA12 locus; the relationship between the CJD and the expansion is unknown [
A 46-year-old woman with SCA12 from Changsha in the Hunan region of China was reported to have 51 repeats. Disease onset was at age 34 years with mild progressive upper- and lower-limb ataxia, dysarthria, and dysphagia. MRI showed mild cerebellar cortical atrophy with little change over 12 years. International Cooperative Ataxia Rating Scale (ICARS) score was 6 at 12 years after symptom onset. An asymptomatic younger brother and an asymptomatic daughter had alleles of 52 repeats.
In an Italian kindred with SCA12, a sister of the proband who had 57 repeats was unaffected at age 70 years.
A 52-year-old woman from India with an allele of 62 CAG triplets did not show symptoms.
Summary of Molecular Genetic Testing Used in the Diagnosis of Spinocerebellar Ataxia Type 12
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Targeted analysis for pathogenic variants in
• An allele with four CAG triplets, detected in an individual of German descent with ataxia and probably unrelated to SCA12, represents the smallest normal allele observed [
• The largest normal allele has 32 CAG repeats; however, the range seems to become wider as more individuals are tested.
• The most common repeat length in all samples studied to date is ten triplets [
• Two Northern Germans with ataxia had CAG repeats of 40 and 41 triplets; it is unclear if their ataxia was related to the expansions [
• A 28-year-old unaffected individual from India with no known family history of degenerative neurologic disorder had a CAG repeat of 45 triplets, a finding of uncertain significance [
• An individual with typical Creutzfeld-Jacob disease (CJD) had an allele of 49 triplets at the SCA12 locus; the relationship between the CJD and the expansion is unknown [
• A 46-year-old woman with SCA12 from Changsha in the Hunan region of China was reported to have 51 repeats. Disease onset was at age 34 years with mild progressive upper- and lower-limb ataxia, dysarthria, and dysphagia. MRI showed mild cerebellar cortical atrophy with little change over 12 years. International Cooperative Ataxia Rating Scale (ICARS) score was 6 at 12 years after symptom onset. An asymptomatic younger brother and an asymptomatic daughter had alleles of 52 repeats.
• In an Italian kindred with SCA12, a sister of the proband who had 57 repeats was unaffected at age 70 years.
• A 52-year-old woman from India with an allele of 62 CAG triplets did not show symptoms.
## Allele Sizes
An allele with four CAG triplets, detected in an individual of German descent with ataxia and probably unrelated to SCA12, represents the smallest normal allele observed [
The largest normal allele has 32 CAG repeats; however, the range seems to become wider as more individuals are tested.
The most common repeat length in all samples studied to date is ten triplets [
Two Northern Germans with ataxia had CAG repeats of 40 and 41 triplets; it is unclear if their ataxia was related to the expansions [
A 28-year-old unaffected individual from India with no known family history of degenerative neurologic disorder had a CAG repeat of 45 triplets, a finding of uncertain significance [
An individual with typical Creutzfeld-Jacob disease (CJD) had an allele of 49 triplets at the SCA12 locus; the relationship between the CJD and the expansion is unknown [
A 46-year-old woman with SCA12 from Changsha in the Hunan region of China was reported to have 51 repeats. Disease onset was at age 34 years with mild progressive upper- and lower-limb ataxia, dysarthria, and dysphagia. MRI showed mild cerebellar cortical atrophy with little change over 12 years. International Cooperative Ataxia Rating Scale (ICARS) score was 6 at 12 years after symptom onset. An asymptomatic younger brother and an asymptomatic daughter had alleles of 52 repeats.
In an Italian kindred with SCA12, a sister of the proband who had 57 repeats was unaffected at age 70 years.
A 52-year-old woman from India with an allele of 62 CAG triplets did not show symptoms.
• An allele with four CAG triplets, detected in an individual of German descent with ataxia and probably unrelated to SCA12, represents the smallest normal allele observed [
• The largest normal allele has 32 CAG repeats; however, the range seems to become wider as more individuals are tested.
• The most common repeat length in all samples studied to date is ten triplets [
• Two Northern Germans with ataxia had CAG repeats of 40 and 41 triplets; it is unclear if their ataxia was related to the expansions [
• A 28-year-old unaffected individual from India with no known family history of degenerative neurologic disorder had a CAG repeat of 45 triplets, a finding of uncertain significance [
• An individual with typical Creutzfeld-Jacob disease (CJD) had an allele of 49 triplets at the SCA12 locus; the relationship between the CJD and the expansion is unknown [
• A 46-year-old woman with SCA12 from Changsha in the Hunan region of China was reported to have 51 repeats. Disease onset was at age 34 years with mild progressive upper- and lower-limb ataxia, dysarthria, and dysphagia. MRI showed mild cerebellar cortical atrophy with little change over 12 years. International Cooperative Ataxia Rating Scale (ICARS) score was 6 at 12 years after symptom onset. An asymptomatic younger brother and an asymptomatic daughter had alleles of 52 repeats.
• In an Italian kindred with SCA12, a sister of the proband who had 57 repeats was unaffected at age 70 years.
• A 52-year-old woman from India with an allele of 62 CAG triplets did not show symptoms.
## Clinical Testing
Summary of Molecular Genetic Testing Used in the Diagnosis of Spinocerebellar Ataxia Type 12
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
Targeted analysis for pathogenic variants in
## Testing Strategy
## Clinical Characteristics
Spinocerebellar ataxia type 12 (SCA12) typically presents with action tremor of the arms or head followed by development of mild ataxia and/or limb dysmetria, along with generalized hyperreflexia; however, intrafamilial variability can be considerable.
Onset ranges from age eight to 62 years, but is typically in midlife. The mean age of onset in the index SCA12 kindred [
The action tremor is most prominent in the limbs, but can occur in the trunk, neck, lips, and tongue [
Signs of cerebellar dysfunction (e.g., ataxia, dysmetria) tend to be less prominent and less disabling in individuals with SCA12 than in other types of SCA.
Some members of the American pedigree developed bradykinesia or dementia. Eight of the ten affected individuals of the American pedigree have the combination of action tremor of the head or arms, hyperreflexia, mild cerebellar dysfunction, subtle bradykinesia, and paucity of spontaneous movement.
In contrast, individuals of Indian descent tend to have fewer parkinsonian features; some have pyramidal signs and cognitive impairment. Some Indian families have prominent cerebellar findings. As many as 50% of affected individuals of Indian descent have a sensory or sensory motor neuropathy.
SCA12 progresses slowly and may not have a major impact on longevity. Several affected individuals in the American kindred with SCA12 remained employed throughout adulthood.
Three affected members of two Italian families, each with an expanded repeat of 57 triplets, had onset between age 45 and 60 years with action tremor of head and hands, impaired fine motor movements, or gait instability. Progression was also slow.
Preliminary findings in the brain of one individual with SCA12 suggest atrophy of the cerebral cortex and loss of cerebellar Purkinje cells, without evidence of tangles, senile plaques, Lewy bodies, or Pick bodies [O'Hearn, unpublished data].
With evaluation of increasing numbers of affected individuals from India, a correlation between longer repeat length and younger age of onset has been detected [Srivastava & Mukherji, unpublished data].
The penetrance is unknown, but as noted some individuals with an expansion may have a very late onset, or potentially may never develop the disease. However, relatively few at-risk individuals without clinical evidence of SCA12 have been tested.
A moderate degree of anticipation has been observed in SCA12.
The presence of SCA12 in more than 35 families from India appears to make SCA12 the second most common form of SCA in India, less prevalent than SCA2 and equal to or slightly more prevalent than SCA1 [
SCA12 has been detected primarily in a single ethnic group from northern India [
SCA12 has been detected in a single family in North America [
Two of 159 unrelated Italian patients with cerebellar ataxia were found to have SCA12, both from the Ferrara Province of northeastern Italy [
No cases of SCA12 were detected among 1598 individuals with ataxia in Poland [
No cases of SCA12 were detected among 45 autosomal dominant ataxia families in Portugal [
Among persons who presented with ataxia of unknown etiology, one individual in Singapore [
## Clinical Description
Spinocerebellar ataxia type 12 (SCA12) typically presents with action tremor of the arms or head followed by development of mild ataxia and/or limb dysmetria, along with generalized hyperreflexia; however, intrafamilial variability can be considerable.
Onset ranges from age eight to 62 years, but is typically in midlife. The mean age of onset in the index SCA12 kindred [
The action tremor is most prominent in the limbs, but can occur in the trunk, neck, lips, and tongue [
Signs of cerebellar dysfunction (e.g., ataxia, dysmetria) tend to be less prominent and less disabling in individuals with SCA12 than in other types of SCA.
Some members of the American pedigree developed bradykinesia or dementia. Eight of the ten affected individuals of the American pedigree have the combination of action tremor of the head or arms, hyperreflexia, mild cerebellar dysfunction, subtle bradykinesia, and paucity of spontaneous movement.
In contrast, individuals of Indian descent tend to have fewer parkinsonian features; some have pyramidal signs and cognitive impairment. Some Indian families have prominent cerebellar findings. As many as 50% of affected individuals of Indian descent have a sensory or sensory motor neuropathy.
SCA12 progresses slowly and may not have a major impact on longevity. Several affected individuals in the American kindred with SCA12 remained employed throughout adulthood.
Three affected members of two Italian families, each with an expanded repeat of 57 triplets, had onset between age 45 and 60 years with action tremor of head and hands, impaired fine motor movements, or gait instability. Progression was also slow.
## Neuropathology
Preliminary findings in the brain of one individual with SCA12 suggest atrophy of the cerebral cortex and loss of cerebellar Purkinje cells, without evidence of tangles, senile plaques, Lewy bodies, or Pick bodies [O'Hearn, unpublished data].
## Genotype-Phenotype Correlations
With evaluation of increasing numbers of affected individuals from India, a correlation between longer repeat length and younger age of onset has been detected [Srivastava & Mukherji, unpublished data].
## Penetrance
The penetrance is unknown, but as noted some individuals with an expansion may have a very late onset, or potentially may never develop the disease. However, relatively few at-risk individuals without clinical evidence of SCA12 have been tested.
## Anticipation
A moderate degree of anticipation has been observed in SCA12.
## Prevalence
The presence of SCA12 in more than 35 families from India appears to make SCA12 the second most common form of SCA in India, less prevalent than SCA2 and equal to or slightly more prevalent than SCA1 [
SCA12 has been detected primarily in a single ethnic group from northern India [
SCA12 has been detected in a single family in North America [
Two of 159 unrelated Italian patients with cerebellar ataxia were found to have SCA12, both from the Ferrara Province of northeastern Italy [
No cases of SCA12 were detected among 1598 individuals with ataxia in Poland [
No cases of SCA12 were detected among 45 autosomal dominant ataxia families in Portugal [
Among persons who presented with ataxia of unknown etiology, one individual in Singapore [
## Genetically Related (Allelic) Disorders
Pathogenic variants in
Aside from this Iranian pedigree (see
## Differential Diagnosis
The key to the differential diagnosis of spinocerebellar ataxia type 12 (SCA12) is the presence of prominent upper-extremity tremor; minimal gait ataxia; a variety of signs and symptoms associated with the cerebral cortex, the cerebellum, and in some cases the basal ganglia; slow progression; and a dominant pattern of inheritance. SCA12 typically has a more prominent action tremor and fewer signs of cerebellar dysfunction than other SCAs.
Diagnoses to consider in the differential diagnosis:
A small Japanese family with a somewhat different phenotype and without the SCA12 repeat expansion has been mapped to a region of chromosome 5q that includes
• A small Japanese family with a somewhat different phenotype and without the SCA12 repeat expansion has been mapped to a region of chromosome 5q that includes
## Management
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 12, the following evaluations are recommended:
Medical history
Tremor rating and gait ataxia assessment
Evaluation for peripheral neuropathy and autonomic dysfunction
Radiologic investigation to evaluate for associated brain structural damage which can influence the disease course
Symptomatic treatment including the following may be of great value:
Pharmacologic agents, including beta-blockers, clonazepam and phenobarbital derivatives, and benzodiazepines to decrease tremor amplitude. Modest success has been observed in some affected individuals.
Supplements of antioxidants, which may have some beneficial effects. However, their effect on disease outcome has not been validated through clinical trials.
Treatment of psychiatric syndromes as needed
Physical therapy to help maintain strength, flexibility, and independent mobility
Technical assistance with writing and other fine-motor tasks
A safe home environment can minimize the risk of injury from falls.
Annual reevaluation may be helpful for disability assessment and identification of comorbidities.
See
Search
Recommended:
Education of affected individuals and their families
Neuroimaging studies as appropriate to exclude the presence of other lesions, particularly after falls
• Medical history
• Tremor rating and gait ataxia assessment
• Evaluation for peripheral neuropathy and autonomic dysfunction
• Radiologic investigation to evaluate for associated brain structural damage which can influence the disease course
• Pharmacologic agents, including beta-blockers, clonazepam and phenobarbital derivatives, and benzodiazepines to decrease tremor amplitude. Modest success has been observed in some affected individuals.
• Supplements of antioxidants, which may have some beneficial effects. However, their effect on disease outcome has not been validated through clinical trials.
• Treatment of psychiatric syndromes as needed
• Physical therapy to help maintain strength, flexibility, and independent mobility
• Technical assistance with writing and other fine-motor tasks
• Education of affected individuals and their families
• Neuroimaging studies as appropriate to exclude the presence of other lesions, particularly after falls
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 12, the following evaluations are recommended:
Medical history
Tremor rating and gait ataxia assessment
Evaluation for peripheral neuropathy and autonomic dysfunction
Radiologic investigation to evaluate for associated brain structural damage which can influence the disease course
• Medical history
• Tremor rating and gait ataxia assessment
• Evaluation for peripheral neuropathy and autonomic dysfunction
• Radiologic investigation to evaluate for associated brain structural damage which can influence the disease course
## Treatment of Manifestations
Symptomatic treatment including the following may be of great value:
Pharmacologic agents, including beta-blockers, clonazepam and phenobarbital derivatives, and benzodiazepines to decrease tremor amplitude. Modest success has been observed in some affected individuals.
Supplements of antioxidants, which may have some beneficial effects. However, their effect on disease outcome has not been validated through clinical trials.
Treatment of psychiatric syndromes as needed
Physical therapy to help maintain strength, flexibility, and independent mobility
Technical assistance with writing and other fine-motor tasks
• Pharmacologic agents, including beta-blockers, clonazepam and phenobarbital derivatives, and benzodiazepines to decrease tremor amplitude. Modest success has been observed in some affected individuals.
• Supplements of antioxidants, which may have some beneficial effects. However, their effect on disease outcome has not been validated through clinical trials.
• Treatment of psychiatric syndromes as needed
• Physical therapy to help maintain strength, flexibility, and independent mobility
• Technical assistance with writing and other fine-motor tasks
## Prevention of Secondary Complications
A safe home environment can minimize the risk of injury from falls.
## Surveillance
Annual reevaluation may be helpful for disability assessment and identification of comorbidities.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Other
Recommended:
Education of affected individuals and their families
Neuroimaging studies as appropriate to exclude the presence of other lesions, particularly after falls
• Education of affected individuals and their families
• Neuroimaging studies as appropriate to exclude the presence of other lesions, particularly after falls
## Genetic Counseling
Spinocerebellar ataxia type 12 (SCA12) is inherited in an autosomal dominant manner.
Most individuals diagnosed with SCA12 have an affected parent.
It is appropriate to offer molecular genetic testing to a symptomatic parent.
Note: Although most individuals diagnosed with SCA12 have an affected parent, the family history 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 late onset of the disease in the affected parent.
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 affected or has the
Although it is conceivable that an expanded allele at or near the disease threshold in a parent could expand to a fully penetrant allele in transmission to one sib but remain unexpanded in another sib, such a situation has not yet been reported.
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
Requests for prenatal testing for typically adult-onset conditions that do not affect intellect are not common. While cognitive impairment may be a late manifestation of SCA12, it is less prominent than in many other neurodegenerative disorders. 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 SCA12 have an affected parent.
• It is appropriate to offer molecular genetic testing to a symptomatic parent.
• 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 affected or has the
• Although it is conceivable that an expanded allele at or near the disease threshold in a parent could expand to a fully penetrant allele in transmission to one sib but remain unexpanded in another sib, such a situation has not yet been reported.
• 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
Spinocerebellar ataxia type 12 (SCA12) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with SCA12 have an affected parent.
It is appropriate to offer molecular genetic testing to a symptomatic parent.
Note: Although most individuals diagnosed with SCA12 have an affected parent, the family history 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 late onset of the disease in the affected parent.
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 affected or has the
Although it is conceivable that an expanded allele at or near the disease threshold in a parent could expand to a fully penetrant allele in transmission to one sib but remain unexpanded in another sib, such a situation has not yet been reported.
• Most individuals diagnosed with SCA12 have an affected parent.
• It is appropriate to offer molecular genetic testing to a symptomatic parent.
• 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 affected or has the
• Although it is conceivable that an expanded allele at or near the disease threshold in a parent could expand to a fully penetrant allele in transmission to one sib but remain unexpanded in another sib, such a situation has not yet been reported.
## 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 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
Requests for prenatal testing for typically adult-onset conditions that do not affect intellect are not common. While cognitive impairment may be a late manifestation of SCA12, it is less prominent than in many other neurodegenerative disorders. 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
Lincoln House
1-3 Brixton Road
London SW9 6DE
United Kingdom
Ataxia UK
Lincoln House, Kennington Park, 1-3 Brixton Road
London SW9 6DE
United Kingdom
2600 Fernbrook Lane
Suite 119
Minneapolis MN 55447
Spain
Sanford Research
2301 East 60th Street North
Sioux Falls SD 57104
•
• Lincoln House
• 1-3 Brixton Road
• London SW9 6DE
• United Kingdom
•
•
• Ataxia UK
• Lincoln House, Kennington Park, 1-3 Brixton Road
• London SW9 6DE
• United Kingdom
•
•
• 2600 Fernbrook Lane
• Suite 119
• Minneapolis MN 55447
•
•
•
•
• Spain
•
•
•
•
•
• Sanford Research
• 2301 East 60th Street North
• Sioux Falls SD 57104
•
## Molecular Genetics
Spinocerebellar Ataxia Type 12: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 12 (
The CAG repeat expansion associated with spinocerebellar ataxia type 12 (SCA12) appears to be located within a promoter region of
## Molecular Genetic Pathogenesis
The CAG repeat expansion associated with spinocerebellar ataxia type 12 (SCA12) appears to be located within a promoter region of
## References
## Literature Cited
## Chapter Notes
Susan E Holmes, PhD (2004-present)Russell L Margolis, MD (2004-present)Mitali Mukherji, PhD (2004-present)Elizabeth O'Hearn, MD; Johns Hopkins University (2004-2012)*KK Sinha, MD, FRCP (2004-present)Achal K Srivastava, MBBS, MD, DM (2004-present)
*Dr O’Hearn died November 15, 2012
13 December 2018 (ma) Chapter retired: extremely rare
17 November 2011 (me) Comprehensive update posted live
12 March 2007 (cd) Revision: mutation scanning no longer clinically available
20 February 2007 (me) Comprehensive update posted live
1 October 2004 (me) Review posted live
1 June 2004 (rm) Original submission
• 13 December 2018 (ma) Chapter retired: extremely rare
• 17 November 2011 (me) Comprehensive update posted live
• 12 March 2007 (cd) Revision: mutation scanning no longer clinically available
• 20 February 2007 (me) Comprehensive update posted live
• 1 October 2004 (me) Review posted live
• 1 June 2004 (rm) Original submission
## Author History
Susan E Holmes, PhD (2004-present)Russell L Margolis, MD (2004-present)Mitali Mukherji, PhD (2004-present)Elizabeth O'Hearn, MD; Johns Hopkins University (2004-2012)*KK Sinha, MD, FRCP (2004-present)Achal K Srivastava, MBBS, MD, DM (2004-present)
*Dr O’Hearn died November 15, 2012
## Revision History
13 December 2018 (ma) Chapter retired: extremely rare
17 November 2011 (me) Comprehensive update posted live
12 March 2007 (cd) Revision: mutation scanning no longer clinically available
20 February 2007 (me) Comprehensive update posted live
1 October 2004 (me) Review posted live
1 June 2004 (rm) Original submission
• 13 December 2018 (ma) Chapter retired: extremely rare
• 17 November 2011 (me) Comprehensive update posted live
• 12 March 2007 (cd) Revision: mutation scanning no longer clinically available
• 20 February 2007 (me) Comprehensive update posted live
• 1 October 2004 (me) Review posted live
• 1 June 2004 (rm) Original submission
|
[
"S Bahl, K Virdi, U Mittal, MP Sachdeva, AK Kalla, SE Holmes, E O'Hearn, RL Margolis, S Jain, AK Srivastava, M Mukerji. Evidence of a common founder for SCA12 in the Indian population.. Ann Hum Genet 2005;69:528-34",
"A Brusco, C Gellera, C Cagnoli, A Saluto, A Castucci, C Michielotto, V Fetoni, C Mariotti, N Migone, S Di Donato, F Taroni. Molecular genetics of hereditary spinocerebellar ataxia: mutation analysis of spinocerebellar ataxia genes and CAG/CTG repeat expansion detection in 225 Italian families.. Arch Neurol 2004;61:727-33",
"A Brussino, C Graziano, D Giobbe, M Ferrone, E Dragone, C Arduino, R Lodi, C Tonon, A Gabellini, R Rinaldi, S Miccoli, E Grosso, MC Bellati, L Orsi, N Migone, A Brusco. Spinocerebellar ataxia type 12 identified in two Italian families may mimic sporadic ataxia.. Mov Disord. 2010;25:1269-73",
"JA Cholfin, MJ Sobrido, S Perlman, SM Pulst, DH Geschwind. The SCA12 mutation as a rare cause of spinocerebellar ataxia.. Arch Neurol 2001;58:1833-5",
"RK Dagda, RA Merrill, JT Cribbs, Y Chen, JW Hell, YM Usachev, S Strack. The spinocerebellar ataxia 12 gene product and protein phosphatase 2A regulatory subunit B_2 antagonizes neuronal survival by promoting mitochondrial fission.. J Biol Chem. 2008;283:36241-8",
"RK Dagda, JA Zaucha, BE Wadzinski, S Strack. A developmentally regulated, neuron-specific splice variant of the variable subunit Bbeta targets protein phosphatase 2A to mitochondria and modulates apoptosis.. J Biol Chem 2003;278:24976-85",
"H Fujigasaki, IC Verma, A Camuzat, RL Margolis, C Zander, AS Lebre, L Jamot, R Saxena, I Anand, SE Holmes, CA Ross, A Durr, A Brice. SCA12 is a rare locus for autosomal dominant cerebellar ataxia: a study of an Indian family.. Ann Neurol 2001;49:117-21",
"Y Hellenbroich, W Schulz-Schaeffer, MF Nitschke, J Kohnke, G Handler, K Burk, E Schwinger, C Zuhlke. Coincidence of a large SCA12 repeat allele with a case of Creutzfeld-Jacob disease.. J Neurol Neurosurg Psychiatry 2004;75:937-8",
"SE Holmes, EE O'Hearn, MG McInnis, DA Gorelick-Feldman, JJ Kleiderlein, C Callahan, NG Kwak, RG Ingersoll-Ashworth, M Sherr, AJ Sumner, AH Sharp, U Ananth, WK Seltzer, MA Boss, AM Vieria-Saecker, JT Epplen, O Riess, CA Ross, RL Margolis. Expansion of a novel CAG trinucleotide repeat in the 5' region of PPP2R2B is associated with SCA12.. Nat Genet 1999;23:391-2",
"H Jiang, B Tang, K Xia, Y Zhou, B Xu, G Zhao, H Li, L Shen, Q Pan, F Cai. Spinocerebellar ataxia type 6 in Mainland China: molecular and clinical features in four families.. J Neurol Sci 2005;236:25-9",
"C Laurent, D Niehaus, S Bauche, DF Levinson, S Soubigou, S Pimstone, M Hayden, I Mbanga, R Emsley, JF Deleuze, J Mallet. CAG repeat polymorphisms in KCNN3 (HSKCa3) and PPP2R2B show no association or linkage to schizophrenia.. Am J Med Genet 2003;116B:45-50",
"CH Lin, CM Chen, YT Hou, YR Wu, HM Hsieh-Li, MT Su, GJ Lee-Chen. The CAG repeat in SCA12 functions as a cis element to up-regulate PPP2R2B expression.. Hum Genet. 2010;128:205-12",
"E O'Hearn, SE Holmes, PC Calvert, CA Ross, RL Margolis. SCA-12: Tremor with cerebellar and cortical atrophy is associated with a CAG repeat expansion.. Neurology 2001;56:299-303",
"K Sato, I Yabe, Y Fukuda, H Soma, Y Nakahara, S Tsuji, H Sasaki. Mapping of autosomal dominant cerebellar ataxia without the pathogenic PPP2R2B mutation to the locus for spinocerebellar ataxia 12.. Arch Neurol. 2010;67:1257-62",
"KK Sinha, PF Worth, DK Jha, S Sinha, VJ Stinton, MB Davis, NW Wood, MG Sweeney, KP Bhatia. Autosomal dominant cerebellar ataxia: SCA2 is the most frequent mutation in eastern India.. J Neurol Neurosurg Psychiatry 2004b;75:448-52",
"AK Srivastava, S Choudhry, MS Gopinath, S Roy, M Tripathi, SK Brahmachari, S Jain. Molecular and clinical correlation in five Indian families with spinocerebellar ataxia 12.. Ann Neurol 2001;50:796-800",
"A Sułek-Piatkowska, E Zdzienicka, M Raczyńska-Rakowicz, W Krysa, M Rajkiewicz, W Szirkowiec, J Zaremba. The occurrence of spinocerebellar ataxias caused by dynamic mutations in Polish patients.. Neurol Neurochir Pol. 2010;44:238-45",
"A Sułek, D Hoffman-Zacharska, M Bednarska-Makaruk, W Szirkowiec, J Zaremba. Polymorphism of trinucleotide repeats in non-translated regions of SCA8 and SCA12 genes: allele distribution in a Polish control group.. J Appl Genet 2004;45:101-5",
"HF Tsai, CS Liu, TM Leu, FC Wen, SJ Lin, CC Liu, DK Yang, C Li, M Hsieh. Analysis of trinucleotide repeats in different SCA loci in spinocerebellar ataxia patients and in normal population of Taiwan.. Acta Neurol Scand 2004;109:355-60",
"C Van Hoof, J Goris. Phosphatases in apoptosis: to be or not to be, PP2A is in the heart of the question.. Biochim Biophys Acta 2003;1640:97-104",
"JC van Swieten, E Brusse, BM de Graaf, E Krieger, R van de Graaf, I de Koning, A Maat-Kievit, P Leegwater, D Dooijes, BA Oostra, P Heutink. A mutation in the fibroblast growth factor 14 gene is associated with autosomal dominant cerebellar ataxia. Am J Hum Genet 2003;72:191-9",
"J Vale, P Bugalho, I Silveira, J Sequeiros, J Guimarães, P Coutinho. Autosomal dominant cerebellar ataxia: frequency analysis and clinical characterization of 45 families from Portugal.. Eur J Neurol. 2010;17:124-8",
"J Wang, L Shen, L Lei, Q Xu, J Zhou, Y Liu, W Guan, Q Pan, K Xia, B Tang, H Jiang. Spinocerebellar ataxias in mainland China: an updated genetic analysis among a large cohort of familial and sporadic cases.. Zhong Nan Da Xue Xue Bao Yi Xue Ban. 2011a;36:482-9",
"YC Wang, CM Lee, LC Lee, LC Tung, HM Hsieh-Li, GJ Lee-Chen, MT Su. Mitochondrial dysfunction and oxidative stress contribute to the pathogenesis of spinocerebellar ataxia type 12 (SCA12).. J Biol Chem. 2011b;286:21742-54",
"PF Worth, NW Wood. Spinocerebellar ataxia type 12 is rare in the United Kingdom.. Neurology 2001;56:419-20",
"QY Xie, XL Liang, XH Li. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005;22:71-3",
"Y Zhao, EK Tan, HY Law, CS Yoon, MC Wong, I Ng. Prevalence and ethnic differences of autosomal-dominant cerebellar ataxia in Singapore.. Clin Genet 2002;62:478-81"
] |
1/10/2004
|
17/11/2011
|
12/3/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sca13
|
sca13
|
[
"SCA13",
"SCA13",
"KCNC3 Congenital-Onset Non-Progressive Cerebellar Ataxia",
"KCNC3 Childhood-Onset Progressive Cerebellar Ataxia with Delayed Milestones",
"KCNC3 Adult-Onset Progressive Cerebellar Ataxia",
"Voltage-gated potassium channel KCNC3",
"KCNC3",
"Spinocerebellar Ataxia Type 13"
] |
Spinocerebellar Ataxia Type 13
|
Michael F Waters
|
Summary Spinocerebellar ataxia type 13 (SCA13) is a phenotypic spectrum that includes both non-progressive infantile-onset ataxia and progressive childhood-onset and adult-onset cerebellar ataxia. Three phenotypes are seen: Cerebellar hypoplasia with non-progressive infantile-onset limb, truncal, and gait ataxia with mild-to-moderate intellectual disability and occasionally seizures and/or psychiatric manifestations. Cognition and motor skills improve over time. Childhood-onset slowly progressive cerebellar atrophy with slowly progressive cerebellar ataxia and dysarthria, delayed motor milestones, and mild-to-moderate intellectual disability Adult-onset progressive cerebellar atrophy with progressive ataxia and spasticity The diagnosis of spinocerebellar ataxia type 13 (SCA13) is established in a proband with suggestive clinical and brain imaging findings and a heterozygous SCA13 is inherited in an autosomal dominant manner. In rare instances, an individual diagnosed with SCA13 has the disorder as the result of a
|
Congenital-onset non-progressive cerebellar ataxia
Childhood-onset progressive cerebellar ataxia w/delayed milestones
Adult-onset progressive cerebellar ataxia
For other genetic causes of these phenotypes, see
• Congenital-onset non-progressive cerebellar ataxia
• Childhood-onset progressive cerebellar ataxia w/delayed milestones
• Adult-onset progressive cerebellar ataxia
## Diagnosis
Formal diagnostic criteria for spinocerebellar ataxia type 13 (SCA13) have not been established.
SCA13
Congenital-onset non-progressive severe cerebellar hypoplasia on brain MRI [
Ataxia
Gait and/or appendicular
Dysarthria
Cognitive impairment
Delayed motor milestones
Delayed speech acquisition
Tremor/myoclonus
Seizures
Gradual lifetime improvement in motor and cognitive function
Cognitive impairment
Seizures
Delayed motor milestones
Cerebellar atrophy on brain MRI
Ataxia
Gait and/or appendicular
Truncal ataxia
Titubation
Hypotonia
Dysarthria
Impaired sound localization
On brain MRI:
All affected individuals show age-related progressive mild-to-moderately severe cerebellar atrophy that is primarily midline. This has been evident as early as age three years.
Atrophy of the brain stem and/or cerebral cortex can be observed.
The diagnosis of SCA13
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
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 phenotypes associated with SCA13 are indistinguishable from other congenital-onset and adult-onset ataxias, affected individuals are likely to be diagnosed using a multigene panel (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 13
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.
Since SCA13 occurs through a dominant-negative or gain-of-function mechanism [
• Congenital-onset non-progressive severe cerebellar hypoplasia on brain MRI [
• Ataxia
• Gait and/or appendicular
• Dysarthria
• Gait and/or appendicular
• Dysarthria
• Cognitive impairment
• Delayed motor milestones
• Delayed speech acquisition
• Delayed motor milestones
• Delayed speech acquisition
• Tremor/myoclonus
• Seizures
• Gradual lifetime improvement in motor and cognitive function
• Gait and/or appendicular
• Dysarthria
• Delayed motor milestones
• Delayed speech acquisition
• Cognitive impairment
• Seizures
• Delayed motor milestones
• Cerebellar atrophy on brain MRI
• Ataxia
• Gait and/or appendicular
• Truncal ataxia
• Titubation
• Gait and/or appendicular
• Truncal ataxia
• Titubation
• Hypotonia
• Dysarthria
• Impaired sound localization
• On brain MRI:
• All affected individuals show age-related progressive mild-to-moderately severe cerebellar atrophy that is primarily midline. This has been evident as early as age three years.
• Atrophy of the brain stem and/or cerebral cortex can be observed.
• All affected individuals show age-related progressive mild-to-moderately severe cerebellar atrophy that is primarily midline. This has been evident as early as age three years.
• Atrophy of the brain stem and/or cerebral cortex can be observed.
• Gait and/or appendicular
• Truncal ataxia
• Titubation
• All affected individuals show age-related progressive mild-to-moderately severe cerebellar atrophy that is primarily midline. This has been evident as early as age three years.
• Atrophy of the brain stem and/or cerebral cortex can be observed.
## Suggestive Findings
SCA13
Congenital-onset non-progressive severe cerebellar hypoplasia on brain MRI [
Ataxia
Gait and/or appendicular
Dysarthria
Cognitive impairment
Delayed motor milestones
Delayed speech acquisition
Tremor/myoclonus
Seizures
Gradual lifetime improvement in motor and cognitive function
Cognitive impairment
Seizures
Delayed motor milestones
Cerebellar atrophy on brain MRI
Ataxia
Gait and/or appendicular
Truncal ataxia
Titubation
Hypotonia
Dysarthria
Impaired sound localization
On brain MRI:
All affected individuals show age-related progressive mild-to-moderately severe cerebellar atrophy that is primarily midline. This has been evident as early as age three years.
Atrophy of the brain stem and/or cerebral cortex can be observed.
• Congenital-onset non-progressive severe cerebellar hypoplasia on brain MRI [
• Ataxia
• Gait and/or appendicular
• Dysarthria
• Gait and/or appendicular
• Dysarthria
• Cognitive impairment
• Delayed motor milestones
• Delayed speech acquisition
• Delayed motor milestones
• Delayed speech acquisition
• Tremor/myoclonus
• Seizures
• Gradual lifetime improvement in motor and cognitive function
• Gait and/or appendicular
• Dysarthria
• Delayed motor milestones
• Delayed speech acquisition
• Cognitive impairment
• Seizures
• Delayed motor milestones
• Cerebellar atrophy on brain MRI
• Ataxia
• Gait and/or appendicular
• Truncal ataxia
• Titubation
• Gait and/or appendicular
• Truncal ataxia
• Titubation
• Hypotonia
• Dysarthria
• Impaired sound localization
• On brain MRI:
• All affected individuals show age-related progressive mild-to-moderately severe cerebellar atrophy that is primarily midline. This has been evident as early as age three years.
• Atrophy of the brain stem and/or cerebral cortex can be observed.
• All affected individuals show age-related progressive mild-to-moderately severe cerebellar atrophy that is primarily midline. This has been evident as early as age three years.
• Atrophy of the brain stem and/or cerebral cortex can be observed.
• Gait and/or appendicular
• Truncal ataxia
• Titubation
• All affected individuals show age-related progressive mild-to-moderately severe cerebellar atrophy that is primarily midline. This has been evident as early as age three years.
• Atrophy of the brain stem and/or cerebral cortex can be observed.
## Establishing the Diagnosis
The diagnosis of SCA13
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
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 phenotypes associated with SCA13 are indistinguishable from other congenital-onset and adult-onset ataxias, affected individuals are likely to be diagnosed using a multigene panel (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 13
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.
Since SCA13 occurs through a dominant-negative or gain-of-function mechanism [
## Option 1
For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 13
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.
Since SCA13 occurs through a dominant-negative or gain-of-function mechanism [
## Clinical Characteristics
The phenotypic spectrum of spinocerebellar ataxia type 13 (SCA13) originally clustered into two presentations: congenital-onset ataxia with little progression, typically accompanied by mild-to-moderate intellectual disability and occasionally seizures [
In all affected individuals:
Non-progressive limb, truncal, gait ataxia
Dysarthria
Tremor
Delayed gross and/or fine motor milestones
Cognitive impairment that is mild to moderate and relatively domain-specific to language
Gradual lifetime improvement in motor and cognitive function
Variably present:
Nystagmus
Hyperreflexia
Psychiatric manifestations
Seizures
Life expectancy is unknown, but many affected individuals have been surveyed and examined at age 50 years and older [Author, personal observation].
In the family described by
Life span is not shortened and many persons live beyond age 70 years; assistance with gait may be required as the disease progresses.
The
MRI findings may include cerebellar atrophy with little change over years. Notably, imaging evidence suggests that cerebellar atrophy may significantly precede overt clinical symptomatology.
Life expectancy is unknown, but many affected individuals have been surveyed and examined at age 60 years and older [Author, personal observation].
While the known pathogenic variants in
The
The
The
The
The
The prevalence of SCA13 is not known. Only one person with SCA13 was identified in a cohort of 327 probands with ataxia [
• Non-progressive limb, truncal, gait ataxia
• Dysarthria
• Tremor
• Delayed gross and/or fine motor milestones
• Cognitive impairment that is mild to moderate and relatively domain-specific to language
• Gradual lifetime improvement in motor and cognitive function
• Nystagmus
• Hyperreflexia
• Psychiatric manifestations
• Seizures
• The
• The
• The
• The
• The
## Clinical Description
The phenotypic spectrum of spinocerebellar ataxia type 13 (SCA13) originally clustered into two presentations: congenital-onset ataxia with little progression, typically accompanied by mild-to-moderate intellectual disability and occasionally seizures [
In all affected individuals:
Non-progressive limb, truncal, gait ataxia
Dysarthria
Tremor
Delayed gross and/or fine motor milestones
Cognitive impairment that is mild to moderate and relatively domain-specific to language
Gradual lifetime improvement in motor and cognitive function
Variably present:
Nystagmus
Hyperreflexia
Psychiatric manifestations
Seizures
Life expectancy is unknown, but many affected individuals have been surveyed and examined at age 50 years and older [Author, personal observation].
In the family described by
Life span is not shortened and many persons live beyond age 70 years; assistance with gait may be required as the disease progresses.
The
MRI findings may include cerebellar atrophy with little change over years. Notably, imaging evidence suggests that cerebellar atrophy may significantly precede overt clinical symptomatology.
Life expectancy is unknown, but many affected individuals have been surveyed and examined at age 60 years and older [Author, personal observation].
• Non-progressive limb, truncal, gait ataxia
• Dysarthria
• Tremor
• Delayed gross and/or fine motor milestones
• Cognitive impairment that is mild to moderate and relatively domain-specific to language
• Gradual lifetime improvement in motor and cognitive function
• Nystagmus
• Hyperreflexia
• Psychiatric manifestations
• Seizures
## Congenital-Onset Cerebellar Hypoplasia with Non-Progressive Cerebellar Ataxia
In all affected individuals:
Non-progressive limb, truncal, gait ataxia
Dysarthria
Tremor
Delayed gross and/or fine motor milestones
Cognitive impairment that is mild to moderate and relatively domain-specific to language
Gradual lifetime improvement in motor and cognitive function
Variably present:
Nystagmus
Hyperreflexia
Psychiatric manifestations
Seizures
Life expectancy is unknown, but many affected individuals have been surveyed and examined at age 50 years and older [Author, personal observation].
• Non-progressive limb, truncal, gait ataxia
• Dysarthria
• Tremor
• Delayed gross and/or fine motor milestones
• Cognitive impairment that is mild to moderate and relatively domain-specific to language
• Gradual lifetime improvement in motor and cognitive function
• Nystagmus
• Hyperreflexia
• Psychiatric manifestations
• Seizures
## Childhood-Onset Progressive Cerebellar Ataxia with Delayed Milestones
In the family described by
Life span is not shortened and many persons live beyond age 70 years; assistance with gait may be required as the disease progresses.
## Adult-Onset Progressive Spinocerebellar Ataxia
The
MRI findings may include cerebellar atrophy with little change over years. Notably, imaging evidence suggests that cerebellar atrophy may significantly precede overt clinical symptomatology.
Life expectancy is unknown, but many affected individuals have been surveyed and examined at age 60 years and older [Author, personal observation].
## Genotype-Phenotype Correlations
While the known pathogenic variants in
The
The
The
The
The
• The
• The
• The
• The
• The
## Penetrance
## Prevalence
The prevalence of SCA13 is not known. Only one person with SCA13 was identified in a cohort of 327 probands with ataxia [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
See
## Management
To establish the extent of disease and needs in an individual diagnosed with congenital-onset non-progressive spinocerebellar ataxia type 13 or adult-onset progressive SCA13, the multidisciplinary evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital-Onset Non-Progressive SCA13
Use of
Need for social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; FTT = failure to thrive; GERD = gastroesophageal reflux disease; 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 Adult-Onset Progressive SCA13
Use of
Need for social work involvement for caregiver support.
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; 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
Treatment by a multidisciplinary team is recommended for individuals with congenital-onset non-progressive SCA13 (see
Treatment of Manifestations in Individuals with Congenital-Onset Non-Progressive SCA13
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 whether any changes are needed.
Special education law requires that children participating in 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
Treatment of Manifestations in Individuals with Adult-Onset Progressive SCA13
PT (balance exercises, gait training, & muscle strengthening) to maintain mobility & function
OT to optimize ADL
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).
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Weight control & physical activity to avoid obesity & related difficulties with mobility
ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of individuals diagnosed with epilepsy, see
Surveillance by a multidisciplinary team is recommended for individuals with congenital-onset non-progressive SCA13 (see
Recommended Surveillance for Individuals Congenital-Onset Non-Progressive SCA13
Speech/language development
Need for alternative communication method
Patients should receive routine care in the context of a comprehensive program if available.
Ongoing & continuous, especially for 1st several yrs
Recommended Surveillance for Individuals with Adult-Onset Progressive SCA13
Avoid alcohol and sedating drugs, which can exacerbate ataxia.
See
Weight gain during pregnancy can further impair gait ataxia.
Search
• Use of
• Need for social work involvement for parental support.
• Use of
• Need for social work involvement for caregiver 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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
• PT (balance exercises, gait training, & muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• 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).
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Weight control & physical activity to avoid obesity & related difficulties with mobility
• Speech/language development
• Need for alternative communication method
• Patients should receive routine care in the context of a comprehensive program if available.
• Ongoing & continuous, especially for 1st several yrs
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with congenital-onset non-progressive spinocerebellar ataxia type 13 or adult-onset progressive SCA13, the multidisciplinary evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Congenital-Onset Non-Progressive SCA13
Use of
Need for social work involvement for parental support.
ADHD = attention-deficit/hyperactivity disorder; FTT = failure to thrive; GERD = gastroesophageal reflux disease; 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 Adult-Onset Progressive SCA13
Use of
Need for social work involvement for caregiver support.
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; 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
• Use of
• Need for social work involvement for parental support.
• Use of
• Need for social work involvement for caregiver support.
## Treatment of Manifestations
Treatment by a multidisciplinary team is recommended for individuals with congenital-onset non-progressive SCA13 (see
Treatment of Manifestations in Individuals with Congenital-Onset Non-Progressive SCA13
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 whether any changes are needed.
Special education law requires that children participating in 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
Treatment of Manifestations in Individuals with Adult-Onset Progressive SCA13
PT (balance exercises, gait training, & muscle strengthening) to maintain mobility & function
OT to optimize ADL
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).
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Weight control & physical activity to avoid obesity & related difficulties with mobility
ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of individuals 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.
• PT, OT, and speech services will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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
• PT (balance exercises, gait training, & muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• 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).
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Weight control & physical activity to avoid obesity & related difficulties with mobility
## 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
Treatment of Manifestations in Individuals with Adult-Onset Progressive SCA13
PT (balance exercises, gait training, & muscle strengthening) to maintain mobility & function
OT to optimize ADL
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).
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Weight control & physical activity to avoid obesity & related difficulties with mobility
ADL = activities of daily living; ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy
Education of caregivers regarding common seizure presentations is appropriate. For information on non-medical interventions and coping strategies for parents or caregivers of individuals diagnosed with epilepsy, see
• 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 (balance exercises, gait training, & muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• 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).
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Weight control & physical activity to avoid obesity & related difficulties with mobility
## Surveillance
Surveillance by a multidisciplinary team is recommended for individuals with congenital-onset non-progressive SCA13 (see
Recommended Surveillance for Individuals Congenital-Onset Non-Progressive SCA13
Speech/language development
Need for alternative communication method
Patients should receive routine care in the context of a comprehensive program if available.
Ongoing & continuous, especially for 1st several yrs
Recommended Surveillance for Individuals with Adult-Onset Progressive SCA13
• Speech/language development
• Need for alternative communication method
• Patients should receive routine care in the context of a comprehensive program if available.
• Ongoing & continuous, especially for 1st several yrs
## Agents/Circumstances to Avoid
Avoid alcohol and sedating drugs, which can exacerbate ataxia.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Weight gain during pregnancy can further impair gait ataxia.
## Therapies Under Investigation
Search
## Genetic Counseling
Spinocerebellar ataxia type 13 (SCA13) is inherited in an autosomal dominant manner.
Most individuals diagnosed with SCA13 have an affected parent.
In rare instances, an individual diagnosed with SCA13 has the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
The family history of some individuals diagnosed with SCA13 may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
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.
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 individuals diagnosed with SCA13 have an affected parent.
• In rare instances, an individual diagnosed with SCA13 has the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• The family history of some individuals diagnosed with SCA13 may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• 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
Spinocerebellar ataxia type 13 (SCA13) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with SCA13 have an affected parent.
In rare instances, an individual diagnosed with SCA13 has the disorder as the result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If the
The family history of some individuals diagnosed with SCA13 may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
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
• Most individuals diagnosed with SCA13 have an affected parent.
• In rare instances, an individual diagnosed with SCA13 has the disorder as the result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If the
• The family history of some individuals diagnosed with SCA13 may appear to be negative because of failure to recognize the disorder in family members or early death of the parent before the onset of symptoms. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• 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
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
United Kingdom
United Kingdom
Spain
Sanford Research
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
• Spain
•
•
• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia Type 13: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 13 (
Notable
Variants listed in the table have been provided by the author.
ID = intellectual disability
## Molecular Pathogenesis
Notable
Variants listed in the table have been provided by the author.
ID = intellectual disability
## Chapter Notes
Stefan M Pulst, MD; University of Utah (2006-2020)Michael F Waters, MD, PhD (2020-present)
4 June 2020 (bp) Comprehensive update posted live
1 March 2012 (me) Comprehensive update posted live
9 November 2006 (me) Review posted live
19 September 2006 (smp) Original submission
• 4 June 2020 (bp) Comprehensive update posted live
• 1 March 2012 (me) Comprehensive update posted live
• 9 November 2006 (me) Review posted live
• 19 September 2006 (smp) Original submission
## Author History
Stefan M Pulst, MD; University of Utah (2006-2020)Michael F Waters, MD, PhD (2020-present)
## Revision History
4 June 2020 (bp) Comprehensive update posted live
1 March 2012 (me) Comprehensive update posted live
9 November 2006 (me) Review posted live
19 September 2006 (smp) Original submission
• 4 June 2020 (bp) Comprehensive update posted live
• 1 March 2012 (me) Comprehensive update posted live
• 9 November 2006 (me) Review posted live
• 19 September 2006 (smp) Original submission
## References
## Literature Cited
|
[
"K Bürk, DA Sival. Scales for the clinical evaluation of cerebellar disorders.. Handb Clin Neurol. 2018;154:329-39",
"K Bürk, A Strzelczyk, PS Reif, KP Figueroa, SM Pulst. Mesial temporal lobe epilepsy in a patient with spinocerebellar ataxia type 13 (SCA13).. Int J Neurosci 2013;123:278-282",
"M Coutelier, G Coarelli, ML Monin, J Konop, CS Davoine, C Tesson, R Valter, M Anheim, A Behin, G Castelnovo, P Charles, A David, C Ewenczyk, M Fradin, C Goizet, D Hannequin, P Labauge, F Riant, P Sarda, Y Sznajer, F Tison, U Ullmann, L Van Maldergem, F Mochel, A Brice, G Stevanin, A Durr. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.. Brain. 2017;140:1579-94",
"M Coutelier, MB Hammer, G Stevanin, ML Monin, CS Davoine, F Mochel, P Labauge, C Ewenczyk, J Ding, JR Gibbs, D Hannequin, J Melki, A Toutain, V Laugel, S Forlani, P Charles, E Broussolle, S Thobois, A Afenjar, M Anheim, P Calvas, G Castelnovo, T de Broucker, M Vidailhet, A Moulignier, RT Ghnassia, C Tallaksen, C Mignot, C Goizet, I Le Ber, E Ollagnon-Roman, J Pouget, A Brice, A Singleton, A Durr. Efficacy of exome-targeted capture sequencing to detect mutations in known cerebellar ataxia genes.. JAMA Neurol. 2018;75:591-9",
"A Duarri, EA Nibbeling, MR Fokkens, M Meijer, M Boerrigter, CC Verschuuren-Bemelmans, BP Kremer, BP van de Warrenburg, D Dooijes, E Boddeke, RJ Sinke, DS Verbeek. Functional analysis helps to define. PLoS One. 2015;10",
"KP Figueroa, NA Minassian, G Stevanin, M Waters, V Garibyan, S Forlani, A Strzelczyk, K Bürk, A Brice, A Dürr, DM Papazian, SM Pulst. KCNC3: phenotype, mutations, channel biophysics-a study of 260 familial ataxia patients.. Hum Mutat. 2010;31:191-6",
"KP Figueroa, MF Waters, V Garibyan, TD Bird, CM Gomez, LP Ranum, NA Minassian, DM Papazian, SM Pulst. Frequency of KCNC3 DNA variants as causes of spinocerebellar ataxia 13 (SCA13).. PLoS One. 2011;6",
"A Herman-Bert, G Stevanin, JC Netter, O Rascol, D Brassat, P Calvas, A Camuzat, Q Yuan, M Schalling, A Durr, A Brice. Mapping of spinocerebellar ataxia 13 to chromosome 19q13.3-q13.4 in a family with autosomal dominant cerebellar ataxia and mental retardation.. Am J Hum Genet. 2000;67:229-35",
"F Hoche, X Guell, MG Vangel, JC Sherman, JD Schmahmann. The cerebellar cognitive affective/Schmahmann Syndrome Scale.. Brain. 2018;141:248-70",
"RH Joho, EC Hurlock. The role of Kv3-type potassium channels in cerebellar physiology and behavior.. Cerebellum. 2009;8:323-33",
"S Khare, JA Nick, Y Zhang, K Galeano, B Butler, H Khoshbouei, S Rayaprolu, T Hathorn, LPW Ranum, L Smithson, TE Golde, M Paucar, R Morse, M Raff, J Simon, M Nordenskjöld, K Wirdefeldt, DE Rincon-Limas, J Lewis, LK Kaczmarek, P Fernandez-Funez, HS Nick, MF. A Waters. PLoS One. 2017;12",
"S Khare, K Galeano, Y Zhang, JA Nick, J Sampson, HS Nick, SH Subramony, LK Kaczmarek, MF Waters. C-terminal proline deletions in KCNC3 cause delayed channel inactivation and an adult-onset progressive SCA13 with spasticity.. Cerebellum. 2018;17:692-7",
"L Martineau, A Noreau, N. Dupré. Therapies for ataxias.. Curr Treat Options Neurol. 2014;16:300",
"NA Minassian, MC Lin, DM Papazian. Altered Kv3.3 channel gating in early-onset spinocerebellar ataxia type 13.. J Physiol. 2012;590:1599-614",
"S Montaut, E Apartis, JB Chanson, C Ewenczyk, M Renaud, C Guissart, J Muller, AP Legrand, A Durr, V Laugel, M Koenig, C Tranchant, M Anheim. SCA13 causes dominantly inherited non-progressive myoclonus ataxia.. Parkinsonism Relat Disord. 2017;38:80-4",
"AH Németh, AC Kwasniewska, S Lise, R Parolin Schnekenberg, EB Becker, KD Bera, ME Shanks, L Gregory, D Buck, M Zameel Cader, K Talbot, R de Silva, N Fletcher, R Hastings, S Jayawant, PJ Morrison, P Worth, M Taylor, J Tolmie, M O'Regan, R Valentine, E Packham, J Evans, A Seller, J Ragoussis. Next generation sequencing for molecular diagnosis of neurological disorders using ataxias as a model.. Brain. 2013;136:3106-18",
"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",
"SH Subramony, J Advincula, S Perlman, RL Rosales, LV Lee, T Ashizawa, MF Waters. Comprehensive phenotype of the R420H allelic form of spinocerebellar ataxia type 13.. Cerebellum. 2013;12:932-6",
"MF Waters, D Fee, KP Figueroa, D Nolte, U Muller, J Advincula, H Coon, VG Evidente, SM Pulst. An autosomal dominant ataxia maps to 19q13: Allelic heterogeneity of SCA13 or novel locus?. Neurology 2005;65:1111-3",
"MF Waters, SM Pulst. SCA13.. Cerebellum. 2008;7:165-9",
"MF Waters, NA Minassian, G Stevanin, KP Figueroa, JP Bannister, D Nolte, AF Mock, VG Evidente, DB Fee, U Muller, A Durr, A Brice, DM Papazian, SM Pulst. Mutations in voltage-gated potassium channel KCNC3 cause degenerative and developmental central nervous system phenotypes.. Nat Genet 2006;38:447-51"
] |
9/11/2006
|
4/6/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sca14
|
sca14
|
[
"SCA14",
"SCA14",
"Protein kinase C gamma type",
"PRKCG",
"Spinocerebellar Ataxia Type 14"
] |
Spinocerebellar Ataxia Type 14
|
Dong-Hui Chen, Thomas D Bird, Wendy H Raskind
|
Summary Spinocerebellar ataxia type 14 (SCA14) is characterized by slowly progressive cerebellar ataxia, dysarthria, and nystagmus. Axial myoclonus, cognitive impairment, tremor, and sensory loss may also be observed. Parkinsonian features including rigidity and tremor have been described in some families. Findings seen in other ataxia disorders (e.g., dysphagia, dysphonia) may also occur in SCA14. The average age of onset is in the 30s, with a range from childhood to the seventh decade. Life span is not shortened. The diagnosis of SCA14 is established in a proband with a pathogenic variant in SCA14 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the
|
## Diagnosis
Formal diagnostic criteria for spinocerebellar ataxia type 14 have not been established.
Spinocerebellar ataxia type 14 (SCA14)
Slowly progressive cerebellar ataxia
Myoclonus, dystonia, rigidity, and tremor
Sensory loss
Dysarthria
Nystagmus
Cognitive impairment (some individuals)
Depression (some individuals)
Family history consistent with autosomal dominant inheritance
Mild-to-moderately severe cerebellar atrophy that is primarily midline on brain MRI examination
The diagnosis of SCA14
Because the phenotype of SCA14 is indistinguishable from many other inherited disorders with ataxia, recommended molecular genetic testing approaches include use of a
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 Spinocerebellar Ataxia Type 14
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 HGMD [
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 intragenic multiexon deletion of 1,717 nucleotides of genomic DNA has been reported (see
• Slowly progressive cerebellar ataxia
• Myoclonus, dystonia, rigidity, and tremor
• Sensory loss
• Dysarthria
• Nystagmus
• Cognitive impairment (some individuals)
• Depression (some individuals)
• Family history consistent with autosomal dominant inheritance
• Mild-to-moderately severe cerebellar atrophy that is primarily midline on brain MRI examination
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Spinocerebellar ataxia type 14 (SCA14)
Slowly progressive cerebellar ataxia
Myoclonus, dystonia, rigidity, and tremor
Sensory loss
Dysarthria
Nystagmus
Cognitive impairment (some individuals)
Depression (some individuals)
Family history consistent with autosomal dominant inheritance
Mild-to-moderately severe cerebellar atrophy that is primarily midline on brain MRI examination
• Slowly progressive cerebellar ataxia
• Myoclonus, dystonia, rigidity, and tremor
• Sensory loss
• Dysarthria
• Nystagmus
• Cognitive impairment (some individuals)
• Depression (some individuals)
• Family history consistent with autosomal dominant inheritance
• Mild-to-moderately severe cerebellar atrophy that is primarily midline on brain MRI examination
## Establishing the Diagnosis
The diagnosis of SCA14
Because the phenotype of SCA14 is indistinguishable from many other inherited disorders with ataxia, recommended molecular genetic testing approaches include use of a
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 Spinocerebellar Ataxia Type 14
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 HGMD [
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 intragenic multiexon deletion of 1,717 nucleotides of genomic DNA has been reported (see
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
To date, more than 60 individuals and/or families with a pathogenic variant in
Features of Spinocerebellar Ataxia Type 14
Individuals with SCA14 typically present with a slowly progressive pure ataxia, but many individuals also manifest other symptoms. In a cohort study that identified 13 families carrying pathogenic variants in
No genotype-phenotype correlations have been identified.
Clinically unaffected individuals with
The term "olivopontocerebellar atrophy" (OPCA) was used to denote SCA in the past. Prior to the discovery of the genes that differentiate members of the group, the autosomal dominant cerebellar ataxias (ADCA) were divided into subgroups depending on the presence of clinical features in addition to ataxia. ADCA III, to which SCA14 would belong, referred to a pure form of late-onset cerebellar ataxia without additional features.
SCA14 probably accounts for fewer than 1% of all autosomal dominant ataxia diagnoses and accounts for approximately 1.5% to 6.7% of autosomal dominant cerebellar ataxia without trinucleotide repeat expansions [
A founder variant (
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
Clinically unaffected individuals with
## Nomenclature
The term "olivopontocerebellar atrophy" (OPCA) was used to denote SCA in the past. Prior to the discovery of the genes that differentiate members of the group, the autosomal dominant cerebellar ataxias (ADCA) were divided into subgroups depending on the presence of clinical features in addition to ataxia. ADCA III, to which SCA14 would belong, referred to a pure form of late-onset cerebellar ataxia without additional features.
## Prevalence
SCA14 probably accounts for fewer than 1% of all autosomal dominant ataxia diagnoses and accounts for approximately 1.5% to 6.7% of autosomal dominant cerebellar ataxia without trinucleotide repeat expansions [
A founder variant (
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Persons with spinocerebellar ataxia type 14 (SCA14) may present with ataxia that is indistinguishable from other adult-onset inherited or acquired ataxias (see
Note: SCA14 should particularly be considered if the proband or an affected relative displays axial myoclonus, dystonia, or cognitive impairment.
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 14 (SCA14), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 14.
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; MMSE= Mini-Mental State Exam; MoCA= Montreal Cognitive Assessment; SARA= Scale for the Assessment and Rating of Ataxia; WAIS = The Wechsler Adult Intelligence Scale; WISC= Wechsler Intelligence Scales for Children
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 14
PT (balance exercises, gait training, & muscle strengthening) to maintain mobility & function
OT to optimize activities of daily living
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)
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Weight control & physical activity to avoid obesity & related difficulties w/mobility
IEP = individualized education plan; OT = occupational therapy; PT = physical therapy
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 14
Neurologic assessment
Physical medicine, OT/PT assessment of mobility, self-help skills
Speech & language development
Need for alternative communication method
OT = occupational therapy; PT = physical therapy
Alcohol and sedation may worsen gait and coordination.
See
Search
Tremor-controlling drugs do not work well for cerebellar tremors.
• PT (balance exercises, gait training, & muscle strengthening) to maintain mobility & function
• OT to optimize activities of daily living
• 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)
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Weight control & physical activity to avoid obesity & related difficulties w/mobility
• Neurologic assessment
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Speech & language development
• Need for alternative communication method
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 14 (SCA14), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 14.
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; MMSE= Mini-Mental State Exam; MoCA= Montreal Cognitive Assessment; SARA= Scale for the Assessment and Rating of Ataxia; WAIS = The Wechsler Adult Intelligence Scale; WISC= Wechsler Intelligence Scales for Children
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 14
PT (balance exercises, gait training, & muscle strengthening) to maintain mobility & function
OT to optimize activities of daily living
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)
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Weight control & physical activity to avoid obesity & related difficulties w/mobility
IEP = individualized education plan; OT = occupational therapy; PT = physical therapy
• PT (balance exercises, gait training, & muscle strengthening) to maintain mobility & function
• OT to optimize activities of daily living
• 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)
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Weight control & physical activity to avoid obesity & related difficulties w/mobility
## Surveillance
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 14
Neurologic assessment
Physical medicine, OT/PT assessment of mobility, self-help skills
Speech & language development
Need for alternative communication method
OT = occupational therapy; PT = physical therapy
• Neurologic assessment
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Speech & language development
• Need for alternative communication method
## Agents/Circumstances to Avoid
Alcohol and sedation may worsen gait and coordination.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Other
Tremor-controlling drugs do not work well for cerebellar tremors.
## Genetic Counseling
Spinocerebellar ataxia type 14 (SCA14) is inherited in an autosomal dominant manner.
Many individuals diagnosed with SCA14 have an affected parent.
An individual diagnosed with SCA14 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
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with SCA14 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, late onset of the disease in the affected parent, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Intrafamilial variability in age of onset and clinical features is observed in SCA14.
If the proband has a known SCA14-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 theoretic possibility of parental germline mosaicism [
If the parents have not been tested for the
Predictive testing for at-risk relatives is possible once molecular genetic testing has identified the causative pathogenic variant in an affected family member.
This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
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 SCA14, 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.
Once the
Note: Some reported
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testingis. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Many individuals diagnosed with SCA14 have an affected parent.
• An individual diagnosed with SCA14 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
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with SCA14 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, late onset of the disease in the affected parent, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Intrafamilial variability in age of onset and clinical features is observed in SCA14.
• If the proband has a known SCA14-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 theoretic possibility of parental germline mosaicism [
• If the parents have not been tested for the
• Predictive testing for at-risk relatives is possible once molecular genetic testing has identified the causative pathogenic variant in an affected family member.
• This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• 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
Spinocerebellar ataxia type 14 (SCA14) is inherited in an autosomal dominant manner.
## Risk to Family Members
Many individuals diagnosed with SCA14 have an affected parent.
An individual diagnosed with SCA14 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
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with SCA14 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, late onset of the disease in the affected parent, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Intrafamilial variability in age of onset and clinical features is observed in SCA14.
If the proband has a known SCA14-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 theoretic possibility of parental germline mosaicism [
If the parents have not been tested for the
• Many individuals diagnosed with SCA14 have an affected parent.
• An individual diagnosed with SCA14 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
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with SCA14 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, late onset of the disease in the affected parent, or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected or has the pathogenic variant, the risk to the sibs of inheriting the variant is 50%. Intrafamilial variability in age of onset and clinical features is observed in SCA14.
• If the proband has a known SCA14-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 theoretic possibility of parental germline mosaicism [
• If the parents have not been tested for the
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once molecular genetic testing has identified the causative pathogenic variant in an affected family member.
This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
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 SCA14, 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 molecular genetic testing has identified the causative pathogenic variant in an affected family member.
• This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• 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
Note: Some reported
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testingis. 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
Spain
Sanford Research
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
• Spain
•
•
• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia Type 14: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 14 (
The majority of pathogenic variants cluster in exon 4 encoding the regulatory C1 domain. In vitro and in vivo investigations of effects of some of these pathogenic variants on the function of the protein have been performed. Computer simulation studies on three pathogenic missense variants [
Notable
Variants listed in the table have been provided by the authors.
ADCA = autosomal dominant cerebellar ataxia; ID = intellectual disability
Variant designation that does not conform to current naming conventions.
Intragenic multiexon deletion of 1,717 nucleotides of genomic DNA (Chr19:59086740-59088457) (NCBI36)
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The majority of pathogenic variants cluster in exon 4 encoding the regulatory C1 domain. In vitro and in vivo investigations of effects of some of these pathogenic variants on the function of the protein have been performed. Computer simulation studies on three pathogenic missense variants [
Notable
Variants listed in the table have been provided by the authors.
ADCA = autosomal dominant cerebellar ataxia; ID = intellectual disability
Variant designation that does not conform to current naming conventions.
Intragenic multiexon deletion of 1,717 nucleotides of genomic DNA (Chr19:59086740-59088457) (NCBI36)
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Supported by funds from the NORD, the NINDS, and the Department of Veterans Affairs
20 February 2020 (sw) Comprehensive update posted live
18 April 2013 (me) Comprehensive update posted live
23 March 2010 (me) Comprehensive update posted live
8 February 2007 (me) Comprehensive update posted live
21 December 2005 (dhc) Revision: prenatal diagnosis available
28 January 2005 (me) Review posted live
23 September 2004 (dhc) Original submission
• 20 February 2020 (sw) Comprehensive update posted live
• 18 April 2013 (me) Comprehensive update posted live
• 23 March 2010 (me) Comprehensive update posted live
• 8 February 2007 (me) Comprehensive update posted live
• 21 December 2005 (dhc) Revision: prenatal diagnosis available
• 28 January 2005 (me) Review posted live
• 23 September 2004 (dhc) Original submission
## Author Notes
Supported by funds from the NORD, the NINDS, and the Department of Veterans Affairs
## Revision History
20 February 2020 (sw) Comprehensive update posted live
18 April 2013 (me) Comprehensive update posted live
23 March 2010 (me) Comprehensive update posted live
8 February 2007 (me) Comprehensive update posted live
21 December 2005 (dhc) Revision: prenatal diagnosis available
28 January 2005 (me) Review posted live
23 September 2004 (dhc) Original submission
• 20 February 2020 (sw) Comprehensive update posted live
• 18 April 2013 (me) Comprehensive update posted live
• 23 March 2010 (me) Comprehensive update posted live
• 8 February 2007 (me) Comprehensive update posted live
• 21 December 2005 (dhc) Revision: prenatal diagnosis available
• 28 January 2005 (me) Review posted live
• 23 September 2004 (dhc) Original submission
## References
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"H Asai, M Hirano, K Shimada, T Kiriyama, Y Furiya, M Ikeda, T Iwamoto, T Mori, K Nishinaka, N Konishi, F Udaka, S. Ueno. Protein kinase C gamma, a protein causative for dominant ataxia, negatively regulates nuclear import of recessive-ataxia-related aprataxin.. Hum Mol Genet. 2009;18:3533-43",
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"DH Chen, Z Brkanac, CL Verlinde, XJ Tan, L Bylenok, D Nochlin, M Matsushita, H Lipe, J Wolff, M Fernandez, PJ Cimino, TD Bird, WH Raskind. Missense mutations in the regulatory domain of PKC gamma: a new mechanism for dominant nonepisodic cerebellar ataxia.. Am J Hum Genet. 2003;72:839-49",
"DH Chen, PJ Cimino, LP Ranum, HY Zoghbi, I Yabe, L Schut, RL Margolis, HP Lipe, A Feleke, M Matsushita, J Wolff, C Morgan, D Lau, M Fernandez, H Sasaki, WH Raskind, TD Bird. The clinical and genetic spectrum of spinocerebellar ataxia 14.. Neurology. 2005;64:1258-60",
"C Chen, M Kano, A Abeliovich, L Chen, S Bao, JJ Kim, K Hashimoto, RF Thompson, S Tonegawa. Impaired motor coordination correlates with persistent multiple climbing fiber innervation in PKC gamma mutant mice.. Cell. 1995;83:1233-42",
"R Chopra, AH Wasserman, SM Pulst, CI De Zeeuw, VG Shakkottai. Protein kinase C activity is a protective modifier of Purkinje neuron degeneration in cerebellar ataxia.. Hum Mol Genet. 2018;27:1396-1410",
"M Coutelier, G Coarelli, ML Monin, J Konop, CS Davoine, C Tesson, R Valter, M Anheim, A Behin, G Castelnovo, P Charles, A David, C Ewenczyk, M Fradin, C Goizet, D Hannequin, P Labauge, F Riant, P Sarda, Y Sznajer, F Tison, U Ullmann, L Van Maldergem, F Mochel, A Brice, G Stevanin, A Durr. A panel study on patients with dominant cerebellar ataxia highlights the frequency of channelopathies.. Brain. 2017;140:1579-94",
"NJ Craig, MB Durán Alonso, KL Hawker, P Shiels, TA Glencorse, JM Campbell, NK Bennett, M Canham, D Donald, M Gardiner, DP Gilmore, RJ MacDonald, K Maitland, AS McCallion, D Russell, AP Payne, RG Sutcliffe, RW Davies. A candidate gene for human neurodegenerative disorders: a rat PKC gamma mutation causes a Parkinsonian syndrome.. Nat Neurosci. 2001;4:1061-2",
"A Dalski, B Mitulla, K Burk, C Schattenfroh, E Schwinger, C Zuhlke. Mutation of the highly conserved cysteine residue 131 of the SCA14 associated PRKCG gene in a family with slow progressive cerebellar ataxia.. J Neurol. 2006;253:1111-2",
"G Doran, KE Davies, K Talbot. Activation of mutant protein kinase Cgamma leads to aberrant sequestration and impairment of its cellular function.. Biochem Biophys Res Commun. 2008;372:447-53",
"MC Fahey, MA Knight, JH Shaw, RJ Gardner, D du Sart, PJ Lockhart, MB Delatycki, PC Gates, E Storey. Spinocerebellar ataxia type 14: study of a family with an exon 5 mutation in the PRKCG gene.. J Neurol Neurosurg Psychiatry. 2005;76:1720-2",
"EM Foncke, RJ Beukers, CC Tijssen, JH Koelman, MA Tijssen. Myoclonus-dystonia and spinocerebellar ataxia type 14 presenting with similar phenotypes: trunk tremor, myoclonus, and dystonia.. Parkinsonism Relat Disord. 2010;16:288-9",
"C Ganos, S Zittel, M Minnerop, O Schunke, C Heinbokel, C Gerloff, C Zühlke, P Bauer, T Klockgether, A Münchau, T Bäumer. Clinical and neurophysiological profile of four German families with spinocerebellar ataxia type 14.. Cerebellum. 2014;13:89-96",
"K Hiramoto, H Kawakami, K Inoue, T Seki, H Maruyama, H Morino, M Matsumoto, K Kurisu, N Sakai. Identification of a new family of spinocerebellar ataxia type 14 in the Japanese spinocerebellar ataxia population by the screening of PRKCG exon 4.. Mov Disord. 2006;21:1355-60",
"J Ji, ML Hassler, E Shimobayashi, N Paka, R Streit, JP Kapfhammer. Increased protein kinase C gamma activity induces Purkinje cell pathology in a mouse model of spinocerebellar ataxia 14.. Neurobiol Dis. 2014;70:1-11",
"M Kano, K Hashimoto, C Chen, A Abeliovich, A Aiba, H Kurihara, M Watanabe, Y Inoue, S Tonegawa. Impaired synapse elimination during cerebellar development in PKC gamma mutant mice.. Cell. 1995;83:1223-31",
"S Klebe, A Durr, A Rentschler, V Hahn-Barma, M Abele, N Bouslam, L Schols, P Jedynak, S Forlani, E Denis, C Dussert, Y Agid, P Bauer, C Globas, U Wullner, A Brice, O Riess, G. Stevanin. New mutations in protein kinase Cgamma associated with spinocerebellar ataxia type 14.. Ann Neurol. 2005;58:720-9",
"J. Koht, G. Stevanin, A. Durr, E. Mundwiller, A. Brice. Tallaksen CME. SCA14 in Norway, two families with autosomal dominant cerebellar ataxia and a novel mutation in the PRKCG gene.. Acta Neurologica Scandinavica. 2012;125:116-22",
"S Miura, H Nakagawara, H Kaida, M Sugita, K Noda, K Motomura, Y Ohyagi, M Ayabe, H Aizawa, M Ishibashi, T Taniwaki. Expansion of the phenotypic spectrum of SCA14 caused by the Gly128Asp mutation in PRKCG.. Clin Neurol Neurosurg. 2009;111:211-5",
"H Najmabadi, H Hu, M Garshasbi, T Zemojtel, SS Abedini, W Chen, M Hosseini, F Behjati, S Haas, P Jamali, A Zecha, M Mohseni, L Püttmann, LN Vahid, C Jensen, LA Moheb, M Bienek, F Larti, I Mueller, R Weissmann, H Darvish, K Wrogemann, V Hadavi, B Lipkowitz, S Esmaeeli-Nieh, D Wieczorek, R Kariminejad, SG Firouzabadi, M Cohen, Z Fattahi, I Rost, F Mojahedi, C Hertzberg, A Dehghan, A Rajab, MJ Banavandi, J Hoffer, M Falah, L Musante, V Kalscheuer, R Ullmann, AW Kuss, A Tzschach, K Kahrizi, HH Ropers. Deep sequencing reveals 50 novel genes for recessive cognitive disorders.. Nature. 2011;478:57-63",
"D Nolte, M Landendinger, E Schmitt, U. Müller. Spinocerebellar ataxia 14: novel mutation in exon 2 of PRKCG in a German family.. Mov Disord. 2007;22:265-7",
"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 Sailer, SW Scholz, JR Gibbs, A Tucci, JO Johnson, NW Wood, V Plagnol, H Hummerich, J Ding, D Hernandez, J Hardy, HJ Federoff, BJ Traynor, AB Singleton, H Houlden. Exome sequencing in an SCA14 family demonstrates its utility in diagnosing heterogeneous diseases.. Neurology. 2012;79:127-31",
"T Shirafuji, H Shimazaki, T Miyagi, T Ueyama, N Adachi, S Tanaka, I Hide, N Saito, N. Sakai. Spinocerebellar ataxia type 14 caused by a nonsense mutation in the PRKCG gene.. Mol Cell Neurosci. 2019;98:46-53",
"T Seki, N Adachi, Y Ono, H Mochizuki, K Hiramoto, T Amano, H Matsubayashi, M Matsumoto, H Kawakami, N Saito, N. Sakai. Mutant protein kinase Cgamma found in spinocerebellar ataxia type 14 is susceptible to aggregation and causes cell death.. J Biol Chem. 2005;280:29096-106",
"T Seki, T Shimahara, K Yamamoto, N Abe, T Amano, N Adachi, H Takahashi, K Kashiwagi, N Saito, N. Sakai. Mutant gammaPKC found in spinocerebellar ataxia type 14 induces aggregate-independent maldevelopment of dendrites in primary cultured Purkinje cells.. Neurobiol Dis. 2009;33:260-73",
"T Seki, H Takahashi, N Adachi, N Abe, T Shimahara, N Saito, N Sakai. Aggregate formation of mutant protein kinase C gamma found in spinocerebellar ataxia type 14 impairs ubiquitin-proteasome system and induces endoplasmic reticulum stress.. Eur J Neurosci. 2007;26:3126-40",
"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",
"G Stevanin, V Hahn, E Lohmann, N Bouslam, M Gouttard, C Soumphonphakdy, ML Welter, E Ollagnon-Roman, A Lemainque, M Ruberg, A Brice, A Durr. Mutation in the catalytic domain of protein kinase C gamma and extension of the phenotype associated with spinocerebellar ataxia type 14.. Arch Neurol. 2004;61:1242-8",
"H Takahashi, N Adachi, T Shirafuji, S Danno, T Ueyama, M Vendruscolo, AN Shuvaev, T Sugimoto, T Seki, D Hamada, K Irie, H Hirai, N Sakai, N Saito. Identification and characterization of PKCγ, a kinase associated with SCA14, as an amyloidogenic protein.. Hum Mol Genet. 2015;24:525-39",
"J Trzesniewski, S Altmann, L Jäger, JP Kapfhammer. Reduced Purkinje cell size is compatible with near normal morphology and function of the cerebellar cortex in a mouse model of spinocerebellar ataxia.. Exp Neurol. 2019;311:205-12",
"BP van de Warrenburg, NC Notermans, HJ Schelhaas, N van Alfen, RJ Sinke, NV Knoers, MJ Zwarts, BP Kremer. Peripheral nerve involvement in spinocerebellar ataxias.. Arch Neurol. 2004;61:257-61",
"BP van de Warrenburg, DS Verbeek, SJ Piersma, FA Hennekam, PL Pearson, NV Knoers, HP Kremer, RJ Sinke. Identification of a novel SCA14 mutation in a Dutch autosomal dominant cerebellar ataxia family.. Neurology. 2003;61:1760-5",
"J van Gaalen, S Vermeer, M van Veluw, BP van de Warrenburg, D Dooijes. A de novo SCA14 mutation in an isolated case of late-onset cerebellar ataxia.. Mov Disord. 2013;28:1902-3",
"DS Verbeek, J Goedhart, L Bruinsma, RJ Sinke, EA Reits. PKC gamma mutations in spinocerebellar ataxia type 14 affect C1 domain accessibility and kinase activity leading to aberrant MAPK signaling.. J Cell Sci. 2008;121:2339-49",
"DS Verbeek, BP Warrenburg, FA Hennekam, D Dooijes, PF Ippel, CC Verschuuren-Bemelmans, HP Kremer, RJ Sinke. Gly118Asp is a SCA14 founder mutation in the Dutch ataxia population.. Hum Genet. 2005;117:88-91",
"JE Visser, BR Bloem, BP van de Warrenburg. PRKCG mutation (SCA-14) causing a Ramsay Hunt phenotype.. Mov Disord. 2007;22:1024-6",
"MH Vlak, RJ Sinke, GM Rabelink, BP Kremer, BP van de Warrenburg. Novel PRKCG/SCA14 mutation in a Dutch spinocerebellar ataxia family: expanding the phenotype.. Mov Disord. 2006;21:1025-8",
"IM Wedding, J Koht, E Dietrichs, NI Landrø, CM Tallaksen. Cognition is only minimally impaired in Spinocerebellar ataxia type 14 (SCA14): a neuropsychological study of ten Norwegian subjects compared to intrafamilial controls and population norm.. BMC Neurol. 2013;13:186",
"S Wieczorek, L Arning, ER Gizewski, I Alheite, D Timmann. Benign SCA14 phenotype in a German patient associated with a missense mutation in exon 3 of the PRKCG gene.. Mov Disord. 2007;22:2135-6",
"MMK Wong, SD Hoekstra, J Vowles, LM Watson, G Fuller, AH Németh, SA Cowley, O Ansorge, K Talbot, EBE Becker. Neurodegeneration in SCA14 is associated with increased PKCγ kinase activity, mislocalization and aggregation.. Acta Neuropathol Commun. 2018;6:99",
"I Yabe, H Sasaki, DH Chen, WH Raskind, TD Bird, I Yamashita, S Tsuji, S Kikuchi, K Tashiro. Spinocerebellar ataxia type 14 caused by a mutation in protein kinase C gamma.. Arch Neurol. 2003;60:1749-51",
"I Yamashita, H Sasaki, I Yabe, T Fukazawa, S Nogoshi, K Komeichi, A Takada, K Shiraishi, Y Takiyama, M Nishizawa, J Kaneko, H Tanaka, S Tsuji, K. Tashiro. A novel locus for dominant cerebellar ataxia (SCA14) maps to a 10.2-cM interval flanked by D19S206 and D19S605 on chromosome 19q13.4-qter.. Ann Neurol. 2000;48:156-63"
] |
28/1/2005
|
20/2/2020
|
21/12/2005
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sca15
|
sca15
|
[
"SCA15",
"SCA15",
"SCA 15",
"Inositol 1,4,5-trisphosphate receptor type 1",
"ITPR1",
"Spinocerebellar Ataxia Type 15"
] |
Spinocerebellar Ataxia Type 15 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Elsdon Storey
|
Summary Spinocerebellar ataxia type 15 (SCA15) is characterized by slowly progressive gait and limb ataxia, often in combination with ataxic dysarthria, titubation, upper limb postural tremor, mild hyperreflexia, gaze-evoked nystagmus, and impaired vestibuloocular reflex gain. Onset is between ages seven and 72 years, usually with gait ataxia but sometimes with tremor. Affected individuals remain ambulatory for ten to 54 years after symptom onset. Mild dysphagia usually after two or more decades of symptoms has been observed in members of multiple affected families and movement-induced oscillopsia has been described in one member of an affected family. The diagnosis of SCA15 should be considered in individuals in whom the diagnoses of SCA5, SCA6, SCA8, SCA11, SCA12, SCA14, and SCA27 have been excluded by molecular genetic testing (if available) and who fulfill the clinical diagnostic criteria for SCA15. SCA15 is inherited in an autosomal dominant manner. If a parent of the proband is affected, the risk to each sib is 50%. Prenatal testing for pregnancies at increased risk is possible through laboratories offering either testing for the gene of interest or custom testing.
|
## Diagnosis
The diagnosis of spinocerebellar ataxia type 15 (SCA15) should be considered in individuals with the following findings:
Very slowly progressive ataxia (e.g., still independently ambulant after 20-30 years of symptoms)
No other neurologic signs beyond postural and kinetic tremor (which are common and may be the presenting features) and mild hyperreflexia (typically without spasticity, but occasionally with extensor plantar responses)
Family history consistent with autosomal dominant inheritance
Additional findings may include the following:
Gaze-evoked nystagmus (sometimes transient only) in approximately 80% of affected individuals
Impaired vestibuloocular reflex gain (even to the point of producing movement-induced oscillopsia in a minority) in approximately 50% of members of the two families in which it has been tested
Postural head and/or truncal tremor in a minority (probably <30%) of affected individuals
Upper-limb postural tremor that may occasionally occur early in the disease course or, rarely, be the presenting feature
Orolingual dyskinesias, perioral myokymia, and chorea (reported in one family each)
Cognitive impairment noted in two families; it is not clear that this extends beyond the mild (mainly executive) dysfunction common to most cerebellar disorders [
Note: One affected Italian individual with cognitive impairment had bifrontoparietal atrophy; however, it is not certain whether this was attributable to SCA15 or another coexistent process.
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 15
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
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
• Very slowly progressive ataxia (e.g., still independently ambulant after 20-30 years of symptoms)
• No other neurologic signs beyond postural and kinetic tremor (which are common and may be the presenting features) and mild hyperreflexia (typically without spasticity, but occasionally with extensor plantar responses)
• Family history consistent with autosomal dominant inheritance
• Gaze-evoked nystagmus (sometimes transient only) in approximately 80% of affected individuals
• Impaired vestibuloocular reflex gain (even to the point of producing movement-induced oscillopsia in a minority) in approximately 50% of members of the two families in which it has been tested
• Postural head and/or truncal tremor in a minority (probably <30%) of affected individuals
• Upper-limb postural tremor that may occasionally occur early in the disease course or, rarely, be the presenting feature
• Orolingual dyskinesias, perioral myokymia, and chorea (reported in one family each)
• Cognitive impairment noted in two families; it is not clear that this extends beyond the mild (mainly executive) dysfunction common to most cerebellar disorders [
## Clinical Diagnosis
The diagnosis of spinocerebellar ataxia type 15 (SCA15) should be considered in individuals with the following findings:
Very slowly progressive ataxia (e.g., still independently ambulant after 20-30 years of symptoms)
No other neurologic signs beyond postural and kinetic tremor (which are common and may be the presenting features) and mild hyperreflexia (typically without spasticity, but occasionally with extensor plantar responses)
Family history consistent with autosomal dominant inheritance
Additional findings may include the following:
Gaze-evoked nystagmus (sometimes transient only) in approximately 80% of affected individuals
Impaired vestibuloocular reflex gain (even to the point of producing movement-induced oscillopsia in a minority) in approximately 50% of members of the two families in which it has been tested
Postural head and/or truncal tremor in a minority (probably <30%) of affected individuals
Upper-limb postural tremor that may occasionally occur early in the disease course or, rarely, be the presenting feature
Orolingual dyskinesias, perioral myokymia, and chorea (reported in one family each)
Cognitive impairment noted in two families; it is not clear that this extends beyond the mild (mainly executive) dysfunction common to most cerebellar disorders [
Note: One affected Italian individual with cognitive impairment had bifrontoparietal atrophy; however, it is not certain whether this was attributable to SCA15 or another coexistent process.
• Very slowly progressive ataxia (e.g., still independently ambulant after 20-30 years of symptoms)
• No other neurologic signs beyond postural and kinetic tremor (which are common and may be the presenting features) and mild hyperreflexia (typically without spasticity, but occasionally with extensor plantar responses)
• Family history consistent with autosomal dominant inheritance
• Gaze-evoked nystagmus (sometimes transient only) in approximately 80% of affected individuals
• Impaired vestibuloocular reflex gain (even to the point of producing movement-induced oscillopsia in a minority) in approximately 50% of members of the two families in which it has been tested
• Postural head and/or truncal tremor in a minority (probably <30%) of affected individuals
• Upper-limb postural tremor that may occasionally occur early in the disease course or, rarely, be the presenting feature
• Orolingual dyskinesias, perioral myokymia, and chorea (reported in one family each)
• Cognitive impairment noted in two families; it is not clear that this extends beyond the mild (mainly executive) dysfunction common to most cerebellar disorders [
## Molecular Genetic Testing
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 15
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
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include a range of techniques such as quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
## Testing Strategy
## Clinical Characteristics
Clinical information on spinocerebellar ataxia type 15 (SCA15) is based on findings in 67 affected individuals from 20 families: the index pedigree (an Australian family of Anglo-Celtic descent [
Onset in all 67 affected individuals was between ages seven and 72 years. SCA15 typically presents with very slowly progressive gait ataxia, often in combination with ataxic dysarthria. Head and/or truncal tremor with or without upper-extremity tremor is seen in fewer than 30%. It may begin simultaneously with (or even occasionally precede) gait ataxia. Deterioration in handwriting, motion-induced instability (e.g., on escalators), and myoclonus were the first symptoms in one individual each.
Progression of SCA15 is notably slow. All nine affected members of the two Australian pedigrees remained independently ambulant after an average of 31 years of symptoms (range 10-54 years); of these nine, two used canes. Most of the affected members of one Japanese pedigree were ambulant 20 years after onset; in another, one affected individual required a wheelchair when assessed after 40 years of symptoms. After ten years of gait ataxia, two affected individuals from the Australian pedigree were able to perform tandem gait, but were unable to hop on one foot within a 30-cm (1 foot) square; one had minor difficulties on the half-turn. All 13 members of the French pedigrees remained independently ambulatory after an average of 22 years (range 6-43 years); of these, two with an average duration of symptoms of 42 years used unilateral supports. Eight of ten members of the German pedigrees were ambulatory after an average of nine years; of these, one used a crutch after 19 years of symptoms.
Two of nine members of the two Australian pedigrees, two of nine members of the six French pedigrees in whom it was ascertained, four of ten members of the five German pedigrees, and five of nine members of two of the Italian pedigrees in whom it was ascertained reported mild dysphagia that typically developed after two or more decades of symptoms. One Australian family member reported onset of a movement-induced oscillopsia 40 years after initial symptoms of movement-induced unsteadiness.
Life-threatening complications such as severe bulbar dysfunction have not become evident during the disease course. From the limited clinical information available, cognition does not typically appear to be affected. While cognitive impairment has been noted in two families, this may represent the mild executive dysfunction commonly seen in many cerebellar disorders.
A Japanese family with a single-nucleotide variant
The penetrance is unknown. Based on the even segregation ratio in older generations of the known SCA15 pedigrees, penetrance is likely to be high or complete in these families. The late age of onset in some cases (≤72 years) may confound attempts to establish penetrance. Apparently unaffected parents of three affected sibs were reported in one Japanese pedigree, although detailed information on the parents was not available [
First-hand information from each member of the 22 parent-offspring pairs for whom age of onset information is available [
Note: The molecular mechanism of most pathogenic variants (i.e., deletion) does not suggest that anticipation is likely.
The sole family in which SCA16 was originally described has now been shown by molecular genetic testing to have SCA15; therefore, the designation SCA16 has been subsumed by SCA15.
The designation SCA16 is currently an "empty" term, as are SCA9 and SCA24 [
Preliminary information from
In a German series of 56 families with autosomal dominant ataxias in whom the SCA conditions caused by trinucleotide repeat expansion (SCA1, SCA2, SCA3, SCA6, SCA7,
An Italian series of 60 pedigrees segregating an autosomal dominant SCA phenotype, in which testing for SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, and DRPLA was negative, reported one family with SCA15 (1.7%) [
A French series of 333 pedigrees segregating an autosomal dominant SCA phenotype, in which testing for SCA1, SCA2, SCA3,SCA 6, SCA7, SCA17, and DRPLA was negative and for which testing in some pedigrees was also negative for SCA5, SCA10, SCA11, SCA12, SCA13, SCA14, and
A Japanese series of 74 pedigrees (with at least 2 affected members) with SCA, in which SCA1, SCA2, SCA3, SCA6, SCA31, and DRPLA had been excluded, reported one pedigree with SCA15, for a rate of 1.4% [
## Clinical Description
Clinical information on spinocerebellar ataxia type 15 (SCA15) is based on findings in 67 affected individuals from 20 families: the index pedigree (an Australian family of Anglo-Celtic descent [
Onset in all 67 affected individuals was between ages seven and 72 years. SCA15 typically presents with very slowly progressive gait ataxia, often in combination with ataxic dysarthria. Head and/or truncal tremor with or without upper-extremity tremor is seen in fewer than 30%. It may begin simultaneously with (or even occasionally precede) gait ataxia. Deterioration in handwriting, motion-induced instability (e.g., on escalators), and myoclonus were the first symptoms in one individual each.
Progression of SCA15 is notably slow. All nine affected members of the two Australian pedigrees remained independently ambulant after an average of 31 years of symptoms (range 10-54 years); of these nine, two used canes. Most of the affected members of one Japanese pedigree were ambulant 20 years after onset; in another, one affected individual required a wheelchair when assessed after 40 years of symptoms. After ten years of gait ataxia, two affected individuals from the Australian pedigree were able to perform tandem gait, but were unable to hop on one foot within a 30-cm (1 foot) square; one had minor difficulties on the half-turn. All 13 members of the French pedigrees remained independently ambulatory after an average of 22 years (range 6-43 years); of these, two with an average duration of symptoms of 42 years used unilateral supports. Eight of ten members of the German pedigrees were ambulatory after an average of nine years; of these, one used a crutch after 19 years of symptoms.
Two of nine members of the two Australian pedigrees, two of nine members of the six French pedigrees in whom it was ascertained, four of ten members of the five German pedigrees, and five of nine members of two of the Italian pedigrees in whom it was ascertained reported mild dysphagia that typically developed after two or more decades of symptoms. One Australian family member reported onset of a movement-induced oscillopsia 40 years after initial symptoms of movement-induced unsteadiness.
Life-threatening complications such as severe bulbar dysfunction have not become evident during the disease course. From the limited clinical information available, cognition does not typically appear to be affected. While cognitive impairment has been noted in two families, this may represent the mild executive dysfunction commonly seen in many cerebellar disorders.
## Genotype-Phenotype Correlations
A Japanese family with a single-nucleotide variant
## Penetrance
The penetrance is unknown. Based on the even segregation ratio in older generations of the known SCA15 pedigrees, penetrance is likely to be high or complete in these families. The late age of onset in some cases (≤72 years) may confound attempts to establish penetrance. Apparently unaffected parents of three affected sibs were reported in one Japanese pedigree, although detailed information on the parents was not available [
## Anticipation
First-hand information from each member of the 22 parent-offspring pairs for whom age of onset information is available [
Note: The molecular mechanism of most pathogenic variants (i.e., deletion) does not suggest that anticipation is likely.
## Nomenclature
The sole family in which SCA16 was originally described has now been shown by molecular genetic testing to have SCA15; therefore, the designation SCA16 has been subsumed by SCA15.
The designation SCA16 is currently an "empty" term, as are SCA9 and SCA24 [
## Prevalence
Preliminary information from
In a German series of 56 families with autosomal dominant ataxias in whom the SCA conditions caused by trinucleotide repeat expansion (SCA1, SCA2, SCA3, SCA6, SCA7,
An Italian series of 60 pedigrees segregating an autosomal dominant SCA phenotype, in which testing for SCA1, SCA2, SCA3, SCA6, SCA7, SCA8, SCA10, SCA12, and DRPLA was negative, reported one family with SCA15 (1.7%) [
A French series of 333 pedigrees segregating an autosomal dominant SCA phenotype, in which testing for SCA1, SCA2, SCA3,SCA 6, SCA7, SCA17, and DRPLA was negative and for which testing in some pedigrees was also negative for SCA5, SCA10, SCA11, SCA12, SCA13, SCA14, and
A Japanese series of 74 pedigrees (with at least 2 affected members) with SCA, in which SCA1, SCA2, SCA3, SCA6, SCA31, and DRPLA had been excluded, reported one pedigree with SCA15, for a rate of 1.4% [
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
The differential diagnosis of SCA15 is that of a (relatively) pure, slowly progressive, dominantly inherited ataxia, perhaps with early tremor. SCA5,
Head tremor, if present in addition, is more strongly suggestive of SCA15 (than of the other types of inherited ataxia). The disease course is more aggressive in
The radiologic picture of SCA15 is that of a pure cerebellar atrophy, which may also be seen in SCA4, SCA5, SCA6, SCA8,
The clinical characteristics of the other hereditary ataxias can be found in
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 15 (SCA15), the following evaluations are recommended:
Clinical evaluation
MRI to determine the pattern and extent of cerebellar atrophy and confirm the absence of extracerebellar changes
Consultation with a clinical geneticist and/or genetic counselor
Education for affected individuals and their families is the cornerstone of management.
Physical and occupational therapy, as used for ataxic syndromes of any etiology, may be employed.
Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity.
To date significant dysphagia has not been an issue for individuals with SCA15; however, if significant dysphagia were to develop, a speech pathologist expert in the management of neurogenic dysphagia should be asked to help guide management.
Secondary complications are unlikely in the early years of the disease.
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
Later, risk of falls can be reduced via appropriate gait aids and home modifications; if falls are frequent, a personal alarm system may be required.
To limit the likelihood of fractures resulting from falls, bone density should be estimated and osteoporosis treated if present.
Follow up by a neurologist with consultation from physiatrists and physical and occupational therapists every two or three years is appropriate.
Because individuals with ataxic syndromes in general have abnormal sensitivity to the motor effects of alcohol, it is reasonable to limit alcohol intake to lessen the risk of falls.
See
Search
Treatment of symptomatic tremor has not been reported in SCA15. At least in the Australian pedigrees, tremor did not cause major functional disability.
• Clinical evaluation
• MRI to determine the pattern and extent of cerebellar atrophy and confirm the absence of extracerebellar changes
• Consultation with a clinical geneticist and/or genetic counselor
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 15 (SCA15), the following evaluations are recommended:
Clinical evaluation
MRI to determine the pattern and extent of cerebellar atrophy and confirm the absence of extracerebellar changes
Consultation with a clinical geneticist and/or genetic counselor
• Clinical evaluation
• MRI to determine the pattern and extent of cerebellar atrophy and confirm the absence of extracerebellar changes
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Education for affected individuals and their families is the cornerstone of management.
Physical and occupational therapy, as used for ataxic syndromes of any etiology, may be employed.
Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity.
To date significant dysphagia has not been an issue for individuals with SCA15; however, if significant dysphagia were to develop, a speech pathologist expert in the management of neurogenic dysphagia should be asked to help guide management.
## Prevention of Secondary Complications
Secondary complications are unlikely in the early years of the disease.
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
Later, risk of falls can be reduced via appropriate gait aids and home modifications; if falls are frequent, a personal alarm system may be required.
To limit the likelihood of fractures resulting from falls, bone density should be estimated and osteoporosis treated if present.
## Surveillance
Follow up by a neurologist with consultation from physiatrists and physical and occupational therapists every two or three years is appropriate.
## Agents/Circumstances to Avoid
Because individuals with ataxic syndromes in general have abnormal sensitivity to the motor effects of alcohol, it is reasonable to limit alcohol intake to lessen the risk of falls.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Other
Treatment of symptomatic tremor has not been reported in SCA15. At least in the Australian pedigrees, tremor did not cause major functional disability.
## Genetic Counseling
Spinocerebellar ataxia type 15 is inherited in an autosomal dominant manner.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Spinocerebellar ataxia type 15 is inherited in an autosomal dominant manner.
## Risk to Family Members
## 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
United Kingdom
United Kingdom
Spain
Sanford Research
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
• Spain
•
•
• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia Type 15: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 15 (
Exons 1-10 of
Exons 1-40 of
Exons 1-44 of
Exons 1-48 of
All of
A p.Pro1059Leu pathogenic variant (disturbing a highly conserved residue) has also been presumptively linked with a Japanese SCA15 pedigree [
Selected
Variants listed in the table have been provided by the author.
• Exons 1-10 of
• Exons 1-40 of
• Exons 1-44 of
• Exons 1-48 of
• All of
## Chapter Notes
Professor Storey is a neurologist to the Neurogenetics Clinics at the Alfred, and Royal Melbourne Hospitals, Melbourne, Victoria, Australia.
25 April 2024 (ma) Chapter retired: outdated
12 June 2014 (me) Comprehensive update posted live
21 April 2011 (cd) Revision: molecular genetic testing available clinically
10 December 2009 (me) Comprehensive update posted live
30 May 2006 (me) Review posted live
7 February 2006 (es) Original submission
• 25 April 2024 (ma) Chapter retired: outdated
• 12 June 2014 (me) Comprehensive update posted live
• 21 April 2011 (cd) Revision: molecular genetic testing available clinically
• 10 December 2009 (me) Comprehensive update posted live
• 30 May 2006 (me) Review posted live
• 7 February 2006 (es) Original submission
## Author Notes
Professor Storey is a neurologist to the Neurogenetics Clinics at the Alfred, and Royal Melbourne Hospitals, Melbourne, Victoria, Australia.
## Revision History
25 April 2024 (ma) Chapter retired: outdated
12 June 2014 (me) Comprehensive update posted live
21 April 2011 (cd) Revision: molecular genetic testing available clinically
10 December 2009 (me) Comprehensive update posted live
30 May 2006 (me) Review posted live
7 February 2006 (es) Original submission
• 25 April 2024 (ma) Chapter retired: outdated
• 12 June 2014 (me) Comprehensive update posted live
• 21 April 2011 (cd) Revision: molecular genetic testing available clinically
• 10 December 2009 (me) Comprehensive update posted live
• 30 May 2006 (me) Review posted live
• 7 February 2006 (es) Original submission
## References
## Literature Cited
|
[] |
30/5/2006
|
12/6/2014
|
21/4/2011
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sca17
|
sca17
|
[
"Huntington Disease-Like 4",
"SCA17",
"SCA17",
"Huntington Disease-Like 4",
"TATA-box-binding protein",
"TBP",
"Spinocerebellar Ataxia Type 17"
] |
Spinocerebellar Ataxia Type 17
|
Yasuko Toyoshima, Osamu Onodera, Mitsunori Yamada, Shoji Tsuji, Hitoshi Takahashi
|
Summary Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia, dementia, and involuntary movements, including chorea and dystonia. Psychiatric symptoms, pyramidal signs, and rigidity are common. The age of onset ranges from three to 55 years. Individuals with full-penetrance alleles develop neurologic and/or psychiatric symptoms by age 50 years. Ataxia and psychiatric abnormalities are frequently the initial findings, followed by involuntary movement, parkinsonism, dementia, and pyramidal signs. Brain MRI shows variable atrophy of the cerebrum, brain stem, and cerebellum. The clinical features correlate with the length of the polyglutamine expansion but are not absolutely predictive of the clinical course. The diagnosis of SCA17 is established in a proband by identification of an abnormal CAG/CAA repeat expansion in SCA17 is inherited in an autosomal dominant manner. Offspring of affected individuals are at a 50% risk of inheriting the expanded
|
## Diagnosis
Spinocerebellar ataxia type 17 (SCA17)
Ataxia
Dementia
Involuntary movements – e.g., chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia)
Psychiatric symptoms
The diagnosis of SCA17
The CAA CAG CAA interruption between (CAG)
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 17
See
See
PCR amplification will likely detect CAG/CAA repeat expansions of 66 or fewer.
• Ataxia
• Dementia
• Involuntary movements – e.g., chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia)
• Psychiatric symptoms
• For an introduction to multigene panels click
## Suggestive Findings
Spinocerebellar ataxia type 17 (SCA17)
Ataxia
Dementia
Involuntary movements – e.g., chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia)
Psychiatric symptoms
• Ataxia
• Dementia
• Involuntary movements – e.g., chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia)
• Psychiatric symptoms
## Establishing the Diagnosis
The diagnosis of SCA17
The CAA CAG CAA interruption between (CAG)
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 17
See
See
PCR amplification will likely detect CAG/CAA repeat expansions of 66 or fewer.
• For an introduction to multigene panels click
## Clinical Characteristics
Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia (95%), dementia (~90%), and involuntary movements (~70%), including chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia) [
Onset ranges from age three to 75 years (mean: 34.6 years) [
Although the disease course is variable, ataxia and psychiatric abnormalities are frequently the initial findings, followed by involuntary movement, parkinsonism, dementia, and pyramidal signs.
Immunohistochemistry for the expanded polyglutamine (polyQ) tracts shows diffuse labeling of the neuronal nucleoplasm.
Note: Intranuclear inclusions are a much less common finding than diffuse labeling. No labeling is detectable in the cytoplasm or in the neuropil. Glial cell involvement is occasionally seen.
In individuals who are homozygous for an expanded allele in the full-penetrance range, nuclear polyQ pathology involves other CNS regions including the cerebral cortex, thalamus, and brain stem [
Frequency of Clinical Features in Spinocerebellar Ataxia Type 17 Correlated with
DTRs = deep tendon reflexes
Four homozygous individuals and one compound heterozygous individual have been reported [
The penetrance of alleles of 41-44 repeats is estimated at 50% and the penetrance of alleles of 45-48 repeats is estimated at greater than 80% [
Individuals with 41 CAA/CAG repeats developed ataxia and mild dementia [
Four individuals with 42 CAG/CAA repeats developed a relatively benign phenotype consisting of mild gait ataxia, dysarthria, and dysdiadochokinesia [
An individual with 43 CAG/CAA repeats developed ataxia with dementia at age 52 years [
An individual with 46 CAG/CAA repeats developed symptoms at age 75 years, the latest onset observed to date [
Asymptomatic elderly individuals with 43-49 CAG/CAA repeats have also been reported [
Heterozygous
Instability of the
The phenomenon termed anticipation, a trend toward an earlier age at onset and more severe disease manifestations in offspring of an affected individual, is infrequently documented in families with SCA17. In addition, because of low penetrance of the intermediate alleles (41-48 repeats), the age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be predicted by family history or size of expansion.
Fewer than 100 families with SCA17 have been reported.
The prevalence of SCA17 in the Japanese population is estimated at 0.47:1,000,000. SCA17 accounts for approximately 0.3% of autosomal dominant SCA [
The minimum prevalence of SCA17 in northeast England is 0.16:100,000 [
In a study of the Yugoslav population, none of the 115 individuals with autosomal dominant cerebellar ataxia or simplex cases of adult-onset ataxia had SCA17 [
The prevalence of SCA17 may be underestimated because some individuals with SCA17 have a phenotype similar to that of
• Individuals with 41 CAA/CAG repeats developed ataxia and mild dementia [
• Four individuals with 42 CAG/CAA repeats developed a relatively benign phenotype consisting of mild gait ataxia, dysarthria, and dysdiadochokinesia [
• An individual with 43 CAG/CAA repeats developed ataxia with dementia at age 52 years [
• An individual with 46 CAG/CAA repeats developed symptoms at age 75 years, the latest onset observed to date [
• Asymptomatic elderly individuals with 43-49 CAG/CAA repeats have also been reported [
• Heterozygous
## Clinical Description
Spinocerebellar ataxia type 17 (SCA17) is characterized by ataxia (95%), dementia (~90%), and involuntary movements (~70%), including chorea and dystonia (blepharospasm, torticollis, writer's cramp, foot dystonia) [
Onset ranges from age three to 75 years (mean: 34.6 years) [
Although the disease course is variable, ataxia and psychiatric abnormalities are frequently the initial findings, followed by involuntary movement, parkinsonism, dementia, and pyramidal signs.
Immunohistochemistry for the expanded polyglutamine (polyQ) tracts shows diffuse labeling of the neuronal nucleoplasm.
Note: Intranuclear inclusions are a much less common finding than diffuse labeling. No labeling is detectable in the cytoplasm or in the neuropil. Glial cell involvement is occasionally seen.
In individuals who are homozygous for an expanded allele in the full-penetrance range, nuclear polyQ pathology involves other CNS regions including the cerebral cortex, thalamus, and brain stem [
## Genotype-Phenotype Correlations
Frequency of Clinical Features in Spinocerebellar Ataxia Type 17 Correlated with
DTRs = deep tendon reflexes
Four homozygous individuals and one compound heterozygous individual have been reported [
## Heterozygotes
Frequency of Clinical Features in Spinocerebellar Ataxia Type 17 Correlated with
DTRs = deep tendon reflexes
## Homozygotes
Four homozygous individuals and one compound heterozygous individual have been reported [
## Penetrance
The penetrance of alleles of 41-44 repeats is estimated at 50% and the penetrance of alleles of 45-48 repeats is estimated at greater than 80% [
Individuals with 41 CAA/CAG repeats developed ataxia and mild dementia [
Four individuals with 42 CAG/CAA repeats developed a relatively benign phenotype consisting of mild gait ataxia, dysarthria, and dysdiadochokinesia [
An individual with 43 CAG/CAA repeats developed ataxia with dementia at age 52 years [
An individual with 46 CAG/CAA repeats developed symptoms at age 75 years, the latest onset observed to date [
Asymptomatic elderly individuals with 43-49 CAG/CAA repeats have also been reported [
Heterozygous
• Individuals with 41 CAA/CAG repeats developed ataxia and mild dementia [
• Four individuals with 42 CAG/CAA repeats developed a relatively benign phenotype consisting of mild gait ataxia, dysarthria, and dysdiadochokinesia [
• An individual with 43 CAG/CAA repeats developed ataxia with dementia at age 52 years [
• An individual with 46 CAG/CAA repeats developed symptoms at age 75 years, the latest onset observed to date [
• Asymptomatic elderly individuals with 43-49 CAG/CAA repeats have also been reported [
• Heterozygous
## Nomenclature
## Anticipation
Instability of the
The phenomenon termed anticipation, a trend toward an earlier age at onset and more severe disease manifestations in offspring of an affected individual, is infrequently documented in families with SCA17. In addition, because of low penetrance of the intermediate alleles (41-48 repeats), the age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be predicted by family history or size of expansion.
## Prevalence
Fewer than 100 families with SCA17 have been reported.
The prevalence of SCA17 in the Japanese population is estimated at 0.47:1,000,000. SCA17 accounts for approximately 0.3% of autosomal dominant SCA [
The minimum prevalence of SCA17 in northeast England is 0.16:100,000 [
In a study of the Yugoslav population, none of the 115 individuals with autosomal dominant cerebellar ataxia or simplex cases of adult-onset ataxia had SCA17 [
The prevalence of SCA17 may be underestimated because some individuals with SCA17 have a phenotype similar to that of
## Genetically Related (Allelic) Disorders
No other phenotypes are known to be associated with germline pathogenic variants in
## Differential Diagnosis
Inherited Conditions to Consider in the Differential Diagnosis of Spinocerebellar Ataxia Type 17 (SCA17)
AD = autosomal dominant; AR = autosomal recessive; CK = creatine kinase; DiffDx = differential diagnosis; MOI = mode of inheritance; XL = X-linked
Huntington disease-like 1 is caused by a specific pathogenic variant (8 extra octapeptide repeats) in the prion protein gene,
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 17 (SCA17), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Neuropsychological testing to evaluate for dementia and/or psychiatric disturbance
Brain MRI to evaluate areas and degree of atrophy
Neurology consultation, if not completed prior to initial diagnosis
Consultation with a clinical geneticist and/or genetic counselor
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 17
The side effects of psychotropic medications and ASMs (e.g., depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dyskinesia) can be major secondary complications in persons with SCA17. For some individuals, the side effects of certain therapeutics may be worse than the symptoms of the disease; such individuals may benefit from total or intermittent discontinuation of the treatment or reduction in dose.
Affected individuals should be followed annually or semiannually by a neurologist or more frequently if symptoms are progressing rapidly, as may happen in the advanced stages [
Agents with sedative/hypnotic properties, such as ethanol or certain medications, may markedly increase incoordination.
See
Search
• Neuropsychological testing to evaluate for dementia and/or psychiatric disturbance
• Brain MRI to evaluate areas and degree of atrophy
• Neurology consultation, if not completed prior to initial diagnosis
• Consultation with a clinical geneticist and/or genetic counselor
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 17 (SCA17), the following evaluations (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Neuropsychological testing to evaluate for dementia and/or psychiatric disturbance
Brain MRI to evaluate areas and degree of atrophy
Neurology consultation, if not completed prior to initial diagnosis
Consultation with a clinical geneticist and/or genetic counselor
• Neuropsychological testing to evaluate for dementia and/or psychiatric disturbance
• Brain MRI to evaluate areas and degree of atrophy
• Neurology consultation, if not completed prior to initial diagnosis
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 17
## Prevention of Secondary Complications
The side effects of psychotropic medications and ASMs (e.g., depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dyskinesia) can be major secondary complications in persons with SCA17. For some individuals, the side effects of certain therapeutics may be worse than the symptoms of the disease; such individuals may benefit from total or intermittent discontinuation of the treatment or reduction in dose.
## Surveillance
Affected individuals should be followed annually or semiannually by a neurologist or more frequently if symptoms are progressing rapidly, as may happen in the advanced stages [
## Agents/Circumstances to Avoid
Agents with sedative/hypnotic properties, such as ethanol or certain medications, may markedly increase incoordination.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Spinocerebellar ataxia type 17 (SCA17) is inherited in an autosomal dominant manner.
Note: A novel pathomechanism, referred to as digenic
Approximately 50% of individuals diagnosed with SCA17 have an affected parent.
A proband with SCA17 may have the disorder as a result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If an expansion (>40 CAG/CAA repeats) of
The family history of some individuals diagnosed with SCA17 may appear to be negative because of failure to recognize the disorder in family members due to its extremely variable phenotype, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
* Based on the family history of the 59 reported families with affected individuals [
If one of the parents of the proband has an expanded
If an expansion (>40 CAG/CAA repeats) of
If the parents have not been tested for the expanded
Each child of an individual with SCA17 has a 50% chance of inheriting the expanded
The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be precisely predicted by family history or size of expansion.
Compared with other SCA subtypes caused by expanded trinucleotide repeats, anticipation is rare in SCA17 because CAA interruptions within 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 molecular diagnosis of SCA17 has been confirmed in an affected family member. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
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 SCA17, it is appropriate to consider testing of symptomatic individuals regardless of age.
Once a diagnosis of SCA17 has been established by molecular genetic testing in an affected family member, prenatal and preimplantation genetic testing for SCA17 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.
• Approximately 50% of individuals diagnosed with SCA17 have an affected parent.
• A proband with SCA17 may have the disorder as a result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If an expansion (>40 CAG/CAA repeats) of
• The family history of some individuals diagnosed with SCA17 may appear to be negative because of failure to recognize the disorder in family members due to its extremely variable phenotype, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If one of the parents of the proband has an expanded
• If an expansion (>40 CAG/CAA repeats) of
• If the parents have not been tested for the expanded
• Each child of an individual with SCA17 has a 50% chance of inheriting the expanded
• The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be precisely predicted by family history or size of expansion.
• Compared with other SCA subtypes caused by expanded trinucleotide repeats, anticipation is rare in SCA17 because CAA interruptions within 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 molecular diagnosis of SCA17 has been confirmed in an affected family member. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• 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
Spinocerebellar ataxia type 17 (SCA17) is inherited in an autosomal dominant manner.
Note: A novel pathomechanism, referred to as digenic
## Risk to Family Members
Approximately 50% of individuals diagnosed with SCA17 have an affected parent.
A proband with SCA17 may have the disorder as a result of a
Molecular genetic testing is recommended for the parents of a proband with an apparent
If an expansion (>40 CAG/CAA repeats) of
The family history of some individuals diagnosed with SCA17 may appear to be negative because of failure to recognize the disorder in family members due to its extremely variable phenotype, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
* Based on the family history of the 59 reported families with affected individuals [
If one of the parents of the proband has an expanded
If an expansion (>40 CAG/CAA repeats) of
If the parents have not been tested for the expanded
Each child of an individual with SCA17 has a 50% chance of inheriting the expanded
The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be precisely predicted by family history or size of expansion.
Compared with other SCA subtypes caused by expanded trinucleotide repeats, anticipation is rare in SCA17 because CAA interruptions within the
• Approximately 50% of individuals diagnosed with SCA17 have an affected parent.
• A proband with SCA17 may have the disorder as a result of a
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• If an expansion (>40 CAG/CAA repeats) of
• The family history of some individuals diagnosed with SCA17 may appear to be negative because of failure to recognize the disorder in family members due to its extremely variable phenotype, early death of the parent before the onset of symptoms, late onset of the disease in the affected parent, or reduced penetrance in a parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If one of the parents of the proband has an expanded
• If an expansion (>40 CAG/CAA repeats) of
• If the parents have not been tested for the expanded
• Each child of an individual with SCA17 has a 50% chance of inheriting the expanded
• The age of onset, severity, specific symptoms, and progression of the disease are variable and cannot be precisely predicted by family history or size of expansion.
• Compared with other SCA subtypes caused by expanded trinucleotide repeats, anticipation is rare in SCA17 because CAA interruptions within 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 molecular diagnosis of SCA17 has been confirmed in an affected family member. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
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 SCA17, 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 molecular diagnosis of SCA17 has been confirmed in an affected family member. Such testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• 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 a diagnosis of SCA17 has been established by molecular genetic testing in an affected family member, prenatal and preimplantation genetic testing for SCA17 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
United Kingdom
United Kingdom
Spain
Sanford Research
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• United Kingdom
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## Molecular Genetics
Spinocerebellar Ataxia Type 17: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 17 (
TATA-box-binding protein (TBP) is an important general transcription initiation factor and is the DNA-binding subunit of RNA polymerase II transcription factor D, the multi-subunit complex crucial for the expression of most genes. TBP has a long tract of glutamines in the N-terminus. This region is thought to modulate the DNA binding activity of the C terminus, which affects the rate of transcription complex formation and initiation of transcription.
Unknown, but the contiguous tract of polygutamine encoded by the pathogenic expanded
Because TBP is a fundamental transcription factor expressed ubiquitously in all organs, including the CNS, the question of whether loss of TBP function plays a role in the pathogenesis of spinocerebellar ataxia Type 17 (SCA17) remains to be addressed. In a homozygote, however, no abnormality was observed in growth, and pathologic examination showed no specific changes in the visceral organs [
The trinucleotide CAG repeats, sometimes interrupted by CAA repeats, are in
The molecular genetic testing laboratory most commonly reports the number (length) of trinucleotide repeats for each
• Unknown, but the contiguous tract of polygutamine encoded by the pathogenic expanded
• Because TBP is a fundamental transcription factor expressed ubiquitously in all organs, including the CNS, the question of whether loss of TBP function plays a role in the pathogenesis of spinocerebellar ataxia Type 17 (SCA17) remains to be addressed. In a homozygote, however, no abnormality was observed in growth, and pathologic examination showed no specific changes in the visceral organs [
• The trinucleotide CAG repeats, sometimes interrupted by CAA repeats, are in
• The molecular genetic testing laboratory most commonly reports the number (length) of trinucleotide repeats for each
## Molecular Pathogenesis
TATA-box-binding protein (TBP) is an important general transcription initiation factor and is the DNA-binding subunit of RNA polymerase II transcription factor D, the multi-subunit complex crucial for the expression of most genes. TBP has a long tract of glutamines in the N-terminus. This region is thought to modulate the DNA binding activity of the C terminus, which affects the rate of transcription complex formation and initiation of transcription.
Unknown, but the contiguous tract of polygutamine encoded by the pathogenic expanded
Because TBP is a fundamental transcription factor expressed ubiquitously in all organs, including the CNS, the question of whether loss of TBP function plays a role in the pathogenesis of spinocerebellar ataxia Type 17 (SCA17) remains to be addressed. In a homozygote, however, no abnormality was observed in growth, and pathologic examination showed no specific changes in the visceral organs [
The trinucleotide CAG repeats, sometimes interrupted by CAA repeats, are in
The molecular genetic testing laboratory most commonly reports the number (length) of trinucleotide repeats for each
• Unknown, but the contiguous tract of polygutamine encoded by the pathogenic expanded
• Because TBP is a fundamental transcription factor expressed ubiquitously in all organs, including the CNS, the question of whether loss of TBP function plays a role in the pathogenesis of spinocerebellar ataxia Type 17 (SCA17) remains to be addressed. In a homozygote, however, no abnormality was observed in growth, and pathologic examination showed no specific changes in the visceral organs [
• The trinucleotide CAG repeats, sometimes interrupted by CAA repeats, are in
• The molecular genetic testing laboratory most commonly reports the number (length) of trinucleotide repeats for each
## Chapter Notes
28 July 2022 (sw) Revision: novel pathomechanism suggested: digenic
12 September 2019 (sw) Comprehensive update posted live
17 May 2012 (me) Comprehensive update posted live
1 August 2007 (me) Comprehensive update posted live
29 March 2005 (me) Review posted live
24 August 2004 (yt) Original submission
• 28 July 2022 (sw) Revision: novel pathomechanism suggested: digenic
• 12 September 2019 (sw) Comprehensive update posted live
• 17 May 2012 (me) Comprehensive update posted live
• 1 August 2007 (me) Comprehensive update posted live
• 29 March 2005 (me) Review posted live
• 24 August 2004 (yt) Original submission
## Revision History
28 July 2022 (sw) Revision: novel pathomechanism suggested: digenic
12 September 2019 (sw) Comprehensive update posted live
17 May 2012 (me) Comprehensive update posted live
1 August 2007 (me) Comprehensive update posted live
29 March 2005 (me) Review posted live
24 August 2004 (yt) Original submission
• 28 July 2022 (sw) Revision: novel pathomechanism suggested: digenic
• 12 September 2019 (sw) Comprehensive update posted live
• 17 May 2012 (me) Comprehensive update posted live
• 1 August 2007 (me) Comprehensive update posted live
• 29 March 2005 (me) Review posted live
• 24 August 2004 (yt) Original submission
## References
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Published Guidelines / Consensus Statements
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Literature Cited
Number of CAG/CAA repeats versus age of individuals with SCA17
The clinical features in SCA17 depend on the length of CAG/CAA repeats. The clinical features reported in affected individuals are denoted by letter. For example, A-E denotes affected individuals who have ataxia with parkinsonism.
A = ataxia
D = dementia or psychiatric symptoms
P = pyramidal signs
E = parkinsonism or involuntary movement
For references, see Genotype-Phenotype Correlations,
Correlation between age at onset and length of CAG/CAA repeat in individuals with SCA17
For references, see
|
[
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"RR Hire, SM Katrak, S Vadya, K Radhakrishnan, M Seshadri. Spinocerebellar ataxia type 17 in Indian patients: two cases of homozygous expansions.. Clin Genet 2011;80:472-7",
"JY Kim, SY Kim, JM Kim, YK Kim, KY Yoon, JY Kim. Spinocerebellar ataxia type 17 mutation as a causative and susceptibility gene in parkinsonism.. Neurology 2009;72:1385-9",
"R Koide, S Kobayashi, T Shimohata, T Ikeuchi, M Maruyama, M Saito, M Yamada, H Takahashi, S Tsuji. A neurological disease caused by an expanded CAG trinucleotide repeat in the TATA-binding protein gene: a new polyglutamine disease?. Hum Mol Genet 1999;8:2047-53",
"JL Laplanche, KH Hachimi, I Durieux, P Thuillet, L Defebvre, N Delasnerie-Lauprêtre, K Peoc'h, JF Foncin, A Destée. Prominent psychiatric features and early onset in an inherited prion disease with a new insertional mutation in the prion protein gene.. Brain. 1999;122:2375-86",
"K Lasek, R Lencer, C Gaser, J Hagenah, U Walter, A Wolters, N Kock, S Steinlechner, M Nagel, C Zühlke, MF Nitschke, K Brockmann, C Klein, A Rolfs, F Binkofski. Morphological basis for the spectrum of clinical deficits in spinocerebellar ataxia 17 (SCA17).. Brain 2006;129:2341-52",
"S Magri, L Nanetti, C Gellera, E Sarto, E Rizzo, A Mongelli, B Ricci, R Fancellu, L Sambati, P Cortelli, A Brusco, MG Bruzzone, C Mariotti, D Di Bella, F Taroni. Digenic inheritance of STUB1 variants and TBP polyglutamine expansions explains the incomplete penetrance of SCA17 and SCA48.. Genet Med. 2022;24:29-40",
"F Maltecca, A Filla, I Castaldo, G Coppola, NA Fragassi, M Carella, A Bruni, S Cocozza, G Casari, A Servadio, G De Michele. Intergenerational instability and marked anticipation in SCA-17.. Neurology 2003;61:1441-3",
"RL Margolis, E O'Hearn, A Rosenblatt, V Willour, SE Holmes, ML Franz, C Callahan, HS Hwang, JC Troncoso, CA Ross. A disorder similar to Huntington's disease is associated with a novel CAG repeat expansion.. Ann Neurol. 2001;50:373-80",
"C Mariotti, D Alpini, R Fancellu, P Soliveri, M Grisoli, S Ravaglia, C Lovati, V Fetoni, G Giaccone, A Castucci, F Taroni, C Gellera, S Di Donato. Spinocerebellar ataxia type 17 (SCA 17): oculomotor phenotype and clinical characterization of 15 Italian patients.. J Neurol 2007;254:1538-46",
"H Maruyama, Y Izumi, H Morino, M Oda, H Toji, S Nakamura, H Kawakami. Difference in disease-free survival curve and regional distribution according to subtype of spinocerebellar ataxia: a study of 1,286 Japanese patients.. Am J Med Genet 2002;114:578-83",
"RC Moore, F Xiang, J Monaghan, D Han, Z Zhang, L Edström, M Anvret, SB Prusiner. Huntington disease phenocopy is a familial prion disease.. Am J Hum Genet. 2001;69:1385-8",
"K Nakamura, SY Jeong, T Uchihara, M Anno, K Nagashima, T Nagashima, S Ikeda, S Tsuji, I Kanazawa. SCA17, a novel autosomal dominant cerebellar ataxia caused by an expanded polyglutamine in TATA-binding protein.. Hum Mol Genet 2001;10:1441-8",
"A Nanda, SA Jackson, JD Schwankhaus, WS Metzer. Case of spinocerebellar ataxia type 17 (SCA 17) associated with only 41 repeats of the TATA-binding protein (TBP) gene.. Mov Disord 2007;22:436",
"TT Nielsen, S Mardosiene, A Lokkegaard, J Stokholm, S Ehrenfels, S Bech, L Friberg, JK Nielsen, JE Nielsen. Severe and rapidly progressing cognitive phenotype in a SCA17-family with only marginally expanded CAG/CAA repeats in the TATA-box binding protein gene: a case report.. BMC Neurol 2012;12:73-7",
"D Nolte, E Sobanski, A Wissen, JU Regula, C Lichy, U Müller. Spinocerebellar ataxia type 17 associated with an expansion of 42 glutamine residues in TATA-box binding protein gene.. J Neurol Neurosurg Psychiatry. 2010;81:1396-9",
"M Oda, H Maruyama, O Komure, H Morino, H Terasawa, Y Izumi, T Imamura, M Yasuda, K Ichikawa, M Ogawa, M Matsumoto, H Kawakami. Possible reduced penetrance of expansion of 44 to 47 CAG/CAA repeats in the TATA-binding protein gene in spinocerebellar ataxia type 17.. Arch Neurol 2004;61:209-12",
"H Park, BS Jeon, JH Shin, SH Park. A patient with 41 CAG repeats in SCA17 presenting with parkinsonism and chorea.. Parkinsonism Relat Disord. 2016;22:106-7",
"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",
"MC Reis, J Patrun, N Ackl, P Winter, M Scheifele, A Danek, D Nolte. A severe dementia syndrome caused by intron retention and cryptic splice site activation in STUB1 and exacerbated by TBP repeat expansions.. Front Mol Neurosci. 2022;15",
"A Rolfs, AH Koeppen, I Bauer, P Bauer, S Buhlmann, H Topka, L Schols, O Riess. Clinical features and neuropathology of autosomal dominant spinocerebellar ataxia (SCA17).. Ann Neurol 2003;54:367-75",
"A Shatunov, EA Fridman, FI Pagan, J Leib, A Singleton, M Hallett, LG Goldfarb. Small de novo duplication in the repeat region of the TATA-box-binding protein gene manifest with a phenotype similar to variant Creutzfeldt-Jakob disease.. Clin Genet 2004;66:496-501",
"I Silveira, C Miranda, L Guimaraes, MC Moreira, I Alonso, P Mendonca, A Ferro, J Pinto-Basto, J Coelho, F Ferreirinha, J Poirier, E Parreira, J Vale, C Januario, C Barbot, A Tuna, J Barros, R Koide, S Tsuji, SE Holmes, RL Margolis, L Jardim, M Pandolfo, P Coutinho, J Sequeiros. Trinucleotide repeats in 202 families with ataxia: a small expanded (CAG)n allele at the SCA17 locus.. Arch Neurol 2002;59:623-9",
"G Stevanin, A Brice. Spinocerebellar ataxia 17 (SCA 17) and Huntington’s disease-like 4 (HDL4).. Cerebellum 2008;7:170-8",
"G Stevanin, H Fujigasaki, AS Lebre, A Camuzat, C Jeannequin, C Dode, J Takahashi, C San, R Bellance, A Brice, A Durr. Huntington's disease-like phenotype due to trinucleotide repeat expansions in the TBP and JPH3 genes.. Brain 2003;126:1599-603",
"SA Schneider, RH Walker, K Bhatia. The Huntington’s disease-like syndromes: what to consider in patients with a negative Huntington’s disease gene test.. Nat Clin Pract Neurol 2007;3:517-25",
"Y Toyoshima, H Takahashi. Spinocerebellar ataxia type 17 (SCA17).. Adv Exp Med Biol. 2018;1049:219-31",
"Y Toyoshima, M Yamada, O Onodera, M Shimohata, C Inenaga, N Fujita, M Morita, S Tsuji, H Takahashi. SCA 17 homozygote showing Huntington's disease-like phenotype.. Ann Neurol 2004;55:281-6",
"YR Wu, HC Fung, GJ Lee-Chen, K Gwinn-Hardy, LS Ro, ST Chen, HM Hsieh-Li, HY Lin, CY Lin, SN Li, CM Chen. Analysis of polyglutamine-coding repeats in the TATA-binding protein in different neurodegenerative diseases.. J Neural Transm. 2005;112:539-46",
"F Xiang, EW Almqvist, M Huq, A Lundin, MR Hayden, L Edstrom, M Anvret, Z Zhang. A Huntington disease-like neurodegenerative disorder maps to chromosome 20p.. Am J Hum Genet 1998;63:1431-8",
"C Zühlke, A Dalski, E Schwinger, U Finckh. Spinocerebellar ataxia type 17: report of a family with reduced penetrance of an unstable Gln49 TBP allele, haplotype analysis supporting a founder effect for unstable alleles and comparative analysis of SCA17 genotypes.. BMC Med Genet 2005;6:27",
"C Zühlke, U Gehlken, Y Hellenbroich, E Schwinger, K Bürk. Phenotypical variability of expanded alleles in the TATA-binding protein gene. Reduced penetrance in SCA17?. J Neurol 2003a;250:161-3",
"C Zühlke, Y Hellenbroich, A Dalski, N Kononowa, J Hagenah, P Vieregge, O Riess, C Klein, E Schwinger. Different types of repeat expansion in the TATA-binding protein gene are associated with a new form of inherited ataxia.. Eur J Hum Genet 2001;9:160-4",
"CH Zühlke, M Spranger, S Spranger, R Voigt, M Lanz, U Gehlken, F Hinrichs, E Schwinger. SCA17 caused by homozygous repeat expansion in TBP due to partial isodisomy 6.. Eur J Hum Genet 2003b;11:629-32"
] |
29/3/2005
|
12/9/2019
|
28/7/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sca2
|
sca2
|
[
"SCA2",
"SCA 2",
"SCA2",
"Ataxin-2",
"ATXN2",
"Spinocerebellar Ataxia Type 2"
] |
Spinocerebellar Ataxia Type 2
|
Stefan M Pulst
|
Summary Spinocerebellar ataxia type 2 (SCA2) is characterized by progressive cerebellar ataxia, including nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis or parkinsonism. Pyramidal findings are present; deep tendon reflexes are brisk early on and absent later in the course. Age of onset is typically in the fourth decade with a ten- to 15-year disease duration. The diagnosis of SCA2 rests on the use of molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in SCA2 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting the causative CAG trinucleotide repeat expansion. The repeat may expand significantly, especially when transmitted by the father. Prenatal testing for a pregnancy at increased risk is possible if the diagnosis has been established by molecular genetic testing in an affected family member.
|
## Diagnosis
Spinocerebellar ataxia type 2 (SCA2)
Slowly progressive ataxia and dysarthria
Nystagmus and slow saccadic eye movements
Family history consistent with autosomal dominant inheritance
The diagnosis of SCA2
Note: Interruption of a CAG expanded allele by a CAA repeat does not mitigate the pathogenicity of the repeat size because both CAG and CAA code for glutamine [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in SCA2
See
See
Detects abnormal number of CAG trinucleotide repeats. PCR amplification detects smaller CAG trinucleotide repeat expansions up to ~100 repeats. Southern blotting is required to detect highly expanded CAG trinucleotide repeat expansions (>100 repeats) and may be indicated in symptomatic infants and children [
Note: Testing individuals with a positive family history of ataxia has a much higher yield than testing individuals with ataxia without an obvious family history.
In the series reported by
In the series reported by
• Slowly progressive ataxia and dysarthria
• Nystagmus and slow saccadic eye movements
• Family history consistent with autosomal dominant inheritance
• For an introduction to multigene panels click
• In the series reported by
• In the series reported by
## Suggestive Findings
Spinocerebellar ataxia type 2 (SCA2)
Slowly progressive ataxia and dysarthria
Nystagmus and slow saccadic eye movements
Family history consistent with autosomal dominant inheritance
• Slowly progressive ataxia and dysarthria
• Nystagmus and slow saccadic eye movements
• Family history consistent with autosomal dominant inheritance
## Establishing the Diagnosis
The diagnosis of SCA2
Note: Interruption of a CAG expanded allele by a CAA repeat does not mitigate the pathogenicity of the repeat size because both CAG and CAA code for glutamine [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in SCA2
See
See
Detects abnormal number of CAG trinucleotide repeats. PCR amplification detects smaller CAG trinucleotide repeat expansions up to ~100 repeats. Southern blotting is required to detect highly expanded CAG trinucleotide repeat expansions (>100 repeats) and may be indicated in symptomatic infants and children [
Note: Testing individuals with a positive family history of ataxia has a much higher yield than testing individuals with ataxia without an obvious family history.
In the series reported by
In the series reported by
• For an introduction to multigene panels click
• In the series reported by
• In the series reported by
## Clinical Characteristics
Spinocerebellar ataxia type 2 (SCA2) is characterized by slowly progressive ataxia and dysarthria associated with the ocular findings of nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis. Tendon reflexes are brisk during the first years of life, but absent later. Mean age of onset is typically in the fourth decade with a ten- to 15-year disease duration. The disease is more rapidly progressive when onset occurs before age 20 years.
In the original study from Cuba, the earliest symptoms included gait ataxia often accompanied by leg cramps [
In individuals with molecularly confirmed
Similar findings were also reported by
An SCA2 phenotype that includes L-dopa-responsive parkinsonism has been reported [
In addition,
An affected individual with white matter pathology has been described [
Nerve biopsy has shown moderate loss of large myelinated fibers [
The widest range of age of onset is observed among individuals with fewer than 40 CAG repeats. Some individuals with alleles of 33 and 34 repeats have had onset after age 60 years. In one study, the presence of 37 repeats was associated with ages of onset ranging from 20 to 60 years [
For larger repeat sizes, the variability in age of onset is less; repeat sizes greater than 45 are almost always associated with disease onset before age 20 years [
Homozygosity for expanded
See
Anticipation (i.e., an increase in the severity of the phenotype and earlier age of onset in later generations) has been observed in SCA2. The tendency of the
Paternal transmission of alleles with full penetrance or reduced penetrance is most likely to demonstrate meiotic instability and result in anticipation, although large expansions can also be seen in maternally inherited alleles [
Terms used in the past for SCA2 and other hereditary ataxias include Marie's ataxia, OPCA, and
In the Baylor College of Medicine ataxia clinic, SCA2 was the most common ADCA (18%) [
In a large series from several ataxia clinics in Germany, SCA2 represented 14% of ADCA pedigrees [
SCA2 is the most common type of ADCA in Korea [
• The widest range of age of onset is observed among individuals with fewer than 40 CAG repeats. Some individuals with alleles of 33 and 34 repeats have had onset after age 60 years. In one study, the presence of 37 repeats was associated with ages of onset ranging from 20 to 60 years [
• For larger repeat sizes, the variability in age of onset is less; repeat sizes greater than 45 are almost always associated with disease onset before age 20 years [
## Clinical Description
Spinocerebellar ataxia type 2 (SCA2) is characterized by slowly progressive ataxia and dysarthria associated with the ocular findings of nystagmus, slow saccadic eye movements, and in some individuals, ophthalmoparesis. Tendon reflexes are brisk during the first years of life, but absent later. Mean age of onset is typically in the fourth decade with a ten- to 15-year disease duration. The disease is more rapidly progressive when onset occurs before age 20 years.
In the original study from Cuba, the earliest symptoms included gait ataxia often accompanied by leg cramps [
In individuals with molecularly confirmed
Similar findings were also reported by
An SCA2 phenotype that includes L-dopa-responsive parkinsonism has been reported [
In addition,
An affected individual with white matter pathology has been described [
Nerve biopsy has shown moderate loss of large myelinated fibers [
## Genotype-Phenotype Correlations
The widest range of age of onset is observed among individuals with fewer than 40 CAG repeats. Some individuals with alleles of 33 and 34 repeats have had onset after age 60 years. In one study, the presence of 37 repeats was associated with ages of onset ranging from 20 to 60 years [
For larger repeat sizes, the variability in age of onset is less; repeat sizes greater than 45 are almost always associated with disease onset before age 20 years [
Homozygosity for expanded
• The widest range of age of onset is observed among individuals with fewer than 40 CAG repeats. Some individuals with alleles of 33 and 34 repeats have had onset after age 60 years. In one study, the presence of 37 repeats was associated with ages of onset ranging from 20 to 60 years [
• For larger repeat sizes, the variability in age of onset is less; repeat sizes greater than 45 are almost always associated with disease onset before age 20 years [
## Penetrance
See
## Anticipation
Anticipation (i.e., an increase in the severity of the phenotype and earlier age of onset in later generations) has been observed in SCA2. The tendency of the
Paternal transmission of alleles with full penetrance or reduced penetrance is most likely to demonstrate meiotic instability and result in anticipation, although large expansions can also be seen in maternally inherited alleles [
## Nomenclature
Terms used in the past for SCA2 and other hereditary ataxias include Marie's ataxia, OPCA, and
## Prevalence
In the Baylor College of Medicine ataxia clinic, SCA2 was the most common ADCA (18%) [
In a large series from several ataxia clinics in Germany, SCA2 represented 14% of ADCA pedigrees [
SCA2 is the most common type of ADCA in Korea [
## Genetically Related (Allelic) Disorders
In addition to ataxia, L-dopa-responsive parkinsonism with or without ataxia has been reported in individuals and families with the
## Differential Diagnosis
It is difficult and often impossible to distinguish spinocerebellar ataxia type 2 (SCA2) from the other hereditary ataxias (see
SCA2-related
Proportion of Individuals with SCA2 Manifesting Phenotypic Features Compared with Individuals with SCA1, SCA3, and SCA6
Percentages modified from
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 2 (SCA2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Neurologic examination
Ophthalmologic examination
Baseline assessment of cognition
Neuroimaging
Consultation with a clinical geneticist and/or genetic counselor
Management of individuals remains supportive as no known therapy to delay or halt the progression of the disease exists.
Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity.
Canes and walkers help prevent falls.
Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.
Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria.
Weighted eating utensils and dressing hooks help maintain a sense of independence.
When dysphagia becomes troublesome, video esophagrams can identify the consistency of food least likely to trigger aspiration.
Improvement of severe tremor with thalamic stimulation has been reported in one individual [
The American Academy of Neurology has developed guidelines for the treatment of motor dysfunction in patients with ataxia [
No dietary factor has been shown to curtail symptoms; however, vitamin supplements are recommended, particularly if caloric intake is reduced.
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
Affected individuals should be examined at least annually by a physician experienced in movement disorders and ataxia.
Alcohol and medications known to affect cerebellar function should be avoided.
See
Search
Tremor-controlling drugs do not work well for cerebellar tremors.
• Neurologic examination
• Ophthalmologic examination
• Baseline assessment of cognition
• Neuroimaging
• Consultation with a clinical geneticist and/or genetic counselor
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 2 (SCA2), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Neurologic examination
Ophthalmologic examination
Baseline assessment of cognition
Neuroimaging
Consultation with a clinical geneticist and/or genetic counselor
• Neurologic examination
• Ophthalmologic examination
• Baseline assessment of cognition
• Neuroimaging
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Management of individuals remains supportive as no known therapy to delay or halt the progression of the disease exists.
Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity.
Canes and walkers help prevent falls.
Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.
Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria.
Weighted eating utensils and dressing hooks help maintain a sense of independence.
When dysphagia becomes troublesome, video esophagrams can identify the consistency of food least likely to trigger aspiration.
Improvement of severe tremor with thalamic stimulation has been reported in one individual [
The American Academy of Neurology has developed guidelines for the treatment of motor dysfunction in patients with ataxia [
## Prevention of Secondary Complications
No dietary factor has been shown to curtail symptoms; however, vitamin supplements are recommended, particularly if caloric intake is reduced.
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
## Surveillance
Affected individuals should be examined at least annually by a physician experienced in movement disorders and ataxia.
## Agents/Circumstances to Avoid
Alcohol and medications known to affect cerebellar function should be avoided.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Other
Tremor-controlling drugs do not work well for cerebellar tremors.
## Genetic Counseling
Spinocerebellar ataxia type 2 (SCA2) is inherited in an autosomal dominant manner.
Most individuals diagnosed with SCA2 have an affected parent.
A proband with SCA2 may have the disorder as the result of an expansion of a reduced-penetrance allele or a longer normal allele inherited from an unaffected parent.
Recommendations for the evaluation of apparently asymptomatic parents of a proband include physical examination and consideration of
Although most individuals diagnosed with SCA2 have an affected parent or a parent with a longer normal allele, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband has an
If an expanded
Each child of an individual with SCA2 has a 50% chance of inheriting an expanded
Further
Large expansions are almost exclusively observed when the repeat is passed through the paternal germline [
Predictive testing for at-risk relatives is possible once molecular genetic testing has identified an
This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
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 SCA2, 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.
Once an
Note: Prenatal testing must take into account the possibility of a highly expanded
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 SCA2 have an affected parent.
• A proband with SCA2 may have the disorder as the result of an expansion of a reduced-penetrance allele or a longer normal allele inherited from an unaffected parent.
• Recommendations for the evaluation of apparently asymptomatic parents of a proband include physical examination and consideration of
• Although most individuals diagnosed with SCA2 have an affected parent or a parent with a longer normal allele, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband has an
• If an expanded
• Each child of an individual with SCA2 has a 50% chance of inheriting an expanded
• Further
• Large expansions are almost exclusively observed when the repeat is passed through the paternal germline [
• Predictive testing for at-risk relatives is possible once molecular genetic testing has identified an
• This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• 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
Spinocerebellar ataxia type 2 (SCA2) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with SCA2 have an affected parent.
A proband with SCA2 may have the disorder as the result of an expansion of a reduced-penetrance allele or a longer normal allele inherited from an unaffected parent.
Recommendations for the evaluation of apparently asymptomatic parents of a proband include physical examination and consideration of
Although most individuals diagnosed with SCA2 have an affected parent or a parent with a longer normal allele, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband has an
If an expanded
Each child of an individual with SCA2 has a 50% chance of inheriting an expanded
Further
Large expansions are almost exclusively observed when the repeat is passed through the paternal germline [
• Most individuals diagnosed with SCA2 have an affected parent.
• A proband with SCA2 may have the disorder as the result of an expansion of a reduced-penetrance allele or a longer normal allele inherited from an unaffected parent.
• Recommendations for the evaluation of apparently asymptomatic parents of a proband include physical examination and consideration of
• Although most individuals diagnosed with SCA2 have an affected parent or a parent with a longer normal allele, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband has an
• If an expanded
• Each child of an individual with SCA2 has a 50% chance of inheriting an expanded
• Further
• Large expansions are almost exclusively observed when the repeat is passed through the paternal germline [
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once molecular genetic testing has identified an
This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
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 SCA2, 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 molecular genetic testing has identified an
• This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• 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 an
Note: Prenatal testing must take into account the possibility of a highly expanded
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
Spain
Sanford Research
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
• Spain
•
•
• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia Type 2: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 2 (
Normal alleles typically show one or two CAA trinucleotide repeat interruptions. Because the CAA codon also encodes glutamine, these interruptions do not interrupt the glutamine tract at the protein level. The 5' sequence of the
Note: Interruption of a CAG expanded allele by a CAA repeat does not mitigate the pathogenicity of the repeat size because both CAG and CAA code for glutamine [
Variants listed in the table have been provided by the author.
In brains from both unaffected individuals and individuals with SCA2, ataxin-2 has a cytoplasmic localization. It associates with Golgi membranes [
Ataxin-2 interacts with a number of proteins (reviewed in
## References
## Published Guidelines / Consensus Statements
## Literature Cited
## Chapter Notes
14 February 2019 (sw) Comprehensive update posted live
12 November 2015 (me) Comprehensive update posted live
1 August 2013 (me) Comprehensive update posted live
5 October 2010 (me) Comprehensive update posted live
25 January 2006 (me) Comprehensive update posted live
31 October 2003 (me) Comprehensive update posted live
13 January 2001 (me) Comprehensive update posted live
23 October 1998 (pb) Review posted live
2 March 1998 (smp) Original submission
• 14 February 2019 (sw) Comprehensive update posted live
• 12 November 2015 (me) Comprehensive update posted live
• 1 August 2013 (me) Comprehensive update posted live
• 5 October 2010 (me) Comprehensive update posted live
• 25 January 2006 (me) Comprehensive update posted live
• 31 October 2003 (me) Comprehensive update posted live
• 13 January 2001 (me) Comprehensive update posted live
• 23 October 1998 (pb) Review posted live
• 2 March 1998 (smp) Original submission
## Revision History
14 February 2019 (sw) Comprehensive update posted live
12 November 2015 (me) Comprehensive update posted live
1 August 2013 (me) Comprehensive update posted live
5 October 2010 (me) Comprehensive update posted live
25 January 2006 (me) Comprehensive update posted live
31 October 2003 (me) Comprehensive update posted live
13 January 2001 (me) Comprehensive update posted live
23 October 1998 (pb) Review posted live
2 March 1998 (smp) Original submission
• 14 February 2019 (sw) Comprehensive update posted live
• 12 November 2015 (me) Comprehensive update posted live
• 1 August 2013 (me) Comprehensive update posted live
• 5 October 2010 (me) Comprehensive update posted live
• 25 January 2006 (me) Comprehensive update posted live
• 31 October 2003 (me) Comprehensive update posted live
• 13 January 2001 (me) Comprehensive update posted live
• 23 October 1998 (pb) Review posted live
• 2 March 1998 (smp) Original submission
|
[] |
23/10/1998
|
14/2/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sca20
|
sca20
|
[
"SCA20",
"SCA20",
"Spinocerebellar Ataxia Type 20"
] |
Spinocerebellar Ataxia Type 20
|
Elsdon Storey, RJM Gardner
|
Summary Spinocerebellar ataxia type 20 (SCA20) is characterized by a slowly progressive ataxia and dysarthria. Approximately two thirds of those affected also display palatal tremor ("myoclonus") and/or abnormal phonation clinically resembling spasmodic adductor dysphonia. Dysarthria, which may be abrupt in onset, precedes the onset of ataxia in about two thirds of affected individuals, sometimes by a number of years. Hypermetric horizontal saccades (without nystagmus or disturbance of vestibulo-ocular reflex gain) are seen in about half of affected persons. Although minor pyramidal signs (brisk knee jerks, crossed adductor spread) may be seen, spasticity and extensor plantar responses are not. Cognition is normal. Clinical information is based on the findings in 16 personally examined affected members of a single Australian family of Anglo-Celtic descent. The diagnosis of SCA20 is based on clinical findings and neuroimaging. Within five years of disease onset CT scan shows pronounced dentate calcification, typically without concomitant pallidal calcification. In addition to evidence of dentate calcification, MRI shows mild-to-moderate pan cerebellar atrophy and normal cerebrum and brain stem (except for increased inferior olivary T SCA20 is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the pathogenic variant.
|
## Diagnosis
Spinocerebellar ataxia type 20 (SCA20)
Onset with dysarthria (rather than with gait ataxia) that may be abrupt in onset (seen in ~66%)
Palatal tremor (in ~66%)
Family history consistent with autosomal dominant inheritance
Additional findings may include the following:
Hypermetric horizontal saccades (without nystagmus or disturbance of vestibuloocular reflex gain) in about half
Mild hyperreflexia (typically without spasticity or extensor plantar responses) in a minority
Postural tremor of arms with or without involvement of the head (seen in a minority; may be the first symptom)
CT scan (
MRI (
The diagnosis of SCA20
Note: The candidate region for SCA20 lies within the pericentromeric region of chromosome 11, encompassing chr11:44,045,910-69,634,192 (loci D11S903-FGF3). Although the candidate region includes
Molecular genetic testing approaches can include a combination of
Genomic Testing Used in Spinocerebellar Ataxia Type 20
See
For this
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 11q12.2-11q12.3 region.
Targeted duplication analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA), as well as other targeted quantitative methods.
• Onset with dysarthria (rather than with gait ataxia) that may be abrupt in onset (seen in ~66%)
• Palatal tremor (in ~66%)
• Family history consistent with autosomal dominant inheritance
• Hypermetric horizontal saccades (without nystagmus or disturbance of vestibuloocular reflex gain) in about half
• Mild hyperreflexia (typically without spasticity or extensor plantar responses) in a minority
• Postural tremor of arms with or without involvement of the head (seen in a minority; may be the first symptom)
• CT scan (
• MRI (
## Suggestive Findings
Spinocerebellar ataxia type 20 (SCA20)
Onset with dysarthria (rather than with gait ataxia) that may be abrupt in onset (seen in ~66%)
Palatal tremor (in ~66%)
Family history consistent with autosomal dominant inheritance
Additional findings may include the following:
Hypermetric horizontal saccades (without nystagmus or disturbance of vestibuloocular reflex gain) in about half
Mild hyperreflexia (typically without spasticity or extensor plantar responses) in a minority
Postural tremor of arms with or without involvement of the head (seen in a minority; may be the first symptom)
CT scan (
MRI (
• Onset with dysarthria (rather than with gait ataxia) that may be abrupt in onset (seen in ~66%)
• Palatal tremor (in ~66%)
• Family history consistent with autosomal dominant inheritance
• Hypermetric horizontal saccades (without nystagmus or disturbance of vestibuloocular reflex gain) in about half
• Mild hyperreflexia (typically without spasticity or extensor plantar responses) in a minority
• Postural tremor of arms with or without involvement of the head (seen in a minority; may be the first symptom)
• CT scan (
• MRI (
## Establishing the Diagnosis
The diagnosis of SCA20
Note: The candidate region for SCA20 lies within the pericentromeric region of chromosome 11, encompassing chr11:44,045,910-69,634,192 (loci D11S903-FGF3). Although the candidate region includes
Molecular genetic testing approaches can include a combination of
Genomic Testing Used in Spinocerebellar Ataxia Type 20
See
For this
Chromosomal microarray analysis (CMA) using oligonucleotide arrays or SNP arrays. CMA designs in current clinical use target the 11q12.2-11q12.3 region.
Targeted duplication analysis methods can include FISH, quantitative PCR (qPCR), and multiplex ligation-dependent probe amplification (MLPA), as well as other targeted quantitative methods.
## Clinical Characteristics
Clinical information on spinocerebellar ataxia type 20 (SCA20) is based on the index pedigree, an Australian family of Anglo-Celtic descent that is the only family with SCA20 reported to date [
The 16 affected family members had onset between age 19 and 64 years (mean 47).
SCA20 presents with dysarthria without ataxia in a majority (10/16); the dysarthria may be of abrupt (2/16) or subacute (1/16) onset. It often combines the clinical appearance of spasmodic adductor dysphonia with cerebellar dysarthria. Other initial symptoms were dysarthria with simultaneous gait ataxia (2/16), gait ataxia alone (2/16), upper-limb kinetic and isometric tremor (1/16), and episodic vertigo (1/16).
Progression of SCA20, as judged by cross-sectional data, appears to be relatively slow; all affected members of this family were able to walk with or without gait aids except one, who became wheelchair dependent after 40 years of symptoms. Another required a feeding gastrostomy after 15 years of symptoms.
The clinical picture usually includes palatal tremor ("myoclonus") without ear click (10/16), although this finding can be subtle. Gaze-evoked nystagmus is unusual (3/16). In two it was impersistent; in another affected individual persistent downbeating nystagmus was evident. Saccades are typically hypermetric into downgaze (10/16) and horizontally (8/16). The vestibulo-ocular reflex gain, as judged by dynamic vs static visual acuity, is normal, correlating with absence of movement-induced oscillopsia. Minor pyramidal signs (brisk knee jerks, crossed adductor spread) are seen in a minority (5/16), but none have spastic tone or extensor plantar responses. Postural and kinetic tremor of the upper limbs, the presenting feature in one individual, was evident in only one other family member. Only one displayed intention tremor (as distinct from dysmetria and dyssynergia) on the finger/nose test.
Other extrapyramidal features (apart from slowing of repetitive movements without movement decay) are absent. None had a history of cognitive decline.
The penetrance is unknown, as the involved gene has not been identified.
Only four parent-child pairs could be documented by self-report regarding age of onset, which was younger by an average of 12 years in the offspring. This information is inadequate to confirm or refute anticipation. Large CAG/CTG and ATTCT/AGAAT repeats have been excluded in the region of interest [
The prevalence of SCA20 is unknown; it is assumed to be very rare, given that no further individuals have been reported since the publication of the original family in 2008.
## Clinical Description
Clinical information on spinocerebellar ataxia type 20 (SCA20) is based on the index pedigree, an Australian family of Anglo-Celtic descent that is the only family with SCA20 reported to date [
The 16 affected family members had onset between age 19 and 64 years (mean 47).
SCA20 presents with dysarthria without ataxia in a majority (10/16); the dysarthria may be of abrupt (2/16) or subacute (1/16) onset. It often combines the clinical appearance of spasmodic adductor dysphonia with cerebellar dysarthria. Other initial symptoms were dysarthria with simultaneous gait ataxia (2/16), gait ataxia alone (2/16), upper-limb kinetic and isometric tremor (1/16), and episodic vertigo (1/16).
Progression of SCA20, as judged by cross-sectional data, appears to be relatively slow; all affected members of this family were able to walk with or without gait aids except one, who became wheelchair dependent after 40 years of symptoms. Another required a feeding gastrostomy after 15 years of symptoms.
The clinical picture usually includes palatal tremor ("myoclonus") without ear click (10/16), although this finding can be subtle. Gaze-evoked nystagmus is unusual (3/16). In two it was impersistent; in another affected individual persistent downbeating nystagmus was evident. Saccades are typically hypermetric into downgaze (10/16) and horizontally (8/16). The vestibulo-ocular reflex gain, as judged by dynamic vs static visual acuity, is normal, correlating with absence of movement-induced oscillopsia. Minor pyramidal signs (brisk knee jerks, crossed adductor spread) are seen in a minority (5/16), but none have spastic tone or extensor plantar responses. Postural and kinetic tremor of the upper limbs, the presenting feature in one individual, was evident in only one other family member. Only one displayed intention tremor (as distinct from dysmetria and dyssynergia) on the finger/nose test.
Other extrapyramidal features (apart from slowing of repetitive movements without movement decay) are absent. None had a history of cognitive decline.
## Penetrance
The penetrance is unknown, as the involved gene has not been identified.
## Anticipation
Only four parent-child pairs could be documented by self-report regarding age of onset, which was younger by an average of 12 years in the offspring. This information is inadequate to confirm or refute anticipation. Large CAG/CTG and ATTCT/AGAAT repeats have been excluded in the region of interest [
## Prevalence
The prevalence of SCA20 is unknown; it is assumed to be very rare, given that no further individuals have been reported since the publication of the original family in 2008.
## Genetically Related (Allelic) Disorders
No genetically related disorders are known.
## Differential Diagnosis
The differential diagnosis of spinocerebellar ataxia type 20 (SCA20) is essentially that of its component features, as the constellation of progressive, dominantly inherited ataxia, early dentate calcification, and (often) palatal tremor is distinctive.
While dentate calcification is common in the general population with increasing age, affecting 0.7% of those older than age 65 years in one study [
Hyperparathyroidism and pseudohypoparathyroidism (see
Dominant "familial idiopathic brain calcification" (see
In conjunction with progressive ataxia in sporadic (i.e., not inherited) cases, possibly representing a unique degenerative syndrome [
Rarely, in multiple-system atrophy, cerebellar type
In early adult-onset
In a dominant branchial myoclonus syndrome with ataxia (OMIM
• While dentate calcification is common in the general population with increasing age, affecting 0.7% of those older than age 65 years in one study [
• Hyperparathyroidism and pseudohypoparathyroidism (see
• Dominant "familial idiopathic brain calcification" (see
• In conjunction with progressive ataxia in sporadic (i.e., not inherited) cases, possibly representing a unique degenerative syndrome [
• Rarely, in multiple-system atrophy, cerebellar type
• In early adult-onset
• In a dominant branchial myoclonus syndrome with ataxia (OMIM
## Management
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 20 (SCA20), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Careful clinical and neurologic evaluation
Speech assessment
Consultation with a clinical geneticist and/or genetic counselor
Affected persons should be followed by a neurologist with consultation from physiatrists and physical and occupational therapists.
Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity.
Canes and walkers help prevent falls. Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.
Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria or dysphonia.
Weighted eating utensils and dressing hooks help maintain a sense of independence.
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
When dysphagia becomes troublesome, videofluoroscopic swallow evaluation can identify the consistency of food least likely to trigger aspiration.
Secondary complications are unlikely in the early years of the disease.
Later, prevention of falls via appropriate gait aids and home modifications, and (if falls are frequent) a personal alarm system may be required. To limit the likelihood of fractures resulting from falls, bone density should be estimated and osteoporosis treated if present.
Vitamin supplements are recommended, particularly if caloric intake is reduced.
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
The following are appropriate:
Periodic speech assessment if dysphagia becomes a problem
Routine follow up with a neurologist about every two years or as needed
Affected individuals should avoid alcohol as well as medications known to cause nerve damage (e.g., isoniazid).
Search
Tremor-controlling drugs do not work well for cerebellar tremors.
Education for affected individuals and their families is the cornerstone of management.
• Careful clinical and neurologic evaluation
• Speech assessment
• Consultation with a clinical geneticist and/or genetic counselor
• Periodic speech assessment if dysphagia becomes a problem
• Routine follow up with a neurologist about every two years or as needed
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with spinocerebellar ataxia type 20 (SCA20), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Careful clinical and neurologic evaluation
Speech assessment
Consultation with a clinical geneticist and/or genetic counselor
• Careful clinical and neurologic evaluation
• Speech assessment
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
Affected persons should be followed by a neurologist with consultation from physiatrists and physical and occupational therapists.
Although neither exercise nor physical therapy has been shown to stem the progression of incoordination or muscle weakness, individuals should maintain activity.
Canes and walkers help prevent falls. Modification of the home with such conveniences as grab bars, raised toilet seats, and ramps to accommodate motorized chairs may be necessary.
Speech therapy and communication devices such as writing pads and computer-based devices may benefit those with dysarthria or dysphonia.
Weighted eating utensils and dressing hooks help maintain a sense of independence.
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
When dysphagia becomes troublesome, videofluoroscopic swallow evaluation can identify the consistency of food least likely to trigger aspiration.
## Prevention of Secondary Complications
Secondary complications are unlikely in the early years of the disease.
Later, prevention of falls via appropriate gait aids and home modifications, and (if falls are frequent) a personal alarm system may be required. To limit the likelihood of fractures resulting from falls, bone density should be estimated and osteoporosis treated if present.
Vitamin supplements are recommended, particularly if caloric intake is reduced.
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
## Surveillance
The following are appropriate:
Periodic speech assessment if dysphagia becomes a problem
Routine follow up with a neurologist about every two years or as needed
• Periodic speech assessment if dysphagia becomes a problem
• Routine follow up with a neurologist about every two years or as needed
## Agents/Circumstances to Avoid
Affected individuals should avoid alcohol as well as medications known to cause nerve damage (e.g., isoniazid).
## Therapies Under Investigation
Search
## Other
Tremor-controlling drugs do not work well for cerebellar tremors.
Education for affected individuals and their families is the cornerstone of management.
## Genetic Counseling
Spinocerebellar ataxia type 20 (SCA20) is inherited in an autosomal dominant manner.
Almost all individuals diagnosed with SCA20 have an affected parent.
A proband with SCA20 may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Although almost all individuals diagnosed with SCA20 have an affected parent, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation has been performed on the parents of the proband.
If a parent of the proband is affected, the risk to the sibs is 50%.
If the parents are clinically unaffected, the risk to the sibs of a proband is likely to be low.
The optimal time for determination of genetic risk is before 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.
Because the gene in which pathogenic variants are responsible for SCA20 has not been identified, prenatal testing is not possible.
• Almost all individuals diagnosed with SCA20 have an affected parent.
• A proband with SCA20 may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• Although almost all individuals diagnosed with SCA20 have an affected parent, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation has been performed on the parents of the proband.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• If the parents are clinically unaffected, the risk to the sibs of a proband is likely to be low.
• The optimal time for determination of genetic risk is before 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
Spinocerebellar ataxia type 20 (SCA20) is inherited in an autosomal dominant manner.
## Risk to Family Members
Almost all individuals diagnosed with SCA20 have an affected parent.
A proband with SCA20 may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Although almost all individuals diagnosed with SCA20 have an affected parent, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation has been performed on the parents of the proband.
If a parent of the proband is affected, the risk to the sibs is 50%.
If the parents are clinically unaffected, the risk to the sibs of a proband is likely to be low.
• Almost all individuals diagnosed with SCA20 have an affected parent.
• A proband with SCA20 may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• Although almost all individuals diagnosed with SCA20 have an affected parent, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation has been performed on the parents of the proband.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• If the parents are clinically unaffected, the risk to the sibs of a proband is likely to be low.
## Related Genetic Counseling Issues
The optimal time for determination of genetic risk is before 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 is before 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
Because the gene in which pathogenic variants are responsible for SCA20 has not been identified, prenatal testing is not possible.
## Resources
United Kingdom
United Kingdom
Spain
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
• Spain
•
## Molecular Genetics
Spinocerebellar Ataxia Type 20: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 20 (
## Molecular Pathogenesis
## Chapter Notes
18 April 2019 (sw) Comprehensive update posted live
7 June 2012 (me) Comprehensive update posted live
6 January 2009 (es) Revision: 260-kb duplication of 11q12.2-11q12.3 identified as suspected cause of SCA20
27 February 2007 (me) Review posted live
6 February 2007 (es) Original submission
• 18 April 2019 (sw) Comprehensive update posted live
• 7 June 2012 (me) Comprehensive update posted live
• 6 January 2009 (es) Revision: 260-kb duplication of 11q12.2-11q12.3 identified as suspected cause of SCA20
• 27 February 2007 (me) Review posted live
• 6 February 2007 (es) Original submission
## Revision History
18 April 2019 (sw) Comprehensive update posted live
7 June 2012 (me) Comprehensive update posted live
6 January 2009 (es) Revision: 260-kb duplication of 11q12.2-11q12.3 identified as suspected cause of SCA20
27 February 2007 (me) Review posted live
6 February 2007 (es) Original submission
• 18 April 2019 (sw) Comprehensive update posted live
• 7 June 2012 (me) Comprehensive update posted live
• 6 January 2009 (es) Revision: 260-kb duplication of 11q12.2-11q12.3 identified as suspected cause of SCA20
• 27 February 2007 (me) Review posted live
• 6 February 2007 (es) Original submission
## References
## Literature Cited
III:12. CT scan showing heavy dentate calcification and pan cerebellar atrophy in an individual age 62 years with mild ataxia, three years after symptom onset
III:16. CT scan slices at two levels of the dentate showing heavy dentate calcification and mild cerebellar atrophy in an individual age 56 years with very mild ataxia; one year after symptom onset
Note: Roman:arabic numeral combinations refer to pedigree numbers in
MRI axial proton density images showing (a) inferior olivary hypertrophy and (b) low dentate signal consistent with dentate calcification in an individual age 54 years; 16 years after onset
Note: Roman:arabic numeral combinations refer to pedigree numbers in
|
[
"F Barbieri, MT Pellecchia, E Esposito, E Di Stasio, I Castaldo, F Santorelli, A Perretti, L Santoro, G De Michele. Adult-onset familial laryngeal abductor paralysis, cerebellar ataxia, and pure motor neuropathy.. Neurology 2001;56:1412-4",
"JG de Yebenes, A Vazquez, J Rabano, EV de Seijas, DG Urra, MC Obregon, MS Barquero, MA Arribas, JL Moreno, JR Alenda. Hereditary branchial myoclonus with spastic paraparesis and cerebellar ataxia: a new autosomal dominant disorder.. Neurology 1988;38:569-72",
"MG Harrington, P Macpherson, WB McIntosh, BF Allam, I Bone. The significance of the incidental finding of basal ganglia calcification on computed tomography.. J Neurol Neurosurg Psychiatry 1981;44:1168-70",
"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",
"MA Knight, RJ Gardner, M Bahlo, T Matsuura, JA Dixon, SM Forrest, E Storey. Dominantly inherited ataxia and dysphonia with dentate calcification: spinocerebellar ataxia type 20.. Brain 2004;127:1172-81",
"MA Knight, D Hernandez, SJ Diede, HG Dauwerse, I Rafferty, J van de Leemput, SM Forrest, RJM Gardner, E Storey, GJ van Ommen, SJ Tapscott, KH Fischbeck, AB Singleton. A duplication at chromosome 11q12.2-11q12.3 is associated with spinocerebellar ataxia type 20.. Hum Mol Genet 2008;17:3847-53",
"DN Lorenzo, SM Forrest, Y Ikeda, KA Dick, LP Ranum, MA Knight. Spinocerebellar ataxia type 20 is genetically distinct from spinocerebellar ataxia type 5.. Neurology 2006;67:2084-5",
"MR Sperling, C Herrmann. Syndrome of palatal myoclonus and progressive ataxia: two cases with magnetic resonance imaging.. Neurology 1985;35:1212-4",
"E Storey, RJM Gardner. Spinocerebellar ataxia type 20.. Handb Clin Neurol 2012;103:567-73",
"E Storey, MA Knight, SM Forrest, RJ Gardner. Spinocerebellar ataxia type 20.. Cerebellum 2005;4:55-7"
] |
27/2/2007
|
18/4/2019
|
6/1/2009
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sca28
|
sca28
|
[
"SCA28",
"SCA28",
"Mitochondrial inner membrane m-AAA protease component AFG3L2",
"AFG3L2",
"Spinocerebellar Ataxia Type 28"
] |
Spinocerebellar Ataxia Type 28
|
Alessandro Brussino, Alfredo Brusco, Alexandra Durr, Cecilia Mancini
|
Summary Spinocerebellar ataxia type 28 (SCA28) is characterized by young-adult onset, very slowly progressive gait and limb ataxia resulting in coordination and balance problems, dysarthria, ptosis, nystagmus, and ophthalmoparesis. In most individuals, SCA28 presents as a loss of coordination of lower limbs (unsteadiness, gait ataxia). Less frequently, ptosis/ophthalmoplegia, dysarthria, or upper-limb incoordination may occur as the initial finding. The course of the disease is slowly progressive without impairment of functional autonomy even decades after onset. Because the phenotype of SCA28 is indistinguishable from many other inherited disorders with SCA, the diagnosis of SCA28 is established in a proband with typical clinical findings by the identification of a heterozygous pathogenic variant in SCA28 is inherited in an autosomal dominant manner. Most individuals diagnosed with SCA28 have an affected parent; the proportion of cases caused by
|
## Diagnosis
Spinocerebellar ataxia type 28 (SCA28)
Onset generally in young adulthood (but with a wide range: ages 3-76 years)
A slowly progressive gait disorder resulting from cerebellar impairment
Cerebellar dysarthria
Oculomotor abnormalities including ophthalmoparesis, nystagmus and ptosis
Hyperreflexia or brisk deep tendon reflexes
Brain MRI showing cerebellar atrophy predominantly of the superior vermis, with sparing of the brain stem
A family history consistent with autosomal dominant inheritance
The diagnosis of SCA28
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 SCA28 is indistinguishable from many other inherited disorders with SCA, recommended molecular genetic testing approaches include use of a
Note: Single-gene testing (sequence analysis of
For this disorder a multigene panel is recommended (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SCA28
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
Unselected individuals, all exons analyzed [
Autosomal dominant cases, all exons analyzed [
Unselected individuals, only exons 15-16 analyzed [
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.
• Onset generally in young adulthood (but with a wide range: ages 3-76 years)
• A slowly progressive gait disorder resulting from cerebellar impairment
• Cerebellar dysarthria
• Oculomotor abnormalities including ophthalmoparesis, nystagmus and ptosis
• Hyperreflexia or brisk deep tendon reflexes
• Brain MRI showing cerebellar atrophy predominantly of the superior vermis, with sparing of the brain stem
• A family history consistent with autosomal dominant inheritance
• For this disorder a multigene panel is recommended (see
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Spinocerebellar ataxia type 28 (SCA28)
Onset generally in young adulthood (but with a wide range: ages 3-76 years)
A slowly progressive gait disorder resulting from cerebellar impairment
Cerebellar dysarthria
Oculomotor abnormalities including ophthalmoparesis, nystagmus and ptosis
Hyperreflexia or brisk deep tendon reflexes
Brain MRI showing cerebellar atrophy predominantly of the superior vermis, with sparing of the brain stem
A family history consistent with autosomal dominant inheritance
• Onset generally in young adulthood (but with a wide range: ages 3-76 years)
• A slowly progressive gait disorder resulting from cerebellar impairment
• Cerebellar dysarthria
• Oculomotor abnormalities including ophthalmoparesis, nystagmus and ptosis
• Hyperreflexia or brisk deep tendon reflexes
• Brain MRI showing cerebellar atrophy predominantly of the superior vermis, with sparing of the brain stem
• A family history consistent with autosomal dominant inheritance
## Establishing the Diagnosis
The diagnosis of SCA28
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 SCA28 is indistinguishable from many other inherited disorders with SCA, recommended molecular genetic testing approaches include use of a
Note: Single-gene testing (sequence analysis of
For this disorder a multigene panel is recommended (see
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SCA28
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
Unselected individuals, all exons analyzed [
Autosomal dominant cases, all exons analyzed [
Unselected individuals, only exons 15-16 analyzed [
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 this disorder a multigene panel is recommended (see
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Spinocerebellar ataxia type 28 (SCA28) is characterized by young-adult onset, very slowly progressive gait and limb ataxia resulting in coordination and balance problems, dysarthria, ptosis, nystagmus, and ophthalmoparesis.
Reflexes may be increased in the lower limbs and Babinski sign is present in some.
Decreased vibration sense at the ankles is present in some, but superficial sensation is always normal.
Extrapyramidal signs, either parkinsonism (mainly rigidity and/or bradykinesia) or dystonia, have been observed.
During the initial phases of the disease individuals may have impaired speech, but be easy to understand.
Later on, speech becomes slurred so that the affected individual is difficult to understand.
Ptosis
Nystagmus
Ophthalmoparesis with limited horizontal and vertical gaze
No genotype-phenotype correlations can be proposed based on published studies, although persons with the
From the studies of SCA28 published to date, disease penetrance appears to be complete.
According to published data, heterozygous pathogenic variants in
• Reflexes may be increased in the lower limbs and Babinski sign is present in some.
• Decreased vibration sense at the ankles is present in some, but superficial sensation is always normal.
• Extrapyramidal signs, either parkinsonism (mainly rigidity and/or bradykinesia) or dystonia, have been observed.
• During the initial phases of the disease individuals may have impaired speech, but be easy to understand.
• Later on, speech becomes slurred so that the affected individual is difficult to understand.
• Ptosis
• Nystagmus
• Ophthalmoparesis with limited horizontal and vertical gaze
## Clinical Description
Spinocerebellar ataxia type 28 (SCA28) is characterized by young-adult onset, very slowly progressive gait and limb ataxia resulting in coordination and balance problems, dysarthria, ptosis, nystagmus, and ophthalmoparesis.
Reflexes may be increased in the lower limbs and Babinski sign is present in some.
Decreased vibration sense at the ankles is present in some, but superficial sensation is always normal.
Extrapyramidal signs, either parkinsonism (mainly rigidity and/or bradykinesia) or dystonia, have been observed.
During the initial phases of the disease individuals may have impaired speech, but be easy to understand.
Later on, speech becomes slurred so that the affected individual is difficult to understand.
Ptosis
Nystagmus
Ophthalmoparesis with limited horizontal and vertical gaze
• Reflexes may be increased in the lower limbs and Babinski sign is present in some.
• Decreased vibration sense at the ankles is present in some, but superficial sensation is always normal.
• Extrapyramidal signs, either parkinsonism (mainly rigidity and/or bradykinesia) or dystonia, have been observed.
• During the initial phases of the disease individuals may have impaired speech, but be easy to understand.
• Later on, speech becomes slurred so that the affected individual is difficult to understand.
• Ptosis
• Nystagmus
• Ophthalmoparesis with limited horizontal and vertical gaze
## Genotype-Phenotype Correlations
No genotype-phenotype correlations can be proposed based on published studies, although persons with the
## Penetrance
From the studies of SCA28 published to date, disease penetrance appears to be complete.
## Prevalence
According to published data, heterozygous pathogenic variants in
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
The ataxic gait of persons with SCA28 is indistinguishable from that seen in other adult-onset inherited or acquired ataxias. When the family history suggests autosomal dominant inheritance, all other autosomal dominant cerebellar ataxias (ADCAs) have to be considered (see
The most commonly occurring SCAs, those caused by polyglutamine expansions (i.e.,
Mitochondrial disorders, especially those associated with external ophthalmoplegia and ptosis, should be considered as well (see
• The most commonly occurring SCAs, those caused by polyglutamine expansions (i.e.,
## Management
To establish the extent of disease and needs of an individual diagnosed with spinocerebellar ataxia type 28 (SCA28) the following evaluations are recommended if they have not already been completed:
Neurologic examination (including scales to evaluate the severity of cerebellar ataxia and to allow subjective follow up)
Cerebral MRI
Note: MRI is part of the routine evaluation of persons with ataxia; however, in SCA28 no association between the extent of cerebellar atrophy and disease severity or progression has been proven.
Speech assessment and evaluation for swallowing difficulties
Examination by an ophthalmologist
Evaluation of cognitive abilities
Consultation with a clinical geneticist and/or genetic counselor
At present, only symptomatic treatments are available. These include the following:
Crutches (less often canes) and walkers
Home adaptations including grab bars for the bathtub or shower chairs and raised toilet seats as needed
Physical therapy to ameliorate coordination difficulties, especially with tasks such as eating, dressing, walking, and bathing
Stretching exercise for those with pyramidal involvement to avoid contractions and lack of comfort during sleep
Speech-language therapy for dysarthria and swallowing difficulties
Surgical intervention as needed for severe ptosis
Psychological support helps affected individuals cope with the consequences of the disease.
Weight control can facilitate ambulation.
To avoid complications such as aspiration pneumonia, thickened feeds or gastrostomy should be considered.
Annual assessment of the cerebellar ataxia using SARA (Scale for the Assessment and Rating of Cerebellar Ataxia), CCFS (Composite Cerebellar Functional Severity Score), or similar scales should be performed to evaluate stability or progression of the disease.
Monitoring of speech and swallowing difficulties is recommended.
Alcohol consumption and sedatives such as benzodiazepines may worsen gait ataxia and coordination difficulties.
See
Search
• Neurologic examination (including scales to evaluate the severity of cerebellar ataxia and to allow subjective follow up)
• Cerebral MRI
• Note: MRI is part of the routine evaluation of persons with ataxia; however, in SCA28 no association between the extent of cerebellar atrophy and disease severity or progression has been proven.
• Speech assessment and evaluation for swallowing difficulties
• Examination by an ophthalmologist
• Evaluation of cognitive abilities
• Consultation with a clinical geneticist and/or genetic counselor
• Crutches (less often canes) and walkers
• Home adaptations including grab bars for the bathtub or shower chairs and raised toilet seats as needed
• Physical therapy to ameliorate coordination difficulties, especially with tasks such as eating, dressing, walking, and bathing
• Stretching exercise for those with pyramidal involvement to avoid contractions and lack of comfort during sleep
• Speech-language therapy for dysarthria and swallowing difficulties
• Surgical intervention as needed for severe ptosis
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs of an individual diagnosed with spinocerebellar ataxia type 28 (SCA28) the following evaluations are recommended if they have not already been completed:
Neurologic examination (including scales to evaluate the severity of cerebellar ataxia and to allow subjective follow up)
Cerebral MRI
Note: MRI is part of the routine evaluation of persons with ataxia; however, in SCA28 no association between the extent of cerebellar atrophy and disease severity or progression has been proven.
Speech assessment and evaluation for swallowing difficulties
Examination by an ophthalmologist
Evaluation of cognitive abilities
Consultation with a clinical geneticist and/or genetic counselor
• Neurologic examination (including scales to evaluate the severity of cerebellar ataxia and to allow subjective follow up)
• Cerebral MRI
• Note: MRI is part of the routine evaluation of persons with ataxia; however, in SCA28 no association between the extent of cerebellar atrophy and disease severity or progression has been proven.
• Speech assessment and evaluation for swallowing difficulties
• Examination by an ophthalmologist
• Evaluation of cognitive abilities
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
At present, only symptomatic treatments are available. These include the following:
Crutches (less often canes) and walkers
Home adaptations including grab bars for the bathtub or shower chairs and raised toilet seats as needed
Physical therapy to ameliorate coordination difficulties, especially with tasks such as eating, dressing, walking, and bathing
Stretching exercise for those with pyramidal involvement to avoid contractions and lack of comfort during sleep
Speech-language therapy for dysarthria and swallowing difficulties
Surgical intervention as needed for severe ptosis
• Crutches (less often canes) and walkers
• Home adaptations including grab bars for the bathtub or shower chairs and raised toilet seats as needed
• Physical therapy to ameliorate coordination difficulties, especially with tasks such as eating, dressing, walking, and bathing
• Stretching exercise for those with pyramidal involvement to avoid contractions and lack of comfort during sleep
• Speech-language therapy for dysarthria and swallowing difficulties
• Surgical intervention as needed for severe ptosis
## Prevention of Secondary Complications
Psychological support helps affected individuals cope with the consequences of the disease.
Weight control can facilitate ambulation.
To avoid complications such as aspiration pneumonia, thickened feeds or gastrostomy should be considered.
## Surveillance
Annual assessment of the cerebellar ataxia using SARA (Scale for the Assessment and Rating of Cerebellar Ataxia), CCFS (Composite Cerebellar Functional Severity Score), or similar scales should be performed to evaluate stability or progression of the disease.
Monitoring of speech and swallowing difficulties is recommended.
## Agents/Circumstances to Avoid
Alcohol consumption and sedatives such as benzodiazepines may worsen gait ataxia and coordination difficulties.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Spinocerebellar ataxia type 28 (SCA28) is inherited in an autosomal dominant manner.
Most individuals diagnosed with SCA28 have an affected parent.
A proband with SCA28 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 leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a
The family history of some individuals diagnosed with SCA28 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 late onset of the disease in the affected parent. 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 mosaicism for the pathogenic variant and may be mildly/minimally affected.
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 affected, the risk to the sibs of inheriting the variant is 50%.
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
Testing for the pathogenic variant in the absence of definite symptoms of the disease is predictive testing. 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 should involve pre-test interviews in which the motives for requesting the test, the individual's knowledge of SCA28, the possible impact of positive and negative test results, and neurologic status are assessed. 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. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.
For more information, see also 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.
Once the
• Most individuals diagnosed with SCA28 have an affected parent.
• A proband with SCA28 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 leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a
• The family history of some individuals diagnosed with SCA28 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• 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 affected, the risk to the sibs of inheriting the variant is 50%.
• 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
• A parent of the proband has the
• 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
Spinocerebellar ataxia type 28 (SCA28) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with SCA28 have an affected parent.
A proband with SCA28 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 leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a
The family history of some individuals diagnosed with SCA28 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 late onset of the disease in the affected parent. 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 mosaicism for the pathogenic variant and may be mildly/minimally affected.
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 affected, the risk to the sibs of inheriting the variant is 50%.
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
• Most individuals diagnosed with SCA28 have an affected parent.
• A proband with SCA28 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 leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a
• The family history of some individuals diagnosed with SCA28 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• 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 affected, the risk to the sibs of inheriting the variant is 50%.
• 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
• A parent of the proband has the
• The
## Related Genetic Counseling Issues
Testing for the pathogenic variant in the absence of definite symptoms of the disease is predictive testing. 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 should involve pre-test interviews in which the motives for requesting the test, the individual's knowledge of SCA28, the possible impact of positive and negative test results, and neurologic status are assessed. 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. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and evaluations.
For more information, see also 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
## Resources
United Kingdom
France
United Kingdom
Spain
Sanford Research
•
• United Kingdom
•
•
• France
•
•
• United Kingdom
•
•
•
•
• Spain
•
•
• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia Type 28: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 28 (
Variants predicted to be loss-of-function should be interpreted cautiously, and referred as pathogenic only if supported by functional studies. For example, a potential loss-of-function variant in one case results in a truncated protein being produced, suggesting a dominant-negative mechanism [Smets et al 2014üü]. However, in a second case a c.1958dupT variant was passed from an affected mother to her unaffected daughter, strongly suggesting that the variant is not associated with disease [
Variants listed in the table have been provided by the authors.
Both AFG3L2 and paraplegin are mitochondrial proteins, and are highly conserved through evolution – the orthologous protein FtsH being present in
The two proteins have been extensively studied in yeast models (orthologous genes are
Studies in yeast assigned a dual activity to the m-AAA protease for protein degradation and activation (cleavage) [
It conducts protein quality surveillance in the IMM and degrades non-assembled membrane proteins to peptides [
It mediates protein processing and thereby activates certain mitochondrial proteins [
The clustering of missense variants in a narrow region of the protein suggests the presence of a critical functional domain. Several pathogenic variants occur on the same three codons: p.Met666, p.Gly671, and p.Tyr689. Data extracted from ExAC and gnomAD metrics include loss-of-function variants reported in the population (
Overall these data strongly indicate that haplosufficient alleles occur in the population, and that
Yta10-Yta12-deficient yeast cells fail to be complemented by expression of mutated human AFG3L2 protein [
• It conducts protein quality surveillance in the IMM and degrades non-assembled membrane proteins to peptides [
• It mediates protein processing and thereby activates certain mitochondrial proteins [
## Chapter Notes
Telethon Foundation support is gratefully acknowledged (grant GGP07110)
22 March 2018 (ha) Comprehensive update posted live
7 February 2013 (cd) Revision: prenatal diagnosis available
17 May 2011 (me) Review posted live
7 February 2011 (ab) Original submission
• 22 March 2018 (ha) Comprehensive update posted live
• 7 February 2013 (cd) Revision: prenatal diagnosis available
• 17 May 2011 (me) Review posted live
• 7 February 2011 (ab) Original submission
## Acknowledgments
Telethon Foundation support is gratefully acknowledged (grant GGP07110)
## Revision History
22 March 2018 (ha) Comprehensive update posted live
7 February 2013 (cd) Revision: prenatal diagnosis available
17 May 2011 (me) Review posted live
7 February 2011 (ab) Original submission
• 22 March 2018 (ha) Comprehensive update posted live
• 7 February 2013 (cd) Revision: prenatal diagnosis available
• 17 May 2011 (me) Review posted live
• 7 February 2011 (ab) Original submission
## References
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Published Guidelines / Consensus Statements
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Literature Cited
|
[] |
17/5/2011
|
22/3/2018
|
7/2/2013
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sca3
|
sca3
|
[
"Machado-Joseph Disease",
"SCA3",
"Machado-Joseph Disease",
"SCA3",
"Ataxin-3",
"ATXN3",
"Spinocerebellar Ataxia Type 3"
] |
Spinocerebellar Ataxia Type 3
|
Henry Paulson, Vikram Shakkottai
|
Summary Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is characterized by progressive cerebellar ataxia and variable findings including pyramidal signs, a dystonic-rigid extrapyramidal syndrome, significant peripheral amyotrophy and generalized areflexia, progressive external ophthalmoplegia, action-induced facial and lingual fasciculations, and bulging eyes. Neurologic findings tend to evolve as the disorder progresses. The diagnosis of SCA3 is established in a proband with suggestive findings and a heterozygous abnormal CAG trinucleotide repeat expansion in SCA3 is inherited in an autosomal dominant manner. Each child of an affected individual has a 50% chance of inheriting the Once the CAG repeat expansion has been identified in an affected family member, prenatal testing for a pregnancy at increased risk and preimplantation genetic testing are possible. Note: The prenatal finding of an
|
## Diagnosis
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD),
Pyramidal signs
A dystonic-rigid extrapyramidal syndrome
Significant peripheral amyotrophy and generalized areflexia
Progressive external ophthalmoplegia
Action-induced facial and lingual fasciculations; bulging eyes
The diagnosis of SCA3
Note: Pathogenic (CAG)
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 3
See
See
Note: Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene.
• Pyramidal signs
• A dystonic-rigid extrapyramidal syndrome
• Significant peripheral amyotrophy and generalized areflexia
• Progressive external ophthalmoplegia
• Action-induced facial and lingual fasciculations; bulging eyes
## Suggestive Findings
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD),
Pyramidal signs
A dystonic-rigid extrapyramidal syndrome
Significant peripheral amyotrophy and generalized areflexia
Progressive external ophthalmoplegia
Action-induced facial and lingual fasciculations; bulging eyes
• Pyramidal signs
• A dystonic-rigid extrapyramidal syndrome
• Significant peripheral amyotrophy and generalized areflexia
• Progressive external ophthalmoplegia
• Action-induced facial and lingual fasciculations; bulging eyes
## Establishing the Diagnosis
The diagnosis of SCA3
Note: Pathogenic (CAG)
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 3
See
See
Note: Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene.
## Clinical Characteristics
Spinocerebellar ataxia type 3 (SCA3) is characterized by progressive cerebellar ataxia and variable findings including pyramidal signs, a dystonic-rigid extrapyramidal syndrome, significant peripheral amyotrophy and generalized areflexia, progressive external ophthalmoplegia, action-induced facial and lingual fasciculations, and bulging eyes. Neurologic findings tend to evolve as the disorder progresses.
Select Features of Spinocerebellar Ataxia Type 3
Upper motor neuron involvement (hyperreflexia, spasticity) may resemble HSP.
Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
Rigidity is a more reliable indicator than tremor or bradykinesia.
Parkinsonism is often DOPA responsive.
HSP = hereditary spastic paraplegia
Major cognitive decline is infrequent.
Progressive ataxia, nystagmus, diplopia, dysarthria, and hyperreflexia may occur early in the disease. An early sign can be a feeling of unsteadiness on head turning, indicating vestibular dysfunction. Subtle balance issues usually predate hand incoordination.
Upper motor neuron signs often become prominent, and in some families may resemble
Earlier-onset disease (before age ~25 years) often manifests dystonia [
SCA3 should also be considered in cases of familial Parkinsonism, especially in individuals with African ancestry [
Autonomic problems, including bladder and thermoregulation disturbances; both cardiovascular and sudomotor dysfunction may be present [
Disabling sleep disturbances [
Fatigue that is often associated with depression and daytime somnolence [
Impaired executive and emotional functioning, referred to as cerebellar cognitive affective syndrome [
Chronic pain, often in the lumbosacral region [
Vocal cord paralysis, though uncommon, has been described [
Ambulation becomes increasingly difficult, leading to the need for assistive devices (including wheelchair) ten to 15 years following onset.
Profound ataxia of limbs and gait becomes prominent. Individuals with later adult onset and shorter CAG repeats can manifest a disorder that combines ataxia, generalized areflexia, peripheral neuropathy, and muscle wasting.
Saccadic eye movements become slow and ophthalmoparesis develops, resulting initially in upgaze restriction. Dysconjugate eye movements result in diplopia.
At the same time, a number of other "brain stem" signs develop, including temporal and facial atrophy, characteristic action-induced perioral twitches, vestibular symptoms, tongue atrophy and fasciculations, dysphagia, and poor ability to cough and clear secretions.
Often a staring appearance to the eyes is observed, but neither this nor the perioral fasciculations are specific for SCA3.
Evidence of a peripheral polyneuropathy [
Parkinsonism that can respond to dopaminergic agents (e.g., levodopa) occurs in a subset of individuals.
Sitting posture is compromised later in disease, with affected individuals assuming various tilted positions.
Autonomic dysfunction can sometimes be disabling, but is not always related to severity of motor dysfunction or disease duration.
In general, the longest disease-causing CAG repeats cause earlier-onset disease that is more likely to have dystonia as part of the presentation.
In contrast, the shortest disease-causing CAG repeats cause later-onset disease that is more likely to have peripheral manifestations such as neuropathy and weakness. Parkinsonism, which occurs in a subset of affected persons, is not associated with any particular CAG repeat size. Rare intermediate alleles of 45 to about 60 CAG repeats may show variable expressivity; in particular, these rare intermediate alleles can manifest with isolated restless legs syndrome with no other features of disease.
In SCA3, penetrance approaches 100% and is age related.
CAG repeat sizes associated with reduced penetrance of SCA3 are not firmly defined. Of note, an asymptomatic individual age 66 years with 68 CAGs has been reported [
Instability of the CAG repeat expansion has been documented in transmission of the repeat from parent to child. Overall, expansion of the repeat is more common than contraction; thus, anticipation (earlier age of onset and more severe disease manifestations in offspring) occurs in SCA3.
Although the probability of CAG repeat expansion may be greater with paternal than with maternal transmission, the paternal bias is not pronounced (as, for example, in
SCA3 is also known as Machado-Joseph disease (MJD) and Azorean ataxia. In fact, this autosomal dominant form of ataxia, which was first described among immigrants from the Portuguese Azorean islands, was initially known as MJD. In the early 1990s the locus for MJD was identified on chromosome 14 and revealed to be a CAG repeat expansion in
No accurate data are available regarding the prevalence of SCA3 in the general population, though in many populations SCA3 is the most common of the autosomal dominant ataxias, which overall are rare.
Worldwide, SCA3 is thought to be the most common spinocerebellar ataxia (SCA), comprising 20%-50% of families (reviewed in
Countries in which SCA3 is the most common SCA include Portugal (58%-74%), Brazil (69%-92%), China (48%-49%), the Netherlands (44%), Germany (42%), and Japan (28%-63%).
In contrast, countries in which SCA3 is quite rare include Italy (1%) and South Africa (4%) [
In the US and Canada, SCA3 is one of several SCAs comprising the most common autosomal dominant ataxias, with SCA3 accounting for 21%-25% of families [
A large international genetic study showed that a single intragenic haplotype is shared by a majority of the families studied (including those from the Azorean island of Flores), suggesting a single founder variant. However, at least two other haplotypes have been identified in the Portuguese population [
• Upper motor neuron involvement (hyperreflexia, spasticity) may resemble HSP.
• Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
• Rigidity is a more reliable indicator than tremor or bradykinesia.
• Parkinsonism is often DOPA responsive.
• Autonomic problems, including bladder and thermoregulation disturbances; both cardiovascular and sudomotor dysfunction may be present [
• Disabling sleep disturbances [
• Fatigue that is often associated with depression and daytime somnolence [
• Impaired executive and emotional functioning, referred to as cerebellar cognitive affective syndrome [
• Chronic pain, often in the lumbosacral region [
• Vocal cord paralysis, though uncommon, has been described [
• Ambulation becomes increasingly difficult, leading to the need for assistive devices (including wheelchair) ten to 15 years following onset.
• Profound ataxia of limbs and gait becomes prominent. Individuals with later adult onset and shorter CAG repeats can manifest a disorder that combines ataxia, generalized areflexia, peripheral neuropathy, and muscle wasting.
• Saccadic eye movements become slow and ophthalmoparesis develops, resulting initially in upgaze restriction. Dysconjugate eye movements result in diplopia.
• At the same time, a number of other "brain stem" signs develop, including temporal and facial atrophy, characteristic action-induced perioral twitches, vestibular symptoms, tongue atrophy and fasciculations, dysphagia, and poor ability to cough and clear secretions.
• Often a staring appearance to the eyes is observed, but neither this nor the perioral fasciculations are specific for SCA3.
• Evidence of a peripheral polyneuropathy [
• Parkinsonism that can respond to dopaminergic agents (e.g., levodopa) occurs in a subset of individuals.
• Sitting posture is compromised later in disease, with affected individuals assuming various tilted positions.
• Autonomic dysfunction can sometimes be disabling, but is not always related to severity of motor dysfunction or disease duration.
## Clinical Description
Spinocerebellar ataxia type 3 (SCA3) is characterized by progressive cerebellar ataxia and variable findings including pyramidal signs, a dystonic-rigid extrapyramidal syndrome, significant peripheral amyotrophy and generalized areflexia, progressive external ophthalmoplegia, action-induced facial and lingual fasciculations, and bulging eyes. Neurologic findings tend to evolve as the disorder progresses.
Select Features of Spinocerebellar Ataxia Type 3
Upper motor neuron involvement (hyperreflexia, spasticity) may resemble HSP.
Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
Rigidity is a more reliable indicator than tremor or bradykinesia.
Parkinsonism is often DOPA responsive.
HSP = hereditary spastic paraplegia
Major cognitive decline is infrequent.
Progressive ataxia, nystagmus, diplopia, dysarthria, and hyperreflexia may occur early in the disease. An early sign can be a feeling of unsteadiness on head turning, indicating vestibular dysfunction. Subtle balance issues usually predate hand incoordination.
Upper motor neuron signs often become prominent, and in some families may resemble
Earlier-onset disease (before age ~25 years) often manifests dystonia [
SCA3 should also be considered in cases of familial Parkinsonism, especially in individuals with African ancestry [
Autonomic problems, including bladder and thermoregulation disturbances; both cardiovascular and sudomotor dysfunction may be present [
Disabling sleep disturbances [
Fatigue that is often associated with depression and daytime somnolence [
Impaired executive and emotional functioning, referred to as cerebellar cognitive affective syndrome [
Chronic pain, often in the lumbosacral region [
Vocal cord paralysis, though uncommon, has been described [
Ambulation becomes increasingly difficult, leading to the need for assistive devices (including wheelchair) ten to 15 years following onset.
Profound ataxia of limbs and gait becomes prominent. Individuals with later adult onset and shorter CAG repeats can manifest a disorder that combines ataxia, generalized areflexia, peripheral neuropathy, and muscle wasting.
Saccadic eye movements become slow and ophthalmoparesis develops, resulting initially in upgaze restriction. Dysconjugate eye movements result in diplopia.
At the same time, a number of other "brain stem" signs develop, including temporal and facial atrophy, characteristic action-induced perioral twitches, vestibular symptoms, tongue atrophy and fasciculations, dysphagia, and poor ability to cough and clear secretions.
Often a staring appearance to the eyes is observed, but neither this nor the perioral fasciculations are specific for SCA3.
Evidence of a peripheral polyneuropathy [
Parkinsonism that can respond to dopaminergic agents (e.g., levodopa) occurs in a subset of individuals.
Sitting posture is compromised later in disease, with affected individuals assuming various tilted positions.
Autonomic dysfunction can sometimes be disabling, but is not always related to severity of motor dysfunction or disease duration.
• Upper motor neuron involvement (hyperreflexia, spasticity) may resemble HSP.
• Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
• Rigidity is a more reliable indicator than tremor or bradykinesia.
• Parkinsonism is often DOPA responsive.
• Autonomic problems, including bladder and thermoregulation disturbances; both cardiovascular and sudomotor dysfunction may be present [
• Disabling sleep disturbances [
• Fatigue that is often associated with depression and daytime somnolence [
• Impaired executive and emotional functioning, referred to as cerebellar cognitive affective syndrome [
• Chronic pain, often in the lumbosacral region [
• Vocal cord paralysis, though uncommon, has been described [
• Ambulation becomes increasingly difficult, leading to the need for assistive devices (including wheelchair) ten to 15 years following onset.
• Profound ataxia of limbs and gait becomes prominent. Individuals with later adult onset and shorter CAG repeats can manifest a disorder that combines ataxia, generalized areflexia, peripheral neuropathy, and muscle wasting.
• Saccadic eye movements become slow and ophthalmoparesis develops, resulting initially in upgaze restriction. Dysconjugate eye movements result in diplopia.
• At the same time, a number of other "brain stem" signs develop, including temporal and facial atrophy, characteristic action-induced perioral twitches, vestibular symptoms, tongue atrophy and fasciculations, dysphagia, and poor ability to cough and clear secretions.
• Often a staring appearance to the eyes is observed, but neither this nor the perioral fasciculations are specific for SCA3.
• Evidence of a peripheral polyneuropathy [
• Parkinsonism that can respond to dopaminergic agents (e.g., levodopa) occurs in a subset of individuals.
• Sitting posture is compromised later in disease, with affected individuals assuming various tilted positions.
• Autonomic dysfunction can sometimes be disabling, but is not always related to severity of motor dysfunction or disease duration.
## Genotype-Phenotype Correlations
In general, the longest disease-causing CAG repeats cause earlier-onset disease that is more likely to have dystonia as part of the presentation.
In contrast, the shortest disease-causing CAG repeats cause later-onset disease that is more likely to have peripheral manifestations such as neuropathy and weakness. Parkinsonism, which occurs in a subset of affected persons, is not associated with any particular CAG repeat size. Rare intermediate alleles of 45 to about 60 CAG repeats may show variable expressivity; in particular, these rare intermediate alleles can manifest with isolated restless legs syndrome with no other features of disease.
## Penetrance
In SCA3, penetrance approaches 100% and is age related.
CAG repeat sizes associated with reduced penetrance of SCA3 are not firmly defined. Of note, an asymptomatic individual age 66 years with 68 CAGs has been reported [
## Anticipation
Instability of the CAG repeat expansion has been documented in transmission of the repeat from parent to child. Overall, expansion of the repeat is more common than contraction; thus, anticipation (earlier age of onset and more severe disease manifestations in offspring) occurs in SCA3.
Although the probability of CAG repeat expansion may be greater with paternal than with maternal transmission, the paternal bias is not pronounced (as, for example, in
## Nomenclature
SCA3 is also known as Machado-Joseph disease (MJD) and Azorean ataxia. In fact, this autosomal dominant form of ataxia, which was first described among immigrants from the Portuguese Azorean islands, was initially known as MJD. In the early 1990s the locus for MJD was identified on chromosome 14 and revealed to be a CAG repeat expansion in
## Prevalence
No accurate data are available regarding the prevalence of SCA3 in the general population, though in many populations SCA3 is the most common of the autosomal dominant ataxias, which overall are rare.
Worldwide, SCA3 is thought to be the most common spinocerebellar ataxia (SCA), comprising 20%-50% of families (reviewed in
Countries in which SCA3 is the most common SCA include Portugal (58%-74%), Brazil (69%-92%), China (48%-49%), the Netherlands (44%), Germany (42%), and Japan (28%-63%).
In contrast, countries in which SCA3 is quite rare include Italy (1%) and South Africa (4%) [
In the US and Canada, SCA3 is one of several SCAs comprising the most common autosomal dominant ataxias, with SCA3 accounting for 21%-25% of families [
A large international genetic study showed that a single intragenic haplotype is shared by a majority of the families studied (including those from the Azorean island of Flores), suggesting a single founder variant. However, at least two other haplotypes have been identified in the Portuguese population [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Individuals with spinocerebellar ataxia type 3 (SCA3) may present with unexplained ataxia that is part of the larger differential diagnosis of hereditary and acquired ataxias (see
Progressive ataxia, often associated with evidence of upper motor neuron dysfunction including brisk tendon reflexes and extensor plantar responses, can be seen in individuals with SCA3 as well as in many other dominantly inherited ataxias. Thus, it is difficult and often impossible to distinguish SCA3 from the other hereditary ataxias (see
The presence of dystonia and parkinsonian features, including a beneficial response to levodopa or dopamine agonists, can cause diagnostic confusion with
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 3 (SCA3), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 3
Brain MRI &/or spinal cord MRI may be indicated to rule out coincident pathologies.
Consider referral to neuromuscular clinic.
Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
Consider referral to ophthalmologist for corrective measures incl prisms &/or surgery.
Nutritional status;
Aspiration risk.
CCAS scale
Psychiatrist, psychologist, or neuropsychologist if needed.
Community or
Social work involvement for parental support;
Home nursing referral.
BARS = Brief Ataxia Rating Scale; CCAS = cerebellar cognitive affective syndrome; ICARS = International Cooperative Ataxia Rating Scale; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no specific treatment for SCA3. The goals of treatment are to maximize function and reduce complications. Each individual should be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech therapists, social workers, and psychologists depending on the clinical manifestations.
Management remains supportive as no medication has been proven to slow the course of disease, Excellent reviews include
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 3
PT & OT
Self-directed exercise
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADL, incl use of adaptive devices (e.g., weighted eating utensils, dressing hooks)
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
Inpatient rehab w/OT/PT may improve ataxia & functional abilities in patents w/degenerative ataxias.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected individuals should maintain activity.
Oral antispasmodics (baclofen, atropine-like drugs, & hypnotic agents) may yield variable response.
Botulinum toxin
Antispasmodic agents (e.g., anticholinergics, baclofen) or botulinum toxin injections
For generalized dystonia, consider pallidal deep brain stimulation.
Prisms
Corrective surgery for strabismus
Although 4-aminopyridine can ↓ downbeat nystagmus, horizontal nystagmus is much more common in SCA3.
Video esophagram may help define best food consistency.
Education re strategies to mitigate aspiration
Consider nutritional & vitamin supplementation to meet dietary needs.
Avoid obesity, which can exacerbate difficulties w/ambulation & mobility.
Oral agents for bladder spasticity (anticholinergics, mirabegron)
Percutaneous tibial nerve stimulation
Iron replacement if deficient
Levodopa or dopamine agonist
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist; REM = rapid eye movement
Depression scores improved as a consequence of occupational therapy, underscoring the fact that non-pharmacologic measures may also improve affective disorder in SCA3 [
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 3
Neurologic assessment for progression of ataxia; UMN or LMN signs; dystonia & parkinsonism; autonomic dysfunction
Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
Monitor BMI.
Consult a nutritionist.
High-calorie supplementation
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
See
Currently, no medication has been proven to slow or halt the progression of SCA3. The recent promise of nucleotide-based gene silencing strategies in other neurodegenerative diseases such as spinal muscular atrophy, coupled with preclinical success of gene silencing therapy in mouse models of SCA3 [
Ataxia investigators in Europe and in the United States are currently engaged in a collaborative grant application for trial readiness for SCA3 (READISCA) that is seeking to define the natural history of SCA3 and appropriate disease biomarkers [
Troriluzole, a prodrug (i.e., a biologically inactive compound that can be metabolized in the body to produce a drug) of riluzole, is currently being tested as a potential symptomatic treatment for ataxia in several spinocerebellar ataxias including SCA3.
Potassium ion channel modulators have been shown to have symptomatic benefit in animal models of several spinocerebellar ataxias [
Search
• Brain MRI &/or spinal cord MRI may be indicated to rule out coincident pathologies.
• Consider referral to neuromuscular clinic.
• Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
• Consider referral to ophthalmologist for corrective measures incl prisms &/or surgery.
• Nutritional status;
• Aspiration risk.
• CCAS scale
• Psychiatrist, psychologist, or neuropsychologist if needed.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• PT & OT
• Self-directed exercise
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADL, incl use of adaptive devices (e.g., weighted eating utensils, dressing hooks)
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
• Inpatient rehab w/OT/PT may improve ataxia & functional abilities in patents w/degenerative ataxias.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
• Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected individuals should maintain activity.
• Oral antispasmodics (baclofen, atropine-like drugs, & hypnotic agents) may yield variable response.
• Botulinum toxin
• Antispasmodic agents (e.g., anticholinergics, baclofen) or botulinum toxin injections
• For generalized dystonia, consider pallidal deep brain stimulation.
• Prisms
• Corrective surgery for strabismus
• Although 4-aminopyridine can ↓ downbeat nystagmus, horizontal nystagmus is much more common in SCA3.
• Video esophagram may help define best food consistency.
• Education re strategies to mitigate aspiration
• Consider nutritional & vitamin supplementation to meet dietary needs.
• Avoid obesity, which can exacerbate difficulties w/ambulation & mobility.
• Oral agents for bladder spasticity (anticholinergics, mirabegron)
• Percutaneous tibial nerve stimulation
• Iron replacement if deficient
• Levodopa or dopamine agonist
• Neurologic assessment for progression of ataxia; UMN or LMN signs; dystonia & parkinsonism; autonomic dysfunction
• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
• Monitor BMI.
• Consult a nutritionist.
• High-calorie supplementation
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 3 (SCA3), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 3
Brain MRI &/or spinal cord MRI may be indicated to rule out coincident pathologies.
Consider referral to neuromuscular clinic.
Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
Consider referral to ophthalmologist for corrective measures incl prisms &/or surgery.
Nutritional status;
Aspiration risk.
CCAS scale
Psychiatrist, psychologist, or neuropsychologist if needed.
Community or
Social work involvement for parental support;
Home nursing referral.
BARS = Brief Ataxia Rating Scale; CCAS = cerebellar cognitive affective syndrome; ICARS = International Cooperative Ataxia Rating Scale; LMN = lower motor neuron; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Brain MRI &/or spinal cord MRI may be indicated to rule out coincident pathologies.
• Consider referral to neuromuscular clinic.
• Assess best corrected visual acuity; nystagmus, saccades & smooth pursuit; vertical & horizontal gaze limitation; ptosis.
• Consider referral to ophthalmologist for corrective measures incl prisms &/or surgery.
• Nutritional status;
• Aspiration risk.
• CCAS scale
• Psychiatrist, psychologist, or neuropsychologist if needed.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
There is no specific treatment for SCA3. The goals of treatment are to maximize function and reduce complications. Each individual should be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech therapists, social workers, and psychologists depending on the clinical manifestations.
Management remains supportive as no medication has been proven to slow the course of disease, Excellent reviews include
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 3
PT & OT
Self-directed exercise
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADL, incl use of adaptive devices (e.g., weighted eating utensils, dressing hooks)
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
Inpatient rehab w/OT/PT may improve ataxia & functional abilities in patents w/degenerative ataxias.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected individuals should maintain activity.
Oral antispasmodics (baclofen, atropine-like drugs, & hypnotic agents) may yield variable response.
Botulinum toxin
Antispasmodic agents (e.g., anticholinergics, baclofen) or botulinum toxin injections
For generalized dystonia, consider pallidal deep brain stimulation.
Prisms
Corrective surgery for strabismus
Although 4-aminopyridine can ↓ downbeat nystagmus, horizontal nystagmus is much more common in SCA3.
Video esophagram may help define best food consistency.
Education re strategies to mitigate aspiration
Consider nutritional & vitamin supplementation to meet dietary needs.
Avoid obesity, which can exacerbate difficulties w/ambulation & mobility.
Oral agents for bladder spasticity (anticholinergics, mirabegron)
Percutaneous tibial nerve stimulation
Iron replacement if deficient
Levodopa or dopamine agonist
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist; REM = rapid eye movement
Depression scores improved as a consequence of occupational therapy, underscoring the fact that non-pharmacologic measures may also improve affective disorder in SCA3 [
• PT & OT
• Self-directed exercise
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADL, incl use of adaptive devices (e.g., weighted eating utensils, dressing hooks)
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
• Inpatient rehab w/OT/PT may improve ataxia & functional abilities in patents w/degenerative ataxias.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
• Although neither exercise nor PT slows progression of incoordination or muscle weakness, affected individuals should maintain activity.
• Oral antispasmodics (baclofen, atropine-like drugs, & hypnotic agents) may yield variable response.
• Botulinum toxin
• Antispasmodic agents (e.g., anticholinergics, baclofen) or botulinum toxin injections
• For generalized dystonia, consider pallidal deep brain stimulation.
• Prisms
• Corrective surgery for strabismus
• Although 4-aminopyridine can ↓ downbeat nystagmus, horizontal nystagmus is much more common in SCA3.
• Video esophagram may help define best food consistency.
• Education re strategies to mitigate aspiration
• Consider nutritional & vitamin supplementation to meet dietary needs.
• Avoid obesity, which can exacerbate difficulties w/ambulation & mobility.
• Oral agents for bladder spasticity (anticholinergics, mirabegron)
• Percutaneous tibial nerve stimulation
• Iron replacement if deficient
• Levodopa or dopamine agonist
## Surveillance
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 3
Neurologic assessment for progression of ataxia; UMN or LMN signs; dystonia & parkinsonism; autonomic dysfunction
Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
Monitor BMI.
Consult a nutritionist.
High-calorie supplementation
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
• Neurologic assessment for progression of ataxia; UMN or LMN signs; dystonia & parkinsonism; autonomic dysfunction
• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
• Monitor BMI.
• Consult a nutritionist.
• High-calorie supplementation
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Currently, no medication has been proven to slow or halt the progression of SCA3. The recent promise of nucleotide-based gene silencing strategies in other neurodegenerative diseases such as spinal muscular atrophy, coupled with preclinical success of gene silencing therapy in mouse models of SCA3 [
Ataxia investigators in Europe and in the United States are currently engaged in a collaborative grant application for trial readiness for SCA3 (READISCA) that is seeking to define the natural history of SCA3 and appropriate disease biomarkers [
Troriluzole, a prodrug (i.e., a biologically inactive compound that can be metabolized in the body to produce a drug) of riluzole, is currently being tested as a potential symptomatic treatment for ataxia in several spinocerebellar ataxias including SCA3.
Potassium ion channel modulators have been shown to have symptomatic benefit in animal models of several spinocerebellar ataxias [
Search
## Genetic Counseling
Spinocerebellar ataxia type 3 (SCA3) is inherited in an autosomal dominant manner.
Most individuals diagnosed with SCA3 have an affected parent.
A proband with SCA3 may have the disorder as the result of expansion of an intermediate
If neither of the parents of the proband is known have SCA3, recommendations for the evaluation of parents include physical examination and consideration of
The family history of some individuals diagnosed with SCA3 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to have an intermediate or pathogenic
If an expanded CAG repeat cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
If the parents of a proband are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for SCA3 because of the possibility of late onset of SCA3 in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
Each child of an affected individual has a 50% chance of inheriting the
The CAG repeat may expand on transmission from proband to offspring resulting in an earlier age of onset and more severe disease manifestations in offspring (see
Note: If neither parent of a proband with SCA3 has 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 molecular genetic testing has identified an
This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
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 genetic testing has proven beneficial in the Azore Islands, a region with high prevalence of SCA3 [
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 SCA3, it is appropriate to consider testing of symptomatic individuals regardless of age.
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 individuals diagnosed with SCA3 have an affected parent.
• A proband with SCA3 may have the disorder as the result of expansion of an intermediate
• If neither of the parents of the proband is known have SCA3, recommendations for the evaluation of parents include physical examination and consideration of
• The family history of some individuals diagnosed with SCA3 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to have an intermediate or pathogenic
• If an expanded CAG repeat cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
• If the parents of a proband are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for SCA3 because of the possibility of late onset of SCA3 in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Each child of an affected individual has a 50% chance of inheriting the
• The CAG repeat may expand on transmission from proband to offspring resulting in an earlier age of onset and more severe disease manifestations in offspring (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.
• Predictive testing for at-risk relatives is possible once molecular genetic testing has identified an
• This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• 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 genetic testing has proven beneficial in the Azore Islands, a region with high prevalence of SCA3 [
• 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
Spinocerebellar ataxia type 3 (SCA3) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with SCA3 have an affected parent.
A proband with SCA3 may have the disorder as the result of expansion of an intermediate
If neither of the parents of the proband is known have SCA3, recommendations for the evaluation of parents include physical examination and consideration of
The family history of some individuals diagnosed with SCA3 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to have an intermediate or pathogenic
If an expanded CAG repeat cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
If the parents of a proband are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for SCA3 because of the possibility of late onset of SCA3 in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
Each child of an affected individual has a 50% chance of inheriting the
The CAG repeat may expand on transmission from proband to offspring resulting in an earlier age of onset and more severe disease manifestations in offspring (see
• Most individuals diagnosed with SCA3 have an affected parent.
• A proband with SCA3 may have the disorder as the result of expansion of an intermediate
• If neither of the parents of the proband is known have SCA3, recommendations for the evaluation of parents include physical examination and consideration of
• The family history of some individuals diagnosed with SCA3 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to have an intermediate or pathogenic
• If an expanded CAG repeat cannot be detected in the leukocyte DNA of either parent, the risk to sibs is low but greater than that of the general population because of the theoretic possibility of parental germline mosaicism.
• If the parents of a proband are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for SCA3 because of the possibility of late onset of SCA3 in a heterozygous parent or the theoretic possibility of parental germline mosaicism.
• Each child of an affected individual has a 50% chance of inheriting the
• The CAG repeat may expand on transmission from proband to offspring resulting in an earlier age of onset and more severe disease manifestations in offspring (see
## Related Genetic Counseling Issues
Note: If neither parent of a proband with SCA3 has 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 molecular genetic testing has identified an
This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
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 genetic testing has proven beneficial in the Azore Islands, a region with high prevalence of SCA3 [
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 SCA3, 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 molecular genetic testing has identified an
• This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• 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 genetic testing has proven beneficial in the Azore Islands, a region with high prevalence of SCA3 [
• 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 use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
## Resources
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•
• 1425 Alvarado Avenue
• Burlingame CA 94010-5547
•
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
• Spain
•
•
• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia Type 3: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 3 (
SCA3 is one of several SCAs caused by polyglutamine-encoding CAG repeat expansions [
Alleles w/abnormal number of CAG repeats may display somatic instability of the repeat, appearing as "smeared" expanded alleles w/multiple distinct expansion sizes on PCR & Southern blot analyses [
In early studies of the central nervous system, cerebellar tissues tended to have slightly smaller repeat lengths than other brain regions, but higher resolution analysis of somatic expansions employing single cell methods has not been published.
Typically, spermatozoa contain a larger repeat length than leukocytes in the same individuals [
The probability of repeat expansion is greater w/paternal than w/maternal transmission, though the paternal bias is not pronounced.
Methods to Characterize
The design of a triplet-primed PCR (TP-PCR) assay may include conventional PCR primers to size normal repeats and detect expanded repeats in a single assay. The TP-PCR assay itself does not determine repeat size, even alleles in the normal range.
Methods to detect and approximate the size of expanded repeats include long-range PCR sized by gel electrophoresis and Southern blotting. The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/or affected individual as a result of competition by the normal allele during amplification.
Detection of an apparently homozygous repeat does not rule out the presence of an expanded CAG repeat; thus, testing by TP-PCR or expanded repeat analysis is required to detect a repeat expansion.
Southern blotting for the CAG repeat expansion has been described [
Precise sizing of repeats is not necessary as clinical utility for determining the exact repeat number has not been demonstrated.
The smallest unstable repeat reported was 45 CAG repeats [
TP-PCR for the CAG repeat expansion has been described [
Repeats at the lower end of this range may not show the characteristic stutter pattern that indicates an expanded allele.
Notable
Variants listed in the table have been provided by the authors.
• Alleles w/abnormal number of CAG repeats may display somatic instability of the repeat, appearing as "smeared" expanded alleles w/multiple distinct expansion sizes on PCR & Southern blot analyses [
• In early studies of the central nervous system, cerebellar tissues tended to have slightly smaller repeat lengths than other brain regions, but higher resolution analysis of somatic expansions employing single cell methods has not been published.
• Typically, spermatozoa contain a larger repeat length than leukocytes in the same individuals [
• The probability of repeat expansion is greater w/paternal than w/maternal transmission, though the paternal bias is not pronounced.
## Molecular Pathogenesis
SCA3 is one of several SCAs caused by polyglutamine-encoding CAG repeat expansions [
Alleles w/abnormal number of CAG repeats may display somatic instability of the repeat, appearing as "smeared" expanded alleles w/multiple distinct expansion sizes on PCR & Southern blot analyses [
In early studies of the central nervous system, cerebellar tissues tended to have slightly smaller repeat lengths than other brain regions, but higher resolution analysis of somatic expansions employing single cell methods has not been published.
Typically, spermatozoa contain a larger repeat length than leukocytes in the same individuals [
The probability of repeat expansion is greater w/paternal than w/maternal transmission, though the paternal bias is not pronounced.
Methods to Characterize
The design of a triplet-primed PCR (TP-PCR) assay may include conventional PCR primers to size normal repeats and detect expanded repeats in a single assay. The TP-PCR assay itself does not determine repeat size, even alleles in the normal range.
Methods to detect and approximate the size of expanded repeats include long-range PCR sized by gel electrophoresis and Southern blotting. The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/or affected individual as a result of competition by the normal allele during amplification.
Detection of an apparently homozygous repeat does not rule out the presence of an expanded CAG repeat; thus, testing by TP-PCR or expanded repeat analysis is required to detect a repeat expansion.
Southern blotting for the CAG repeat expansion has been described [
Precise sizing of repeats is not necessary as clinical utility for determining the exact repeat number has not been demonstrated.
The smallest unstable repeat reported was 45 CAG repeats [
TP-PCR for the CAG repeat expansion has been described [
Repeats at the lower end of this range may not show the characteristic stutter pattern that indicates an expanded allele.
Notable
Variants listed in the table have been provided by the authors.
• Alleles w/abnormal number of CAG repeats may display somatic instability of the repeat, appearing as "smeared" expanded alleles w/multiple distinct expansion sizes on PCR & Southern blot analyses [
• In early studies of the central nervous system, cerebellar tissues tended to have slightly smaller repeat lengths than other brain regions, but higher resolution analysis of somatic expansions employing single cell methods has not been published.
• Typically, spermatozoa contain a larger repeat length than leukocytes in the same individuals [
• The probability of repeat expansion is greater w/paternal than w/maternal transmission, though the paternal bias is not pronounced.
## Chapter Notes
D Olga McDaniel, PhD; University of Mississippi Medical Center (1998-2006) Henry Paulson, MD, PhD (2006-present) Vikram Shakkottai, MD, PhD (2020-present)Stephanie C Smith, MS; University of Mississippi Medical Center (1998-2006) SH Subramony, MD; University of Mississippi Medical Center (1998-2006) Parminder JS Vig, PhD; University of Mississippi Medical Center (1998-2006)
4 June 2020 (bp) Comprehensive update posted live
24 September 2015 (me) Comprehensive update posted live
17 March 2011 (me) Comprehensive update posted live
3 August 2007 (me) Comprehensive update posted live
30 September 2003 (me) Comprehensive update posted live
24 May 2001 (me) Comprehensive update posted live
10 October 1998 (pb) Review posted live
13 July 1998 (shs) Original submission
• 4 June 2020 (bp) Comprehensive update posted live
• 24 September 2015 (me) Comprehensive update posted live
• 17 March 2011 (me) Comprehensive update posted live
• 3 August 2007 (me) Comprehensive update posted live
• 30 September 2003 (me) Comprehensive update posted live
• 24 May 2001 (me) Comprehensive update posted live
• 10 October 1998 (pb) Review posted live
• 13 July 1998 (shs) Original submission
## Author History
D Olga McDaniel, PhD; University of Mississippi Medical Center (1998-2006) Henry Paulson, MD, PhD (2006-present) Vikram Shakkottai, MD, PhD (2020-present)Stephanie C Smith, MS; University of Mississippi Medical Center (1998-2006) SH Subramony, MD; University of Mississippi Medical Center (1998-2006) Parminder JS Vig, PhD; University of Mississippi Medical Center (1998-2006)
## Revision History
4 June 2020 (bp) Comprehensive update posted live
24 September 2015 (me) Comprehensive update posted live
17 March 2011 (me) Comprehensive update posted live
3 August 2007 (me) Comprehensive update posted live
30 September 2003 (me) Comprehensive update posted live
24 May 2001 (me) Comprehensive update posted live
10 October 1998 (pb) Review posted live
13 July 1998 (shs) Original submission
• 4 June 2020 (bp) Comprehensive update posted live
• 24 September 2015 (me) Comprehensive update posted live
• 17 March 2011 (me) Comprehensive update posted live
• 3 August 2007 (me) Comprehensive update posted live
• 30 September 2003 (me) Comprehensive update posted live
• 24 May 2001 (me) Comprehensive update posted live
• 10 October 1998 (pb) Review posted live
• 13 July 1998 (shs) Original submission
## References
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
## Published Guidelines / Consensus Statements
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
National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
• 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
• National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available
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|
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"K Bürk, M Abele, M Fetter, J Dichgans, M Skalej, F Laccone, O Didierjean, A Brice, T Klockgether. Autosomal dominant cerebellar ataxia type I clinical features and MRI in families with SCA1, SCA2 and SCA3.. Brain 1996;119:1497-505",
"K Bürk, DA Sival. Scales for the clinical evaluation of cerebellar disorders.. Handb Clin Neurol 2018;154:329-39",
"DD Bushart, R Chopra, V Singh, GG Murphy, H Wulff, VG Shakkottai. Targeting potassium channels to treat cerebellar ataxia.. Ann Clin Transl Neurol. 2018;5:297-314",
"C Cagnoli, A Brussino, C Mancini, M Ferrone, L Orsi, P Salmin, P Pappi, E Giorgio, E Pozzi, S Cavalieri, E Di Gregorio, M Ferrero, A Filla, G De Michele, C Gellera, C Mariotti, S Nethisinghe, P Giunti, G Stevanin, A Brusco. Spinocerebellar ataxia tethering PCR: a rapid genetic test for the diagnosis of spinocerebellar ataxia types 1, 2, 3, 6, and 7 by PCR and capillary electrophoresis.. J Mol Diagn. 2018;20:289-97",
"G Cancel, N Abbas, G Stevanin, A Dürr, H Chneiweiss, C Neri, C Duyckaerts, C Penet, HM Cann, Y Agid, A Brice. Marked phenotypic heterogeneity associated with expansion of a CAG repeat sequence at the spinocerebellar ataxia 3/Machado-Joseph disease locus.. Am J Hum Genet 1995;57:809-16",
"DR Carvalho, A La Rocque-Ferreira, IM Rizzo, EU Imamura, CE Speck-Martins. Homozygosity enhances severity in spinocerebellar ataxia type 3.. Pediatr Neurol 2008;38:296-9",
"CR Cecchin, AP Pires, CR Rieder, TL Monte, I Silveira, T Carvalho, ML Saraiva-Pereira, J Sequeiros, LB Jardim. Depressive symptoms in Machado-Joseph disease (SCA3) patients and their relatives.. Community Genet 2007;10:19-26",
"C Costa Mdo, HL Paulson. Toward understanding Machado Joseph disease.. Prog Neurobiol 2012;97:239-57",
"A D'Abreu, M França, L Conz, JH Friedman, AM Nucci, F Cendes, I Lopes-Cendes. Sleep symptoms and their clinical correlates in Machado-Joseph disease.. Acta Neurol Scand 2009;119:277-80",
"A D'Abreu, MC França, HL Paulson, I Lopes-Cendes. Caring for Machado-Joseph disease: current understanding and how to help patients.. Parkinsonism Relat Disord 2010;16:2-7",
"S Duarte-Silva, P Maciel. Pharmacological therapies for Machado-Joseph disease.. Adv Exp Med Biol 2018;1049:369-94",
"A Dürr, G Stevanin, G Cancel, C Duyckaerts, N Abbas, O Didierjean, H Chneiweiss, A Benomar, O Lyon-Caen, J Julien, M Serdaru, C Penet, Y Agid, A Brice. Spinocerebellar ataxia 3 and Machado-Joseph disease: clinical, molecular, and neuropathological features.. Ann Neurol 1996;39:490-9",
"HL Fowler. Machado-Joseph-Azorean disease. A ten-year study.. Arch Neurol 1984;41:921-5",
"MC França, A D'Abreu, JH Friedman, A Nucci, I Lopes-Cendes. Chronic pain in Machado-Joseph disease: a frequent and disabling symptom.. Arch Neurol. 2007;64:1767-70",
"MC França, A D'Abreu, A Nucci, F Cendes, I Lopes-Cendes. Prospective study of peripheral neuropathy in Machado-Joseph disease.. Muscle Nerve 2009;40:1012-8",
"MC França, A D'Abreu, A Nucci, I Lopes-Cendes. Clinical correlates of autonomic dysfunction in patients with Machado-Joseph disease.. Acta Neurol Scand. 2010;121:422-5",
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"C Gaspar, I Lopes-Cendes, S Hayes, J Goto, K Arvidsson, A Dias, I Silveira, P Maciel, P Coutinho, M Lima, YX Zhou, BW Soong, M Watanabe, P Giunti, G Stevanin, O Riess, H Sasaki, M Hsieh, GA Nicholson, E Brunt, JJ Higgins, M Lauritzen, L Tranebjaerg, V Volpini, N Wood, L Ranum, S Tsuji, A Brice, J Sequeiros, GA Rouleau. Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study.. Am J Hum Genet 2001;68:523-8",
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"O Onodera, J Idezuka, S Igarashi, Y Takiyama, K Endo, H Takano, M Oyake, H Tanaka, T Inuzuka, T Hayashi, T Yuasa, J Ito, T Miyatake, S Tsuji. Progressive atrophy of cerebellum and brainstem as a function of age and the size of the expanded CAG repeats in the MJD1 gene in Machado-Joseph disease.. Ann Neurol 1998;43:288-96",
"QS Padiath, AK Srivastava, S Roy, S Jain, SK Brahmachari. Identification of a novel 45 repeat unstable allele associated with a disease phenotype at the MJD1/SCA3 locus.. Am J Med Genet B Neuropsychiatr Genet. 2005;133B:124-6",
"HL Paulson, MK Perez, Y Trottier, JQ Trojanowski, SH Subramony, SS Das, P Vig, JL Mandel, KH Fischbeck, RN Pittman. Intranuclear inclusions of expanded polyglutamine protein in spinocerebellar ataxia type 3.. Neuron 1997;19:333-44",
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"JL Pedroso, P Braga-Neto, AR Martinez, CR Martins, FM Rezende Filho, MA Sobreira-Neto, LB Prado, GF do Prado, MC França, OG Barsottini. Sleep disorders in Machado-Joseph disease.. Curr Opin Psychiatry 2016;29:402-8",
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] |
10/10/1998
|
4/6/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sca36
|
sca36
|
[
"Asidan/SCA36",
"Costa da Morte Ataxia",
"SCA36",
"SCA36",
"Asidan/SCA36",
"Costa da Morte Ataxia",
"Nucleolar protein 56",
"NOP56",
"Spinocerebellar Ataxia Type 36"
] |
Spinocerebellar Ataxia Type 36 – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Manuel Arias, Beatriz Quintáns, María García-Murias, Maria J Sobrido
|
Summary Spinocerebellar ataxia type 36 (SCA36) is characterized by a late-onset, slowly progressive cerebellar syndrome typically associated with sensorineural hearing loss. Other common features are muscle atrophy and denervation, especially of the tongue, as well as pyramidal signs, thus overlapping with motor neuron disorders. Mild frontal-subcortical affective and cognitive decline may be present as the disease progresses. Brain MRI shows atrophy of the cerebellar vermis in initial stages, later evolving to a pattern of olivopontocerebellar atrophy. The diagnosis is suspected based on clinical findings in the absence of primary causes of cerebellar dysfunction. It is supported by a family history consistent with autosomal dominant inheritance, which can include simplex cases (i.e., a single occurrence in a family). Confirmation of the diagnosis relies on detection of an abnormal hexanucleotide GGCCTG repeat expansion in SCA36 is inherited in an autosomal dominant manner. Penetrance is complete, although age-dependent. Offspring of affected individuals have a 50% chance of inheriting the
|
## Diagnosis
The clinical suspicion of spinocerebellar ataxia type 36 (SCA36) is based on the presence of the following nonspecific findings:
Midline cerebellar ataxia of late onset (usually between ages 40 and 60 years) and slow progression
Dysarthria and appendicular ataxia generally following the gait imbalance
Slowly progressive sensorineural hearing loss (SNHL) with onset usually a few years after the cerebellar manifestations
A drop of ≥40 dB in frequencies beyond 2500 Hz can be recorded through pure tonal audiometry.
Brain stem auditory evoked potentials are characterized by absence or reduced amplitude of waves I and II, consistent with a sensorineural hearing loss [
Tongue atrophy and fasciculations, additional signs of motor neuron degeneration in some cases [
Note: Peripheral nerve conduction velocities, both motor and sensory, are usually within normal range. Somatosensory evoked potentials may show mild abnormalities after stimulation in the lower limbs [
Other clinical features variably present: gaze-evoked nystagmus, eyelid ptosis, decreased vibration sense, and cognitive impairment
On brain MRI: atrophy of the superior vermis in initial stages, global cerebellar atrophy in intermediate stages, and olivopontocerebellar atrophy in advanced stages
Cerebellar atrophy is a constant finding, usually starting in the upper vermis and progressing to the hemispheres.
Involvement of the pons and medulla with subcortical atrophy and dilatation of the fourth ventricle is present later on with a pattern of olivopontocerebellar degeneration; however, the "cross sign" brain stem T
White matter abnormalities are generally not a feature of this disease.
Cortical brain atrophy (especially of frontal areas) may be seen in advanced cases [
Family history consistent with autosomal dominant inheritance. Of note, the disease may not be recognized in previous generations because of late onset and/or mild manifestations. Thus, SCA36 should also be considered in simplex cases (i.e., single occurrence in a family) with undiagnosed ataxia, especially in geographic regions where families with SCA36 have been observed (see
To establish the diagnosis of SCA36 in a proband requires identification of a
The number of GGCCTG repeats varies from three to 14, with the nine-repeat allele being the most frequent in persons of northern European background [
Molecular genetic testing is performed as targeted analysis for pathogenic variants to determine the number of GGCCTG hexanucleotide repeats (see
The presence of two normal-sized
If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
Note: Beyond the normal allele range, no clear clinical utility has been demonstrated to date from knowing the exact repeat number; thus, estimation of allele size by Southern blot or other methods is not performed on a routine basis.
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 36
See
Conventional PCR analysis detects normal-sized alleles (3-14 GGCCTG repeats) and expanded alleles in the lower range of alleles of uncertain significance.
Only RP-PCR and/or Southern blot analysis of genomic DNA can detect the presence or absence of a large expanded pathogenic GGCCTG hexanucleotide repeat.
Pathogenic allele size is ~650 to ≥∼2500 GGCCTG repeats.
• Midline cerebellar ataxia of late onset (usually between ages 40 and 60 years) and slow progression
• Dysarthria and appendicular ataxia generally following the gait imbalance
• Slowly progressive sensorineural hearing loss (SNHL) with onset usually a few years after the cerebellar manifestations
• A drop of ≥40 dB in frequencies beyond 2500 Hz can be recorded through pure tonal audiometry.
• Brain stem auditory evoked potentials are characterized by absence or reduced amplitude of waves I and II, consistent with a sensorineural hearing loss [
• A drop of ≥40 dB in frequencies beyond 2500 Hz can be recorded through pure tonal audiometry.
• Brain stem auditory evoked potentials are characterized by absence or reduced amplitude of waves I and II, consistent with a sensorineural hearing loss [
• Tongue atrophy and fasciculations, additional signs of motor neuron degeneration in some cases [
• Note: Peripheral nerve conduction velocities, both motor and sensory, are usually within normal range. Somatosensory evoked potentials may show mild abnormalities after stimulation in the lower limbs [
• Other clinical features variably present: gaze-evoked nystagmus, eyelid ptosis, decreased vibration sense, and cognitive impairment
• On brain MRI: atrophy of the superior vermis in initial stages, global cerebellar atrophy in intermediate stages, and olivopontocerebellar atrophy in advanced stages
• Cerebellar atrophy is a constant finding, usually starting in the upper vermis and progressing to the hemispheres.
• Involvement of the pons and medulla with subcortical atrophy and dilatation of the fourth ventricle is present later on with a pattern of olivopontocerebellar degeneration; however, the "cross sign" brain stem T
• White matter abnormalities are generally not a feature of this disease.
• Cortical brain atrophy (especially of frontal areas) may be seen in advanced cases [
• Cerebellar atrophy is a constant finding, usually starting in the upper vermis and progressing to the hemispheres.
• Involvement of the pons and medulla with subcortical atrophy and dilatation of the fourth ventricle is present later on with a pattern of olivopontocerebellar degeneration; however, the "cross sign" brain stem T
• White matter abnormalities are generally not a feature of this disease.
• Cortical brain atrophy (especially of frontal areas) may be seen in advanced cases [
• Family history consistent with autosomal dominant inheritance. Of note, the disease may not be recognized in previous generations because of late onset and/or mild manifestations. Thus, SCA36 should also be considered in simplex cases (i.e., single occurrence in a family) with undiagnosed ataxia, especially in geographic regions where families with SCA36 have been observed (see
• A drop of ≥40 dB in frequencies beyond 2500 Hz can be recorded through pure tonal audiometry.
• Brain stem auditory evoked potentials are characterized by absence or reduced amplitude of waves I and II, consistent with a sensorineural hearing loss [
• Cerebellar atrophy is a constant finding, usually starting in the upper vermis and progressing to the hemispheres.
• Involvement of the pons and medulla with subcortical atrophy and dilatation of the fourth ventricle is present later on with a pattern of olivopontocerebellar degeneration; however, the "cross sign" brain stem T
• White matter abnormalities are generally not a feature of this disease.
• Cortical brain atrophy (especially of frontal areas) may be seen in advanced cases [
• The number of GGCCTG repeats varies from three to 14, with the nine-repeat allele being the most frequent in persons of northern European background [
• The number of GGCCTG repeats varies from three to 14, with the nine-repeat allele being the most frequent in persons of northern European background [
• The number of GGCCTG repeats varies from three to 14, with the nine-repeat allele being the most frequent in persons of northern European background [
• The presence of two normal-sized
• If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
• The presence of two normal-sized
• If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
• The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
• Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
• The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
• Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
• At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
• Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
• At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
• Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
• The presence of two normal-sized
• If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
• The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
• Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
• At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
• Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
## Suggestive Findings
The clinical suspicion of spinocerebellar ataxia type 36 (SCA36) is based on the presence of the following nonspecific findings:
Midline cerebellar ataxia of late onset (usually between ages 40 and 60 years) and slow progression
Dysarthria and appendicular ataxia generally following the gait imbalance
Slowly progressive sensorineural hearing loss (SNHL) with onset usually a few years after the cerebellar manifestations
A drop of ≥40 dB in frequencies beyond 2500 Hz can be recorded through pure tonal audiometry.
Brain stem auditory evoked potentials are characterized by absence or reduced amplitude of waves I and II, consistent with a sensorineural hearing loss [
Tongue atrophy and fasciculations, additional signs of motor neuron degeneration in some cases [
Note: Peripheral nerve conduction velocities, both motor and sensory, are usually within normal range. Somatosensory evoked potentials may show mild abnormalities after stimulation in the lower limbs [
Other clinical features variably present: gaze-evoked nystagmus, eyelid ptosis, decreased vibration sense, and cognitive impairment
On brain MRI: atrophy of the superior vermis in initial stages, global cerebellar atrophy in intermediate stages, and olivopontocerebellar atrophy in advanced stages
Cerebellar atrophy is a constant finding, usually starting in the upper vermis and progressing to the hemispheres.
Involvement of the pons and medulla with subcortical atrophy and dilatation of the fourth ventricle is present later on with a pattern of olivopontocerebellar degeneration; however, the "cross sign" brain stem T
White matter abnormalities are generally not a feature of this disease.
Cortical brain atrophy (especially of frontal areas) may be seen in advanced cases [
Family history consistent with autosomal dominant inheritance. Of note, the disease may not be recognized in previous generations because of late onset and/or mild manifestations. Thus, SCA36 should also be considered in simplex cases (i.e., single occurrence in a family) with undiagnosed ataxia, especially in geographic regions where families with SCA36 have been observed (see
• Midline cerebellar ataxia of late onset (usually between ages 40 and 60 years) and slow progression
• Dysarthria and appendicular ataxia generally following the gait imbalance
• Slowly progressive sensorineural hearing loss (SNHL) with onset usually a few years after the cerebellar manifestations
• A drop of ≥40 dB in frequencies beyond 2500 Hz can be recorded through pure tonal audiometry.
• Brain stem auditory evoked potentials are characterized by absence or reduced amplitude of waves I and II, consistent with a sensorineural hearing loss [
• A drop of ≥40 dB in frequencies beyond 2500 Hz can be recorded through pure tonal audiometry.
• Brain stem auditory evoked potentials are characterized by absence or reduced amplitude of waves I and II, consistent with a sensorineural hearing loss [
• Tongue atrophy and fasciculations, additional signs of motor neuron degeneration in some cases [
• Note: Peripheral nerve conduction velocities, both motor and sensory, are usually within normal range. Somatosensory evoked potentials may show mild abnormalities after stimulation in the lower limbs [
• Other clinical features variably present: gaze-evoked nystagmus, eyelid ptosis, decreased vibration sense, and cognitive impairment
• On brain MRI: atrophy of the superior vermis in initial stages, global cerebellar atrophy in intermediate stages, and olivopontocerebellar atrophy in advanced stages
• Cerebellar atrophy is a constant finding, usually starting in the upper vermis and progressing to the hemispheres.
• Involvement of the pons and medulla with subcortical atrophy and dilatation of the fourth ventricle is present later on with a pattern of olivopontocerebellar degeneration; however, the "cross sign" brain stem T
• White matter abnormalities are generally not a feature of this disease.
• Cortical brain atrophy (especially of frontal areas) may be seen in advanced cases [
• Cerebellar atrophy is a constant finding, usually starting in the upper vermis and progressing to the hemispheres.
• Involvement of the pons and medulla with subcortical atrophy and dilatation of the fourth ventricle is present later on with a pattern of olivopontocerebellar degeneration; however, the "cross sign" brain stem T
• White matter abnormalities are generally not a feature of this disease.
• Cortical brain atrophy (especially of frontal areas) may be seen in advanced cases [
• Family history consistent with autosomal dominant inheritance. Of note, the disease may not be recognized in previous generations because of late onset and/or mild manifestations. Thus, SCA36 should also be considered in simplex cases (i.e., single occurrence in a family) with undiagnosed ataxia, especially in geographic regions where families with SCA36 have been observed (see
• A drop of ≥40 dB in frequencies beyond 2500 Hz can be recorded through pure tonal audiometry.
• Brain stem auditory evoked potentials are characterized by absence or reduced amplitude of waves I and II, consistent with a sensorineural hearing loss [
• Cerebellar atrophy is a constant finding, usually starting in the upper vermis and progressing to the hemispheres.
• Involvement of the pons and medulla with subcortical atrophy and dilatation of the fourth ventricle is present later on with a pattern of olivopontocerebellar degeneration; however, the "cross sign" brain stem T
• White matter abnormalities are generally not a feature of this disease.
• Cortical brain atrophy (especially of frontal areas) may be seen in advanced cases [
## Establishing the Diagnosis
To establish the diagnosis of SCA36 in a proband requires identification of a
The number of GGCCTG repeats varies from three to 14, with the nine-repeat allele being the most frequent in persons of northern European background [
Molecular genetic testing is performed as targeted analysis for pathogenic variants to determine the number of GGCCTG hexanucleotide repeats (see
The presence of two normal-sized
If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
Note: Beyond the normal allele range, no clear clinical utility has been demonstrated to date from knowing the exact repeat number; thus, estimation of allele size by Southern blot or other methods is not performed on a routine basis.
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 36
See
Conventional PCR analysis detects normal-sized alleles (3-14 GGCCTG repeats) and expanded alleles in the lower range of alleles of uncertain significance.
Only RP-PCR and/or Southern blot analysis of genomic DNA can detect the presence or absence of a large expanded pathogenic GGCCTG hexanucleotide repeat.
Pathogenic allele size is ~650 to ≥∼2500 GGCCTG repeats.
• The number of GGCCTG repeats varies from three to 14, with the nine-repeat allele being the most frequent in persons of northern European background [
• The number of GGCCTG repeats varies from three to 14, with the nine-repeat allele being the most frequent in persons of northern European background [
• The number of GGCCTG repeats varies from three to 14, with the nine-repeat allele being the most frequent in persons of northern European background [
• The presence of two normal-sized
• If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
• The presence of two normal-sized
• If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
• The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
• Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
• The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
• Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
• At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
• Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
• At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
• Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
• The presence of two normal-sized
• If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
• The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
• Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
• At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
• Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
## Molecular Genetic Testing
Molecular genetic testing is performed as targeted analysis for pathogenic variants to determine the number of GGCCTG hexanucleotide repeats (see
The presence of two normal-sized
If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
Note: Beyond the normal allele range, no clear clinical utility has been demonstrated to date from knowing the exact repeat number; thus, estimation of allele size by Southern blot or other methods is not performed on a routine basis.
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 36
See
Conventional PCR analysis detects normal-sized alleles (3-14 GGCCTG repeats) and expanded alleles in the lower range of alleles of uncertain significance.
Only RP-PCR and/or Southern blot analysis of genomic DNA can detect the presence or absence of a large expanded pathogenic GGCCTG hexanucleotide repeat.
Pathogenic allele size is ~650 to ≥∼2500 GGCCTG repeats.
• The presence of two normal-sized
• If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
• The presence of two normal-sized
• If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
• The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
• Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
• The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
• Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
• At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
• Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
• At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
• Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
• The presence of two normal-sized
• If only one allele is detected, additional testing by repeat-primed PCR (RP-PCR) is required to determine if a second
• The diagnosis of SCA36 is ruled out if one allele is detected by conventional PCR and RP-PCR does not detect an expanded allele.
• Although RP-PCR is highly sensitive, it does not determine the number of GGCCTG repeats [
• At the smaller end of the range (e.g., 15 to ~50 repeats) conventional PCR is appropriate.
• Larger alleles can only be detected by RP-PCR and/or Southern blot analysis of genomic DNA.
## Clinical Characteristics
The first clinical observations proposing the existence of a distinctive new type of spinocerebellar ataxia – later designated spinocerebellar ataxia type 36 (SCA36) – were reported independently by
Individuals with SCA36 present with findings of midline cerebellar ataxia around age 50 years (mean 53 years, range 29 to 65 years), followed by dysarthria, appendicular ataxia, and impaired hearing. The first symptoms noticed by affected individuals are usually imbalance and lack of stability while walking. Disease progression is slow and most affected individuals are still able to walk unaided ten years after disease onset.
Although the precise onset of SNHL is difficult to establish, hearing deficit is generally noticed by the affected individuals within a decade following gait imbalance. In a few cases, hearing loss may appear before cerebellar symptoms, possibly as a result of additional environmental factors (e.g., acoustic trauma).
The hearing loss typically evolves slowly, from mild to moderate deficit by the sixth to seventh decades of life. In later stages of the disease, hearing loss can be severe, causing a severe disability in verbal communication.
Significant atrophy and fasciculations affecting skeletal muscle of the trunk and limbs were reported in some families from Japan [
Upper motor neuron (pyramidal) features commonly include hyperreflexia and Babinski sign whereas significant weakness and spasticity (velocity-dependent resistance to passive muscle stretch) are rare.
Although a tendency to show earlier and more severe symptoms has been observed in individuals with larger hexanucleotide repeat expansions, no statistically significant correlation has been demonstrated to date with:
Allele size and age at onset [
SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) score [
Cognitive or affective impairment [
For more information see Molecular Genetics,
From the families reported to date, penetrance of an
Some individuals with SCA36 have reported that their parents lived to a very advanced age without signs of the disease [
A characteristic of many neurodegenerative disorders caused by abnormal expansion of a nucleotide repeat sequence is genetic anticipation (i.e., an increase in severity and earlier onset of disease manifestations in successive generations). Statistically significant evidence of anticipation in SCA36 was not observed in the few large families with SCA36 in which parent-offspring data were available [
When
Similarly, since many Japanese with SCA36 lived in the western Japan region of Chugoku near the Asida river the authors named this disease "Asidan ataxia" [
The prevalence of spinocerebellar ataxia types varies among different countries. In general,
Fewer than 100 families with SCA36 have been reported to date and studies specifically designed to investigate the prevalence of SCA36 have not been performed. The prevalence of SCA36 appears to vary among different countries, with possible regional clusters of affected families.
This prevalence is especially relevant for South America, given the long history of Galician emigration to Latin American countries. In fact, family members from the kindreds studied by
Persons with SCA36 were reported only anecdotally in Spanish regions other than Galicia. The authors are aware of at least three unrelated affected individuals from other areas of Spain, including the individual reported by
In summary, the worldwide distribution of SCA36 is still largely unknown. Most families reported to date come either from northwestern Spain or from western Japan, with some possible clusters in other regions such as Italy or Poland, while virtually no cases were observed to date in other countries.
• Allele size and age at onset [
• SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) score [
• Cognitive or affective impairment [
## Clinical Description
The first clinical observations proposing the existence of a distinctive new type of spinocerebellar ataxia – later designated spinocerebellar ataxia type 36 (SCA36) – were reported independently by
Individuals with SCA36 present with findings of midline cerebellar ataxia around age 50 years (mean 53 years, range 29 to 65 years), followed by dysarthria, appendicular ataxia, and impaired hearing. The first symptoms noticed by affected individuals are usually imbalance and lack of stability while walking. Disease progression is slow and most affected individuals are still able to walk unaided ten years after disease onset.
Although the precise onset of SNHL is difficult to establish, hearing deficit is generally noticed by the affected individuals within a decade following gait imbalance. In a few cases, hearing loss may appear before cerebellar symptoms, possibly as a result of additional environmental factors (e.g., acoustic trauma).
The hearing loss typically evolves slowly, from mild to moderate deficit by the sixth to seventh decades of life. In later stages of the disease, hearing loss can be severe, causing a severe disability in verbal communication.
Significant atrophy and fasciculations affecting skeletal muscle of the trunk and limbs were reported in some families from Japan [
Upper motor neuron (pyramidal) features commonly include hyperreflexia and Babinski sign whereas significant weakness and spasticity (velocity-dependent resistance to passive muscle stretch) are rare.
## Genotype-Phenotype Correlations
Although a tendency to show earlier and more severe symptoms has been observed in individuals with larger hexanucleotide repeat expansions, no statistically significant correlation has been demonstrated to date with:
Allele size and age at onset [
SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) score [
Cognitive or affective impairment [
For more information see Molecular Genetics,
• Allele size and age at onset [
• SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) score [
• Cognitive or affective impairment [
## Penetrance
From the families reported to date, penetrance of an
Some individuals with SCA36 have reported that their parents lived to a very advanced age without signs of the disease [
## Anticipation
A characteristic of many neurodegenerative disorders caused by abnormal expansion of a nucleotide repeat sequence is genetic anticipation (i.e., an increase in severity and earlier onset of disease manifestations in successive generations). Statistically significant evidence of anticipation in SCA36 was not observed in the few large families with SCA36 in which parent-offspring data were available [
## Nomenclature
When
Similarly, since many Japanese with SCA36 lived in the western Japan region of Chugoku near the Asida river the authors named this disease "Asidan ataxia" [
## Prevalence
The prevalence of spinocerebellar ataxia types varies among different countries. In general,
Fewer than 100 families with SCA36 have been reported to date and studies specifically designed to investigate the prevalence of SCA36 have not been performed. The prevalence of SCA36 appears to vary among different countries, with possible regional clusters of affected families.
This prevalence is especially relevant for South America, given the long history of Galician emigration to Latin American countries. In fact, family members from the kindreds studied by
Persons with SCA36 were reported only anecdotally in Spanish regions other than Galicia. The authors are aware of at least three unrelated affected individuals from other areas of Spain, including the individual reported by
In summary, the worldwide distribution of SCA36 is still largely unknown. Most families reported to date come either from northwestern Spain or from western Japan, with some possible clusters in other regions such as Italy or Poland, while virtually no cases were observed to date in other countries.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Given its spectrum of cerebellar and non-cerebellar clinical manifestations, spinocerebellar ataxia type 36 (SCA36) needs to be considered in the differential diagnosis of a range of disorders.
In its initial stages SCA36 is more reminiscent of the pure cerebellar SCAs (ADCA type III), including SCA5,
The age of symptom onset of most of the SCAs included in ADCA type III is younger than that of SCA36 [
Although sensorineural hearing loss (SNHL) is a cardinal feature of SCA36, it is not specific as it has also been reported in SCA31 [
Although the autosomal recessive ataxias often have associated peripheral neuropathy, these disorders can also have pyramidal signs [
As in SCA36, Friedreich ataxia can also include abnormal central auditory pathways [
See also
Likewise, no
Degeneration of bulbospinal motor neurons has also been reported in
• In its initial stages SCA36 is more reminiscent of the pure cerebellar SCAs (ADCA type III), including SCA5,
• The age of symptom onset of most of the SCAs included in ADCA type III is younger than that of SCA36 [
• Although sensorineural hearing loss (SNHL) is a cardinal feature of SCA36, it is not specific as it has also been reported in SCA31 [
• Although the autosomal recessive ataxias often have associated peripheral neuropathy, these disorders can also have pyramidal signs [
• As in SCA36, Friedreich ataxia can also include abnormal central auditory pathways [
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 36 (SCA36) the following evaluations are recommended:
Neurologic examination with appropriate scoring protocols:
SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) is used to monitor disease severity.
The mini-mental state examination (MMSE) may be sufficient for the initial neurologic check-up; however, other cognitive tests more specifically directed to evaluate frontal-subcortical functions may be more appropriate as the disease progresses.
Examination by an otolaryngologist and audiologist, with emphasis in a comprehensive characterization of degree and anatomic level of hearing dysfunction.
Clinical genetics consultation and genetic counseling
Additional brain MRI is not necessary following the diagnosis of SCA36; however, it can be used for complementary follow-up evaluation.
Specific treatment for SCA36 is currently not available. The therapeutic approach should be multidisciplinary and include the following:
Physical and occupational therapy to improve gait, balance, and fine motor coordination. Special attention should be paid to activities of daily life.
Regular physical exercise and weight control to reduce the effect of future balance and walking problems
Walking aids to facilitate ambulation and mobility. The use of a wheelchair is rare; however, it may be necessary in advanced disease stages. Living space may need to be adapted to help with accessibility.
Speech therapy and communication devices for those with dysarthria
Dietary assessment and feeding therapy programs to improve dysphagia and reduce the risk of aspiration
Depending on the severity of hearing loss and the relative impairment at different levels of the auditory tract, consideration of hearing aids on a case by case basis. The utility of cochlear implants in SCA36 is unknown; however, they have been proposed for central auditory impairment in other neurodegenerative ataxias [
Management of emotional and cognitive decline through cognitive therapy, treatment of depression, and psychological support.
The following routine monitoring is recommended after a diagnosis of SCA36 has been confirmed.
At least annual evaluation by a neurologist or more frequently if symptoms are progressing
Annual or biannual evaluation by an otolaryngologist to detect or monitor hearing loss
Surveillance of speech and ambulation
In presymptomatic individuals who tested positive for the
Avoid the following:
Alcohol, as well as drugs with possible side effects on cerebellar function (e.g., phenytoin, carbamazepine, metronidazole, amiodarone, lithium), or the inner ear (e.g., salicilates)
Environmental noise at work and in everyday life (e.g., listening to loud music or videos directly through headphones)
See
Search
• Neurologic examination with appropriate scoring protocols:
• SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) is used to monitor disease severity.
• The mini-mental state examination (MMSE) may be sufficient for the initial neurologic check-up; however, other cognitive tests more specifically directed to evaluate frontal-subcortical functions may be more appropriate as the disease progresses.
• SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) is used to monitor disease severity.
• The mini-mental state examination (MMSE) may be sufficient for the initial neurologic check-up; however, other cognitive tests more specifically directed to evaluate frontal-subcortical functions may be more appropriate as the disease progresses.
• Examination by an otolaryngologist and audiologist, with emphasis in a comprehensive characterization of degree and anatomic level of hearing dysfunction.
• Clinical genetics consultation and genetic counseling
• SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) is used to monitor disease severity.
• The mini-mental state examination (MMSE) may be sufficient for the initial neurologic check-up; however, other cognitive tests more specifically directed to evaluate frontal-subcortical functions may be more appropriate as the disease progresses.
• Physical and occupational therapy to improve gait, balance, and fine motor coordination. Special attention should be paid to activities of daily life.
• Regular physical exercise and weight control to reduce the effect of future balance and walking problems
• Walking aids to facilitate ambulation and mobility. The use of a wheelchair is rare; however, it may be necessary in advanced disease stages. Living space may need to be adapted to help with accessibility.
• Speech therapy and communication devices for those with dysarthria
• Dietary assessment and feeding therapy programs to improve dysphagia and reduce the risk of aspiration
• Depending on the severity of hearing loss and the relative impairment at different levels of the auditory tract, consideration of hearing aids on a case by case basis. The utility of cochlear implants in SCA36 is unknown; however, they have been proposed for central auditory impairment in other neurodegenerative ataxias [
• Management of emotional and cognitive decline through cognitive therapy, treatment of depression, and psychological support.
• At least annual evaluation by a neurologist or more frequently if symptoms are progressing
• Annual or biannual evaluation by an otolaryngologist to detect or monitor hearing loss
• Surveillance of speech and ambulation
• Alcohol, as well as drugs with possible side effects on cerebellar function (e.g., phenytoin, carbamazepine, metronidazole, amiodarone, lithium), or the inner ear (e.g., salicilates)
• Environmental noise at work and in everyday life (e.g., listening to loud music or videos directly through headphones)
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 36 (SCA36) the following evaluations are recommended:
Neurologic examination with appropriate scoring protocols:
SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) is used to monitor disease severity.
The mini-mental state examination (MMSE) may be sufficient for the initial neurologic check-up; however, other cognitive tests more specifically directed to evaluate frontal-subcortical functions may be more appropriate as the disease progresses.
Examination by an otolaryngologist and audiologist, with emphasis in a comprehensive characterization of degree and anatomic level of hearing dysfunction.
Clinical genetics consultation and genetic counseling
Additional brain MRI is not necessary following the diagnosis of SCA36; however, it can be used for complementary follow-up evaluation.
• Neurologic examination with appropriate scoring protocols:
• SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) is used to monitor disease severity.
• The mini-mental state examination (MMSE) may be sufficient for the initial neurologic check-up; however, other cognitive tests more specifically directed to evaluate frontal-subcortical functions may be more appropriate as the disease progresses.
• SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) is used to monitor disease severity.
• The mini-mental state examination (MMSE) may be sufficient for the initial neurologic check-up; however, other cognitive tests more specifically directed to evaluate frontal-subcortical functions may be more appropriate as the disease progresses.
• Examination by an otolaryngologist and audiologist, with emphasis in a comprehensive characterization of degree and anatomic level of hearing dysfunction.
• Clinical genetics consultation and genetic counseling
• SARA (Scale for the Assessment and Rating of Cerebellar Ataxia) is used to monitor disease severity.
• The mini-mental state examination (MMSE) may be sufficient for the initial neurologic check-up; however, other cognitive tests more specifically directed to evaluate frontal-subcortical functions may be more appropriate as the disease progresses.
## Treatment of Manifestations
Specific treatment for SCA36 is currently not available. The therapeutic approach should be multidisciplinary and include the following:
Physical and occupational therapy to improve gait, balance, and fine motor coordination. Special attention should be paid to activities of daily life.
Regular physical exercise and weight control to reduce the effect of future balance and walking problems
Walking aids to facilitate ambulation and mobility. The use of a wheelchair is rare; however, it may be necessary in advanced disease stages. Living space may need to be adapted to help with accessibility.
Speech therapy and communication devices for those with dysarthria
Dietary assessment and feeding therapy programs to improve dysphagia and reduce the risk of aspiration
Depending on the severity of hearing loss and the relative impairment at different levels of the auditory tract, consideration of hearing aids on a case by case basis. The utility of cochlear implants in SCA36 is unknown; however, they have been proposed for central auditory impairment in other neurodegenerative ataxias [
Management of emotional and cognitive decline through cognitive therapy, treatment of depression, and psychological support.
• Physical and occupational therapy to improve gait, balance, and fine motor coordination. Special attention should be paid to activities of daily life.
• Regular physical exercise and weight control to reduce the effect of future balance and walking problems
• Walking aids to facilitate ambulation and mobility. The use of a wheelchair is rare; however, it may be necessary in advanced disease stages. Living space may need to be adapted to help with accessibility.
• Speech therapy and communication devices for those with dysarthria
• Dietary assessment and feeding therapy programs to improve dysphagia and reduce the risk of aspiration
• Depending on the severity of hearing loss and the relative impairment at different levels of the auditory tract, consideration of hearing aids on a case by case basis. The utility of cochlear implants in SCA36 is unknown; however, they have been proposed for central auditory impairment in other neurodegenerative ataxias [
• Management of emotional and cognitive decline through cognitive therapy, treatment of depression, and psychological support.
## Surveillance
The following routine monitoring is recommended after a diagnosis of SCA36 has been confirmed.
At least annual evaluation by a neurologist or more frequently if symptoms are progressing
Annual or biannual evaluation by an otolaryngologist to detect or monitor hearing loss
Surveillance of speech and ambulation
In presymptomatic individuals who tested positive for the
• At least annual evaluation by a neurologist or more frequently if symptoms are progressing
• Annual or biannual evaluation by an otolaryngologist to detect or monitor hearing loss
• Surveillance of speech and ambulation
## Agents/Circumstances to Avoid
Avoid the following:
Alcohol, as well as drugs with possible side effects on cerebellar function (e.g., phenytoin, carbamazepine, metronidazole, amiodarone, lithium), or the inner ear (e.g., salicilates)
Environmental noise at work and in everyday life (e.g., listening to loud music or videos directly through headphones)
• Alcohol, as well as drugs with possible side effects on cerebellar function (e.g., phenytoin, carbamazepine, metronidazole, amiodarone, lithium), or the inner ear (e.g., salicilates)
• Environmental noise at work and in everyday life (e.g., listening to loud music or videos directly through headphones)
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Spinocerebellar ataxia type 36 (SCA36) is inherited in an autosomal dominant manner.
Most individuals diagnosed with SCA36 have an affected parent.
A proband with SCA36 may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Note: Although most of individuals diagnosed with SCA36 have an affected parent, the family history 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 late onset of the disease in the affected parent.
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 affected or has a
The sibs of a proband with clinically unaffected parents are still at increased risk for SCA36 because penetrance is age related.
Testing for the
Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of SCA36, the possible impact of positive and negative test results, and neurologic status are assessed. 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. Another issue to consider is the implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and genetic counseling.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
• Most individuals diagnosed with SCA36 have an affected parent.
• A proband with SCA36 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 is affected or has a
• The sibs of a proband with clinically unaffected parents are still at increased risk for SCA36 because penetrance is age related.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Spinocerebellar ataxia type 36 (SCA36) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with SCA36 have an affected parent.
A proband with SCA36 may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Note: Although most of individuals diagnosed with SCA36 have an affected parent, the family history 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 late onset of the disease in the affected parent.
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 affected or has a
The sibs of a proband with clinically unaffected parents are still at increased risk for SCA36 because penetrance is age related.
• Most individuals diagnosed with SCA36 have an affected parent.
• A proband with SCA36 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 is affected or has a
• The sibs of a proband with clinically unaffected parents are still at increased risk for SCA36 because penetrance is age related.
## Related Genetic Counseling Issues
Testing for the
Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of SCA36, the possible impact of positive and negative test results, and neurologic status are assessed. 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. Another issue to consider is the implications for the at-risk status of other family members. Informed consent should be procured and records kept confidential. Individuals with a positive test result need arrangements for long-term follow-up and genetic counseling.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 a
## Resources
United Kingdom
United Kingdom
Centro Municipal Asociativo “Domingo García Sabell”
Plaza Esteban Lareo, Bloque 17, Sótano
15008 La Coruña
Spain
Spain
Sanford Research
•
• United Kingdom
•
•
• United Kingdom
•
•
• Centro Municipal Asociativo “Domingo García Sabell”
• Plaza Esteban Lareo, Bloque 17, Sótano
• 15008 La Coruña
• Spain
•
•
•
•
•
• Spain
•
•
• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia Type 36: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 36 (
SCA36 is caused by the pathogenic expansion of a noncoding GGCCTG repeat in the first intron of
The presence of a large expanded pathogenic allele does not appear to change NOP56 transcript or protein levels in cells from individuals in whom novel
The intronic expansion induces formation of intranuclear RNA foci in lymphoblastoid cell lines, which may disrupt normal transcription through sequestration or inactivation of splicing and other transcription factors [
Another hypothesis regarding possible mechanisms contributing to SCA36 pathogenicity comes from the evidence that microRNA levels can be affected by repeat expansions.
The possibility that abnormal translation products originate from different reading frames on both stands of the elongated repeat (repeat associated non-ATG (RAN) initiated translation) – as suggested for other repeat expansion disorders [
Changes in the local chromatin structure and epigenetic modifications could also be at play [
Future studies with more detailed measures are needed to fully understand genotype-phenotype relationships in SCA36. Limitations to such investigations include:
Measuring the precise repeat size for large repeat expansions requires labor-intensive, operator-dependent methods such as Southern blot analysis.
It is not known whether
Age of onset is difficult to establish and prone to ascertainment bias in slowly progressive neurodegenerative diseases.
Severity scoring of many neurologic findings (e.g., imbalance, tremor, cognition) is based on clinical scales that can have significant inter-examiner (and other sources of) variability.
No ethnic-specific variants or characteristics of the SCA36 molecular defect have been reported to date.
The mean increase of allele size reported in the large Galician kindreds studied by
Decrease in allele size has also been observed especially on maternal transmission [
Variants listed in the table have been provided by the authors.
• The intronic expansion induces formation of intranuclear RNA foci in lymphoblastoid cell lines, which may disrupt normal transcription through sequestration or inactivation of splicing and other transcription factors [
• Another hypothesis regarding possible mechanisms contributing to SCA36 pathogenicity comes from the evidence that microRNA levels can be affected by repeat expansions.
• The possibility that abnormal translation products originate from different reading frames on both stands of the elongated repeat (repeat associated non-ATG (RAN) initiated translation) – as suggested for other repeat expansion disorders [
• Changes in the local chromatin structure and epigenetic modifications could also be at play [
• Measuring the precise repeat size for large repeat expansions requires labor-intensive, operator-dependent methods such as Southern blot analysis.
• It is not known whether
• Age of onset is difficult to establish and prone to ascertainment bias in slowly progressive neurodegenerative diseases.
• Severity scoring of many neurologic findings (e.g., imbalance, tremor, cognition) is based on clinical scales that can have significant inter-examiner (and other sources of) variability.
• The mean increase of allele size reported in the large Galician kindreds studied by
• Decrease in allele size has also been observed especially on maternal transmission [
## Molecular Pathogenesis
SCA36 is caused by the pathogenic expansion of a noncoding GGCCTG repeat in the first intron of
The presence of a large expanded pathogenic allele does not appear to change NOP56 transcript or protein levels in cells from individuals in whom novel
The intronic expansion induces formation of intranuclear RNA foci in lymphoblastoid cell lines, which may disrupt normal transcription through sequestration or inactivation of splicing and other transcription factors [
Another hypothesis regarding possible mechanisms contributing to SCA36 pathogenicity comes from the evidence that microRNA levels can be affected by repeat expansions.
The possibility that abnormal translation products originate from different reading frames on both stands of the elongated repeat (repeat associated non-ATG (RAN) initiated translation) – as suggested for other repeat expansion disorders [
Changes in the local chromatin structure and epigenetic modifications could also be at play [
Future studies with more detailed measures are needed to fully understand genotype-phenotype relationships in SCA36. Limitations to such investigations include:
Measuring the precise repeat size for large repeat expansions requires labor-intensive, operator-dependent methods such as Southern blot analysis.
It is not known whether
Age of onset is difficult to establish and prone to ascertainment bias in slowly progressive neurodegenerative diseases.
Severity scoring of many neurologic findings (e.g., imbalance, tremor, cognition) is based on clinical scales that can have significant inter-examiner (and other sources of) variability.
No ethnic-specific variants or characteristics of the SCA36 molecular defect have been reported to date.
The mean increase of allele size reported in the large Galician kindreds studied by
Decrease in allele size has also been observed especially on maternal transmission [
Variants listed in the table have been provided by the authors.
• The intronic expansion induces formation of intranuclear RNA foci in lymphoblastoid cell lines, which may disrupt normal transcription through sequestration or inactivation of splicing and other transcription factors [
• Another hypothesis regarding possible mechanisms contributing to SCA36 pathogenicity comes from the evidence that microRNA levels can be affected by repeat expansions.
• The possibility that abnormal translation products originate from different reading frames on both stands of the elongated repeat (repeat associated non-ATG (RAN) initiated translation) – as suggested for other repeat expansion disorders [
• Changes in the local chromatin structure and epigenetic modifications could also be at play [
• Measuring the precise repeat size for large repeat expansions requires labor-intensive, operator-dependent methods such as Southern blot analysis.
• It is not known whether
• Age of onset is difficult to establish and prone to ascertainment bias in slowly progressive neurodegenerative diseases.
• Severity scoring of many neurologic findings (e.g., imbalance, tremor, cognition) is based on clinical scales that can have significant inter-examiner (and other sources of) variability.
• The mean increase of allele size reported in the large Galician kindreds studied by
• Decrease in allele size has also been observed especially on maternal transmission [
## References
## Literature Cited
## Chapter Notes
The Neurogenetics Group of the
Spastic paraplegias, spinocerebellar ataxias, and other movement disorders
Molecular mechanisms of neurodegenerative and neuromuscular diseases
Application of genomics, bioinformatics, and databases to understanding genotype-phenotype relationships
Psychosocial and ethical aspects of translational neurogenetics and genetic counseling
11 February 2021 (ma) Chapter retired: extremely rare; qualified authors not available for update
7 August 2014 (me) Review posted live
13 January 2014 (mjs) Original Submission
• Spastic paraplegias, spinocerebellar ataxias, and other movement disorders
• Molecular mechanisms of neurodegenerative and neuromuscular diseases
• Application of genomics, bioinformatics, and databases to understanding genotype-phenotype relationships
• Psychosocial and ethical aspects of translational neurogenetics and genetic counseling
• 11 February 2021 (ma) Chapter retired: extremely rare; qualified authors not available for update
• 7 August 2014 (me) Review posted live
• 13 January 2014 (mjs) Original Submission
## Author Notes
The Neurogenetics Group of the
Spastic paraplegias, spinocerebellar ataxias, and other movement disorders
Molecular mechanisms of neurodegenerative and neuromuscular diseases
Application of genomics, bioinformatics, and databases to understanding genotype-phenotype relationships
Psychosocial and ethical aspects of translational neurogenetics and genetic counseling
• Spastic paraplegias, spinocerebellar ataxias, and other movement disorders
• Molecular mechanisms of neurodegenerative and neuromuscular diseases
• Application of genomics, bioinformatics, and databases to understanding genotype-phenotype relationships
• Psychosocial and ethical aspects of translational neurogenetics and genetic counseling
## Revision History
11 February 2021 (ma) Chapter retired: extremely rare; qualified authors not available for update
7 August 2014 (me) Review posted live
13 January 2014 (mjs) Original Submission
• 11 February 2021 (ma) Chapter retired: extremely rare; qualified authors not available for update
• 7 August 2014 (me) Review posted live
• 13 January 2014 (mjs) Original Submission
|
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"JP Warner, LH Barron, D Goudie, K Kelly, D Dow, DR Fitzpatrick, DJ Brock. A general method for the detection of large CAG repeat expansions by fluorescent PCR.. J Med Genet. 1996;33:1022-6",
"JL Whitwell, SD Weigand, BF Boeve, ML Senjem, JL Gunter, M DeJesus-Hernandez, NJ Rutherford, M Baker, DS Knopman, ZK Wszolek, JE Parisi, DW Dickson, RC Petersen, R Rademakers, CR Jack, KA Josephs. Neuroimaging signatures of frontotemporal dementia genetics: C9ORF72, tau, progranulin and sporadics.. Brain. 2012;135:794-806"
] |
7/8/2014
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sca37
|
sca37
|
[
"SCA37",
"SCA37",
"Disabled homolog 1",
"DAB1",
"Spinocerebellar Ataxia Type 37"
] |
Spinocerebellar Ataxia Type 37
|
Antoni Matilla-Dueñas, Victor Volpini
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Summary Spinocerebellar ataxia type 37 (SCA37) is characterized by adult onset, dysarthria, slowly progressive gait and limb ataxia with severe dysmetria in the lower extremities, mild dysmetria in the upper extremities, dysphagia, and abnormal ocular movements (dysmetric vertical saccades, irregular and slow vertical smooth pursuit, slow vertical optokinetic nystagmus, and oscillopsia (visual disturbance in which objects appear to oscillate). In most individuals, the initial signs/symptoms include falls, dysarthria, or clumsiness followed by a complete cerebellar syndrome. A distinctive clinical feature is the presence of altered vertical eye movements in early stages of the disease, even preceding ataxia symptoms. Clinical progression is slow and affected individuals usually become wheelchair bound between ten and 33 years after disease onset. The diagnosis of SCA37 is established in a proband by identification of a heterozygous ATTTC repeat insertion within SCA37 is inherited in an autosomal dominant manner. All individuals diagnosed to date with SCA37 have an affected parent. Each child of an individual with SCA37 is at a 50% risk of inheriting the intronic ATTTC repeat insertion within
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## Diagnosis
The phenotypic manifestations of spinocerebellar ataxia type 37 (SCA37) are not specific and no formal diagnostic criteria exist; thus, the diagnosis of SCA37 rests on molecular genetic testing. However, if autosomal dominant inheritance is apparent, or if pure cerebellar ataxia with adult onset, initial dysarthria, and dysmetric vertical saccades are seen in a simplex case, SCA37 should be suspected.
SCA37
Dysarthria (scanning speech), often preceding other cerebellar signs
Altered vertical and horizontal eye movements (e.g., dysmetric saccades, slow and irregular smooth pursuit, and slow optokinetic nystagmus). Abnormalities restricted to the vertical axis may be an initial and predominant feature.
Progressive cerebellar gait ataxia (severe dysmetria in the lower extremities, mild in the upper extremities and trunk)
Late eye movement abnormalities: nystagmus, oscillopsia, asymptomatic saccadic intrusions
Late additional clinical findings: hand tremor, dysphagia
Family history of similarly affected individuals
The diagnosis of SCA37
There are no known alleles of
Targeted analysis for the heterozygous ATTTC repeat insertion in
Long-range PCR followed by Sanger sequencing has performed reliably to unequivocally identify and size the pathogenic ATTTC repeat insertion. For very large ATTTT/ATTTC alleles size could be estimated by automated electrophoresis.
Repeat-primed PCR (RP-PCR) may not be specific for pathogenic SCA37 ATTTC alleles and it is not recommended, due to the potential for false negative results.
Note: The intronic ATTTC repeat insertion is not detected by multigene panel analysis with next-generation sequencing because of the type and size of the repeat insert and its intronic noncoding localization within an Alu element in
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 37
See
See
Long-range PCR combined with Sanger sequencing has been shown to be a reliable method to detect and characterize the ATTTC repeat insertion (see
Insertion of a variable number of ATTTC repeats flanked by two stretches of non-pathogenic polymorphic (ATTTT)
• Dysarthria (scanning speech), often preceding other cerebellar signs
• Altered vertical and horizontal eye movements (e.g., dysmetric saccades, slow and irregular smooth pursuit, and slow optokinetic nystagmus). Abnormalities restricted to the vertical axis may be an initial and predominant feature.
• Progressive cerebellar gait ataxia (severe dysmetria in the lower extremities, mild in the upper extremities and trunk)
• Late eye movement abnormalities: nystagmus, oscillopsia, asymptomatic saccadic intrusions
• Late additional clinical findings: hand tremor, dysphagia
• Family history of similarly affected individuals
• Long-range PCR followed by Sanger sequencing has performed reliably to unequivocally identify and size the pathogenic ATTTC repeat insertion. For very large ATTTT/ATTTC alleles size could be estimated by automated electrophoresis.
• Repeat-primed PCR (RP-PCR) may not be specific for pathogenic SCA37 ATTTC alleles and it is not recommended, due to the potential for false negative results.
## Suggestive Findings
SCA37
Dysarthria (scanning speech), often preceding other cerebellar signs
Altered vertical and horizontal eye movements (e.g., dysmetric saccades, slow and irregular smooth pursuit, and slow optokinetic nystagmus). Abnormalities restricted to the vertical axis may be an initial and predominant feature.
Progressive cerebellar gait ataxia (severe dysmetria in the lower extremities, mild in the upper extremities and trunk)
Late eye movement abnormalities: nystagmus, oscillopsia, asymptomatic saccadic intrusions
Late additional clinical findings: hand tremor, dysphagia
Family history of similarly affected individuals
• Dysarthria (scanning speech), often preceding other cerebellar signs
• Altered vertical and horizontal eye movements (e.g., dysmetric saccades, slow and irregular smooth pursuit, and slow optokinetic nystagmus). Abnormalities restricted to the vertical axis may be an initial and predominant feature.
• Progressive cerebellar gait ataxia (severe dysmetria in the lower extremities, mild in the upper extremities and trunk)
• Late eye movement abnormalities: nystagmus, oscillopsia, asymptomatic saccadic intrusions
• Late additional clinical findings: hand tremor, dysphagia
• Family history of similarly affected individuals
## Establishing the Diagnosis
The diagnosis of SCA37
There are no known alleles of
Targeted analysis for the heterozygous ATTTC repeat insertion in
Long-range PCR followed by Sanger sequencing has performed reliably to unequivocally identify and size the pathogenic ATTTC repeat insertion. For very large ATTTT/ATTTC alleles size could be estimated by automated electrophoresis.
Repeat-primed PCR (RP-PCR) may not be specific for pathogenic SCA37 ATTTC alleles and it is not recommended, due to the potential for false negative results.
Note: The intronic ATTTC repeat insertion is not detected by multigene panel analysis with next-generation sequencing because of the type and size of the repeat insert and its intronic noncoding localization within an Alu element in
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 37
See
See
Long-range PCR combined with Sanger sequencing has been shown to be a reliable method to detect and characterize the ATTTC repeat insertion (see
Insertion of a variable number of ATTTC repeats flanked by two stretches of non-pathogenic polymorphic (ATTTT)
• Long-range PCR followed by Sanger sequencing has performed reliably to unequivocally identify and size the pathogenic ATTTC repeat insertion. For very large ATTTT/ATTTC alleles size could be estimated by automated electrophoresis.
• Repeat-primed PCR (RP-PCR) may not be specific for pathogenic SCA37 ATTTC alleles and it is not recommended, due to the potential for false negative results.
## Allele Sizes
There are no known alleles of
## Single-Gene Testing
Targeted analysis for the heterozygous ATTTC repeat insertion in
Long-range PCR followed by Sanger sequencing has performed reliably to unequivocally identify and size the pathogenic ATTTC repeat insertion. For very large ATTTT/ATTTC alleles size could be estimated by automated electrophoresis.
Repeat-primed PCR (RP-PCR) may not be specific for pathogenic SCA37 ATTTC alleles and it is not recommended, due to the potential for false negative results.
Note: The intronic ATTTC repeat insertion is not detected by multigene panel analysis with next-generation sequencing because of the type and size of the repeat insert and its intronic noncoding localization within an Alu element in
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 37
See
See
Long-range PCR combined with Sanger sequencing has been shown to be a reliable method to detect and characterize the ATTTC repeat insertion (see
Insertion of a variable number of ATTTC repeats flanked by two stretches of non-pathogenic polymorphic (ATTTT)
• Long-range PCR followed by Sanger sequencing has performed reliably to unequivocally identify and size the pathogenic ATTTC repeat insertion. For very large ATTTT/ATTTC alleles size could be estimated by automated electrophoresis.
• Repeat-primed PCR (RP-PCR) may not be specific for pathogenic SCA37 ATTTC alleles and it is not recommended, due to the potential for false negative results.
## Clinical Characteristics
Spinocerebellar ataxia type 37 (SCA37) is characterized by a pure cerebellar ataxia phenotype [
Baseline MRI of the brain revealed general cerebellar atrophy with sparing of the brain stem in the individuals studied [
Severe dysmetria in the lower extremities
Mild dysmetria in the upper extremities, mainly irregular fast alternating movements and dysmetria with the left hand, and mild trunk ataxia. Hand postural and action tremor variably appear with disease progression [
Abnormal ocular movements including dysmetric vertical saccades, irregular and slow vertical smooth pursuit, and slow vertical optokinetic nystagmus
Individuals with long-standing disease showed these abnormalities also in the horizontal axis [
Nystagmus
Oscillopsia (visual disturbance in which objects appear to oscillate)
Individuals described with SCA37 to date do not have sensory deficits, extensor plantar reflexes, fasciculations, epileptic seizures, or cognitive impairment [
A significant inverse correlation between ATTTC insertion size and age of onset is demonstrated in SCA37 [
Moreover, affected females presented at a significantly younger age of onset (average = 40.4 years; average number of ATTTC repeats = 51.9) than males (average = 49.0 years; average number of ATTTC repeats = 52.7) (n = 23; p<0.021) [
In six Portuguese kindreds, the mean age at onset reported was 33.76 (range 18-58) in 21 females and 40.33 (range 27-57) in nine affected Portuguese males [
Lifelong penetrance in SCA37 was 100% in all described families, but penetrance is age dependent [
No evidence of anticipation in the age at onset was identified in the three generations for which data are available from one large Spanish family [
Intergenerational instability with increase in length of the ATTTC repeat (by 2-12 repeats) was reported in all seven paternal transmissions, but in only 9/16 (56%) of the maternal transmissions in Portuguese families [
Thus, the (ATTTC)
To date, 66 affected individuals and seven asymptomatic individuals with the ATTTC repeat insertion within
• Severe dysmetria in the lower extremities
• Mild dysmetria in the upper extremities, mainly irregular fast alternating movements and dysmetria with the left hand, and mild trunk ataxia. Hand postural and action tremor variably appear with disease progression [
• Abnormal ocular movements including dysmetric vertical saccades, irregular and slow vertical smooth pursuit, and slow vertical optokinetic nystagmus
• Individuals with long-standing disease showed these abnormalities also in the horizontal axis [
• Nystagmus
• Oscillopsia (visual disturbance in which objects appear to oscillate)
## Clinical Description
Spinocerebellar ataxia type 37 (SCA37) is characterized by a pure cerebellar ataxia phenotype [
Baseline MRI of the brain revealed general cerebellar atrophy with sparing of the brain stem in the individuals studied [
Severe dysmetria in the lower extremities
Mild dysmetria in the upper extremities, mainly irregular fast alternating movements and dysmetria with the left hand, and mild trunk ataxia. Hand postural and action tremor variably appear with disease progression [
Abnormal ocular movements including dysmetric vertical saccades, irregular and slow vertical smooth pursuit, and slow vertical optokinetic nystagmus
Individuals with long-standing disease showed these abnormalities also in the horizontal axis [
Nystagmus
Oscillopsia (visual disturbance in which objects appear to oscillate)
Individuals described with SCA37 to date do not have sensory deficits, extensor plantar reflexes, fasciculations, epileptic seizures, or cognitive impairment [
• Severe dysmetria in the lower extremities
• Mild dysmetria in the upper extremities, mainly irregular fast alternating movements and dysmetria with the left hand, and mild trunk ataxia. Hand postural and action tremor variably appear with disease progression [
• Abnormal ocular movements including dysmetric vertical saccades, irregular and slow vertical smooth pursuit, and slow vertical optokinetic nystagmus
• Individuals with long-standing disease showed these abnormalities also in the horizontal axis [
• Nystagmus
• Oscillopsia (visual disturbance in which objects appear to oscillate)
## Genotype-Phenotype Correlations
A significant inverse correlation between ATTTC insertion size and age of onset is demonstrated in SCA37 [
Moreover, affected females presented at a significantly younger age of onset (average = 40.4 years; average number of ATTTC repeats = 51.9) than males (average = 49.0 years; average number of ATTTC repeats = 52.7) (n = 23; p<0.021) [
In six Portuguese kindreds, the mean age at onset reported was 33.76 (range 18-58) in 21 females and 40.33 (range 27-57) in nine affected Portuguese males [
## Penetrance
Lifelong penetrance in SCA37 was 100% in all described families, but penetrance is age dependent [
## Anticipation
No evidence of anticipation in the age at onset was identified in the three generations for which data are available from one large Spanish family [
Intergenerational instability with increase in length of the ATTTC repeat (by 2-12 repeats) was reported in all seven paternal transmissions, but in only 9/16 (56%) of the maternal transmissions in Portuguese families [
Thus, the (ATTTC)
## Prevalence
To date, 66 affected individuals and seven asymptomatic individuals with the ATTTC repeat insertion within
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Interstitial deletions encompassing chromosome region 1p32.1-1p32.3 including
Structural variants within the
## Differential Diagnosis
The ataxic gait and the overall clinical picture in persons with spinocerebellar ataxia type 37 (SCA37) are indistinguishable from those seen in other adult-onset inherited or acquired pure cerebellar ataxias. Nevertheless, initial dysarthria and early altered vertical eye movements may be suggestive of SCA37, particularly when consistent within the same family. When the family history suggests autosomal dominant inheritance, all other autosomal dominant spinocerebellar ataxias (SCAs) need to be considered (see
SCAs with a Pure Cerebellar Phenotype to Consider in the Differential Diagnosis of SCA37
Pure slowly progressive cerebellar syndrome
Onset age range: 10-68 yrs; congenital & infantile onset also reported
Downbeat nystagmus, impaired smooth pursuit, & gaze-evoked nystagmus
Adult-onset slowly progressive ataxia
Mild vibratory sensory loss
Occasional dysphagia
Horizontal & vertical nystagmus
Abnormal vestibuloocular reflex
Rare oculomotor findings in presymptomatic persons:
Low-amplitude horizontal gaze-evoked nystagmus
Significantly ↓ eye velocity for upward saccades
Abnormal frequency of square-wave jerks
↓ gain for pursuit tracking
Positional vertigo, downbeat nystagmus, & external ophthalmoplegia also reported in SCA6; not reported in SCA37.
Persons w/presymptomatic SCA37 may also have ↓ gain for pursuit tracking, but in SCA37 saccade velocity is normal & eye movement abnormalities initially affect the vertical axis.
Pure SCA
Irregular visual pursuit movements
Relatively pure, slowly progressive SCA
Hypermetric saccades (typically horizontal & into downgaze)
Normal vestibuloocular reflex gain
Pure cerebellar syndrome
Variable hearing loss of cochlear origin
SCA = spinocerebellar ataxia
SCA30 was linked to 4q34.3-q35.1; the gene and molecular defect remain unknown.
The most common SCAs are those caused by polyglutamine expansions (e.g.,
• Pure slowly progressive cerebellar syndrome
• Onset age range: 10-68 yrs; congenital & infantile onset also reported
• Downbeat nystagmus, impaired smooth pursuit, & gaze-evoked nystagmus
• Adult-onset slowly progressive ataxia
• Mild vibratory sensory loss
• Occasional dysphagia
• Horizontal & vertical nystagmus
• Abnormal vestibuloocular reflex
• Rare oculomotor findings in presymptomatic persons:
• Low-amplitude horizontal gaze-evoked nystagmus
• Significantly ↓ eye velocity for upward saccades
• Abnormal frequency of square-wave jerks
• ↓ gain for pursuit tracking
• Low-amplitude horizontal gaze-evoked nystagmus
• Significantly ↓ eye velocity for upward saccades
• Abnormal frequency of square-wave jerks
• ↓ gain for pursuit tracking
• Low-amplitude horizontal gaze-evoked nystagmus
• Significantly ↓ eye velocity for upward saccades
• Abnormal frequency of square-wave jerks
• ↓ gain for pursuit tracking
• Positional vertigo, downbeat nystagmus, & external ophthalmoplegia also reported in SCA6; not reported in SCA37.
• Persons w/presymptomatic SCA37 may also have ↓ gain for pursuit tracking, but in SCA37 saccade velocity is normal & eye movement abnormalities initially affect the vertical axis.
• Pure SCA
• Irregular visual pursuit movements
• Relatively pure, slowly progressive SCA
• Hypermetric saccades (typically horizontal & into downgaze)
• Normal vestibuloocular reflex gain
• Pure cerebellar syndrome
• Variable hearing loss of cochlear origin
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 37 (SCA37), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Physical examination
Neurologic assessment
Assessment of the full range of symptoms associated with a progressive cerebellar syndrome. Among a range of clinical scoring systems that have been described [
Electrooculographic tests may properly assess progression at the onset of disease.
Specific assessment of the cerebellar cognitive affective syndrome may be considered.
Brain MRI examination
Consultation with speech, physical, behavioral, and occupational therapists
Consultation with a clinical geneticist and/or genetic counselor
No curative treatment is available for individuals with SCA37. Palliative care includes the following:
Speech therapy to improve communication and ameliorate dysphagia
Thickness modification of food and fluids to prevent aspiration
Physical therapy to train balance
Use of external devices (e.g., canes or walkers) when needed to avoid falls
Occupational/behavior therapy
The following are appropriate:
SARA score annually. Note: SARA may not detect disease progression for the first five to seven years.
Electrooculographic tests may be performed every two years (cooperation is required).
Brain MRI volumetry every two years
See
Search
• Physical examination
• Neurologic assessment
• Assessment of the full range of symptoms associated with a progressive cerebellar syndrome. Among a range of clinical scoring systems that have been described [
• Electrooculographic tests may properly assess progression at the onset of disease.
• Specific assessment of the cerebellar cognitive affective syndrome may be considered.
• Brain MRI examination
• Consultation with speech, physical, behavioral, and occupational therapists
• Consultation with a clinical geneticist and/or genetic counselor
• Speech therapy to improve communication and ameliorate dysphagia
• Thickness modification of food and fluids to prevent aspiration
• Physical therapy to train balance
• Use of external devices (e.g., canes or walkers) when needed to avoid falls
• Occupational/behavior therapy
• SARA score annually. Note: SARA may not detect disease progression for the first five to seven years.
• Electrooculographic tests may be performed every two years (cooperation is required).
• Brain MRI volumetry every two years
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 37 (SCA37), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Physical examination
Neurologic assessment
Assessment of the full range of symptoms associated with a progressive cerebellar syndrome. Among a range of clinical scoring systems that have been described [
Electrooculographic tests may properly assess progression at the onset of disease.
Specific assessment of the cerebellar cognitive affective syndrome may be considered.
Brain MRI examination
Consultation with speech, physical, behavioral, and occupational therapists
Consultation with a clinical geneticist and/or genetic counselor
• Physical examination
• Neurologic assessment
• Assessment of the full range of symptoms associated with a progressive cerebellar syndrome. Among a range of clinical scoring systems that have been described [
• Electrooculographic tests may properly assess progression at the onset of disease.
• Specific assessment of the cerebellar cognitive affective syndrome may be considered.
• Brain MRI examination
• Consultation with speech, physical, behavioral, and occupational therapists
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
No curative treatment is available for individuals with SCA37. Palliative care includes the following:
Speech therapy to improve communication and ameliorate dysphagia
Thickness modification of food and fluids to prevent aspiration
Physical therapy to train balance
Use of external devices (e.g., canes or walkers) when needed to avoid falls
Occupational/behavior therapy
• Speech therapy to improve communication and ameliorate dysphagia
• Thickness modification of food and fluids to prevent aspiration
• Physical therapy to train balance
• Use of external devices (e.g., canes or walkers) when needed to avoid falls
• Occupational/behavior therapy
## Surveillance
The following are appropriate:
SARA score annually. Note: SARA may not detect disease progression for the first five to seven years.
Electrooculographic tests may be performed every two years (cooperation is required).
Brain MRI volumetry every two years
• SARA score annually. Note: SARA may not detect disease progression for the first five to seven years.
• Electrooculographic tests may be performed every two years (cooperation is required).
• Brain MRI volumetry every two years
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Spinocerebellar ataxia type 37 (SCA37) is inherited in an autosomal dominant manner.
All individuals diagnosed to date with SCA37 have an affected parent.
A proven
Molecular genetic testing is recommended for the parents of a proband with an apparent
The family history of an individual diagnosed with SCA37 may appear to be negative because of failure to recognize the disorder in family members, age-related penetrance and 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 appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to have the ATTTC repeat insertion within
An ATTTC repeat allele may expand further in length, resulting in transmission of an allele with a larger ATTTC repeat. While possible, no evidence of anticipation has been yet identified [
In sibships with similar ATTTC repeat sizes, female sibs may present at a significantly younger age (see
However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SCA37 because of the possibility of age-related penetrance in a parent (or the theoretic possibility of parental germline mosaicism).
Predictive testing for at-risk relatives is possible once the 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.
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 SCA37, 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.
Once the ATTTC repeat insertion within
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 individuals diagnosed to date with SCA37 have an affected parent.
• A proven
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• The family history of an individual diagnosed with SCA37 may appear to be negative because of failure to recognize the disorder in family members, age-related penetrance and 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 appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to have the ATTTC repeat insertion within
• An ATTTC repeat allele may expand further in length, resulting in transmission of an allele with a larger ATTTC repeat. While possible, no evidence of anticipation has been yet identified [
• In sibships with similar ATTTC repeat sizes, female sibs may present at a significantly younger age (see
• An ATTTC repeat allele may expand further in length, resulting in transmission of an allele with a larger ATTTC repeat. While possible, no evidence of anticipation has been yet identified [
• In sibships with similar ATTTC repeat sizes, female sibs may present at a significantly younger age (see
• However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SCA37 because of the possibility of age-related penetrance in a parent (or the theoretic possibility of parental germline mosaicism).
• An ATTTC repeat allele may expand further in length, resulting in transmission of an allele with a larger ATTTC repeat. While possible, no evidence of anticipation has been yet identified [
• In sibships with similar ATTTC repeat sizes, female sibs may present at a significantly younger age (see
• Predictive testing for at-risk relatives is possible once the 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.
• 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
Spinocerebellar ataxia type 37 (SCA37) is inherited in an autosomal dominant manner.
## Risk to Family Members
All individuals diagnosed to date with SCA37 have an affected parent.
A proven
Molecular genetic testing is recommended for the parents of a proband with an apparent
The family history of an individual diagnosed with SCA37 may appear to be negative because of failure to recognize the disorder in family members, age-related penetrance and 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 appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to have the ATTTC repeat insertion within
An ATTTC repeat allele may expand further in length, resulting in transmission of an allele with a larger ATTTC repeat. While possible, no evidence of anticipation has been yet identified [
In sibships with similar ATTTC repeat sizes, female sibs may present at a significantly younger age (see
However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SCA37 because of the possibility of age-related penetrance in a parent (or the theoretic possibility of parental germline mosaicism).
• All individuals diagnosed to date with SCA37 have an affected parent.
• A proven
• Molecular genetic testing is recommended for the parents of a proband with an apparent
• The family history of an individual diagnosed with SCA37 may appear to be negative because of failure to recognize the disorder in family members, age-related penetrance and 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 appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to have the ATTTC repeat insertion within
• An ATTTC repeat allele may expand further in length, resulting in transmission of an allele with a larger ATTTC repeat. While possible, no evidence of anticipation has been yet identified [
• In sibships with similar ATTTC repeat sizes, female sibs may present at a significantly younger age (see
• An ATTTC repeat allele may expand further in length, resulting in transmission of an allele with a larger ATTTC repeat. While possible, no evidence of anticipation has been yet identified [
• In sibships with similar ATTTC repeat sizes, female sibs may present at a significantly younger age (see
• However, sibs of a proband with clinically unaffected parents are still presumed to be at increased risk for SCA37 because of the possibility of age-related penetrance in a parent (or the theoretic possibility of parental germline mosaicism).
• An ATTTC repeat allele may expand further in length, resulting in transmission of an allele with a larger ATTTC repeat. While possible, no evidence of anticipation has been yet identified [
• In sibships with similar ATTTC repeat sizes, female sibs may present at a significantly younger age (see
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once the 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.
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 SCA37, 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 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.
• 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 ATTTC repeat insertion within
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
Rua 25 de Abril n.º 82
Castro Marim 8950-122
Portugal
United Kingdom
United Kingdom
Spain
Sanford Research
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• Rua 25 de Abril n.º 82
• Castro Marim 8950-122
• Portugal
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• United Kingdom
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• United Kingdom
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• Spain
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• Sanford Research
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## Molecular Genetics
Spinocerebellar Ataxia Type 37: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 37 (
Spinocerebellar ataxia type 37 (SCA37) is a repeat expansion disorder caused by a heterozygous 5'UTR intronic insertion of 31-75 ATTTC repeats, flanked on both sides by an ATTTT repeat tract with more than 58 units each, in
DAB1 functions downstream of reelin, a large glycoprotein secreted by neurons of the developing brain, in a signaling pathway that controls cell positioning in the developing brain and during adult neurogenesis. DAB1 docks to the intracellular part of the reelin very low-density lipoprotein receptor (VLDLR) and apoE receptor type 2 (ApoER2) and becomes tyrosine-phosphorylated following binding of reelin to neurons. In mice, pathogenic variants of Dab1 and Reelin generate highly similar phenotypes;
The ATTTC insertion creates new putative XBP1 transcription factor binding motifs [
Repeat-primed PCR (RP-PCR) may not be specific for pathogenic SCA37 ATTTC alleles (since it would also show positive with the same amplification pattern of long ATTTT repeats) and has the potential for false negative and positive results; thus, it is not a recommended method.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
The (ATTTC)
## Molecular Pathogenesis
Spinocerebellar ataxia type 37 (SCA37) is a repeat expansion disorder caused by a heterozygous 5'UTR intronic insertion of 31-75 ATTTC repeats, flanked on both sides by an ATTTT repeat tract with more than 58 units each, in
DAB1 functions downstream of reelin, a large glycoprotein secreted by neurons of the developing brain, in a signaling pathway that controls cell positioning in the developing brain and during adult neurogenesis. DAB1 docks to the intracellular part of the reelin very low-density lipoprotein receptor (VLDLR) and apoE receptor type 2 (ApoER2) and becomes tyrosine-phosphorylated following binding of reelin to neurons. In mice, pathogenic variants of Dab1 and Reelin generate highly similar phenotypes;
The ATTTC insertion creates new putative XBP1 transcription factor binding motifs [
Repeat-primed PCR (RP-PCR) may not be specific for pathogenic SCA37 ATTTC alleles (since it would also show positive with the same amplification pattern of long ATTTT repeats) and has the potential for false negative and positive results; thus, it is not a recommended method.
Notable
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
The (ATTTC)
## Chapter Notes
The authors have been experts on the genetic diagnosis of inherited ataxias since 1990. They have published more than 50 articles on ataxia research, identifying and describing a few novel spinocerebellar ataxia subtypes including SCA37.
Funding from the Spanish Health Institute Carlos III (ISCIII) is gratefully acknowledged (CPII/00029; FIS PI14/00136; FIS PI14/01159; FIS PI17/00534).
30 May 2019 (sw) Review posted live
14 August 2018 (amd) Original submission
• 30 May 2019 (sw) Review posted live
• 14 August 2018 (amd) Original submission
## Author Notes
The authors have been experts on the genetic diagnosis of inherited ataxias since 1990. They have published more than 50 articles on ataxia research, identifying and describing a few novel spinocerebellar ataxia subtypes including SCA37.
## Acknowledgments
Funding from the Spanish Health Institute Carlos III (ISCIII) is gratefully acknowledged (CPII/00029; FIS PI14/00136; FIS PI14/01159; FIS PI17/00534).
## Revision History
30 May 2019 (sw) Review posted live
14 August 2018 (amd) Original submission
• 30 May 2019 (sw) Review posted live
• 14 August 2018 (amd) Original submission
## References
## Literature Cited
|
[
"M Corral-Juan, C Serrano-Munuera, A Rábano, D Cota-González, A Segarra-Roca, L Ispierto, AT Cano-Orgaz, AD Adarmes, C Méndez-del-Barrio, S Jesús, P Mir, V Volpini, R Alvarez-Ramo, I Sánchez, A Matilla-Dueñas. Clinical, genetic and neuropathological characterisation of spinocerebellar ataxia type 37.. Brain 2018;141:1981-97",
"P Coutinho, L Ruano, JL Loureiro, VT Cruz, J Barros, A Tuna, C Barbot, J Guimarães, I Alonso, I Silveira, J Sequeiros, J Marques Neves, P Serrano, MC Silva. Hereditary ataxia and spastic paraplegia in Portugal: a population-based prevalence study.. JAMA Neurol 2013;70:746-55",
"M Kehrer, K Schäferhoff, M Bonin, A Jauch, A Bevot, A. Tzschach. Interstitial 1p32.1p32.3 deletion in a patient with multiple congenital anomalies.. Am J Med Genet A. 2015;167A:2406-10",
"J Li, J Liu, L Zhao, Y Ma, M Jia, T Lu, Y Ruan, Q Li, W Yue, D Zhang, L Wang. Association study between genes in Reelin signaling pathway and autism identifies DAB1 as a susceptibility gene in a Chinese Han population.. Prog Neuropsychopharmacol Biol Psychiatry. 2013;44:226-32",
"JR Loureiro, CL Oliveira, C Mota, AF Castro, C Costa, JL Loureiro, P Coutinho, S Martins, J Sequeiros, I Silveira. Mutational mechanism for DAB1 (ATTTC)(n) insertion in SCA37: ATTTT repeat lengthening and nucleotide substitution.. Hum Mutat. 2019;40:404-12",
"M Mulatinho, J Llerena, TP Leren, PN Rao, F Quintero-Rivera. Deletion (1)(p32.2-p32.3) detected by array-CGH in a patient with developmental delay/mental retardation, dysmorphic features and low cholesterol: a new microdeletion syndrome?. Am J Med Genet A. 2008;146A:2284-90",
"I Sánchez, E Balagué, A. Matilla-Dueñas. Ataxin-1 mediated regulation of the cerebellar proteome reveals a role in bioenergetics mechanisms which are altered in spinocerebellar ataxia type 1 (SCA1).. Hum Mol Genet. 2016;25:4021-40",
"JA Saute, KC Donis, C Serrano-Munuera, D Genis, LT Ramirez, P Mazzetti, LV Pérez, P Latorre, J Sequeiros, A Matilla-Dueñas, LB Jardim. Ataxia rating scales--psychometric profiles, natural history and their application in clinical trials.. Cerebellum. 2012;11:488-504",
"T Schmitz-Hübsch, ST du Montcel, L Baliko, J Berciano, S Boesch, C Depondt, P Giunti, C Globas, J Infante, JS Kang, B Kremer, C Mariotti, B Melegh, M Pandolfo, M Rakowicz, P Ribai, R Rola, L Schöls, S Szymanski, BP van de Warrenburg, A Dürr, T Klockgether, R Fancellu. Scale for the assessment and rating of ataxia: development of a new clinical scale.. Neurology. 2006;66:1717-20",
"AI Seixas, JR Loureiro, C Costa, A Ordóñez-Ugalde, H Marcelino, CL Oliveira, JL Loureiro, A Dhingra, E Brandão, VT Cruz, A Timóteo, B Quintáns, GA Rouleau, P Rizzu, Á Carracedo, J Bessa, P Heutink, J Sequeiros, MJ Sobrido, P Coutinho, I Silveira. A pentanucleotide ATTTC repeat insertion in the non-coding region of DAB1, mapping to SCA37, causes spinocerebellar ataxia.. Am J Hum Genet 2017;101:87-103",
"C Serrano-Munuera, M Corral-Juan, G Stevanin, H San Nicolás, C Roig, J Corral, B Campos, L de Jorge, C Morcillo-Suárez, A Navarro, S Forlani, A Durr, J Kulisevsky, A Brice, I Sánchez, V Volpini, A. Matilla-Dueñas. New subtype of spinocerebellar ataxia with altered vertical eye movements mapping to chromosome 1p32'.. JAMA Neurology. 2013;70:764-71",
"M Sheldon, DS Rice, G D'Arcangelo, H Yoneshima, K Nakajima, K Mikoshiba, BW Howell, JA Cooper, D Goldowitz, T Curran. Scrambler and yotari disrupt the disabled gene and produce a reeler-like phenotype in mice.. Nature 1997;389:730-3",
"S Yang, S Huang, MA Gaertig, XJ Li, S Li. Age-dependent decrease in chaperone activity impairs MANF expression, leading to Purkinje cell degeneration in inducible SCA17 Mice.. Neuron. 2014;81:349-65",
"M Yano, Y Hayakawa-Yano, A Mele, RB Darnell. Nova2 regulates neuronal migration through an RNA switch in disabled-1 signaling.. Neuron 2010;66:848-58"
] |
30/5/2019
|
GeneReviews®
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sca38
|
sca38
|
[
"SCA38",
"Very long chain fatty acid elongase 5",
"ELOVL5",
"Spinocerebellar Ataxia Type 38"
] |
Spinocerebellar Ataxia Type 38
|
Alfredo Brusco, Eleonora Di Gregorio, Barbara Borroni
|
Summary Spinocerebellar ataxia type 38 (SCA38) is characterized as a pure cerebellar ataxia with symptoms typically manifesting in the fourth decade of life. The most common presenting features are nystagmus and slowly progressive gait ataxia. As the disease progresses, cerebellar symptoms (limb ataxia, dysarthria, dysphagia, diplopia on the horizontal line) may emerge, and affected individuals may experience sensory loss. In the later stages of the condition, ophthalmoparesis followed by ophthalmoplegia may occur. Features that distinguish SCA38 from other spinocerebellar ataxias include The diagnosis of SCA38 is established in a proband with progressive gait ataxia and a heterozygous pathogenic variant in Spinocerebellar ataxia type 38 (SCA38) is inherited in an autosomal dominant manner. All reported individuals diagnosed with SCA38 have an affected parent. The offspring of an affected individual are at 50% risk of inheriting the
|
## Diagnosis
Formal clinical diagnostic criteria for spinocerebellar ataxia 38 (SCA38) have not been established.
Spinocerebellar ataxia type 38 (SCA38)
Slowly progressive gait ataxia with onset in adulthood (3rd-5th decade)
Nystagmus in the lateral and vertical gaze
Hyposmia
Cerebellar atrophy (sometimes referred to as cerebellar hypometabolism when visualized on PET scan) mainly affecting the vermis without atrophy of the cerebral cortex
Normal appearance of the brain stem
The diagnosis of SCA38
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 SCA38 is indistinguishable from many other inherited disorders with SCA, recommended molecular genetic testing approaches include use of a
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 Spinocerebellar Ataxia Type 38
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
Only two pathogenic variants have been identified to date:
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.
• Slowly progressive gait ataxia with onset in adulthood (3rd-5th decade)
• Nystagmus in the lateral and vertical gaze
•
• Hyposmia
• Cerebellar atrophy (sometimes referred to as cerebellar hypometabolism when visualized on PET scan) mainly affecting the vermis without atrophy of the cerebral cortex
• Normal appearance of the brain stem
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Spinocerebellar ataxia type 38 (SCA38)
Slowly progressive gait ataxia with onset in adulthood (3rd-5th decade)
Nystagmus in the lateral and vertical gaze
Hyposmia
Cerebellar atrophy (sometimes referred to as cerebellar hypometabolism when visualized on PET scan) mainly affecting the vermis without atrophy of the cerebral cortex
Normal appearance of the brain stem
• Slowly progressive gait ataxia with onset in adulthood (3rd-5th decade)
• Nystagmus in the lateral and vertical gaze
•
• Hyposmia
• Cerebellar atrophy (sometimes referred to as cerebellar hypometabolism when visualized on PET scan) mainly affecting the vermis without atrophy of the cerebral cortex
• Normal appearance of the brain stem
## Establishing the Diagnosis
The diagnosis of SCA38
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 SCA38 is indistinguishable from many other inherited disorders with SCA, recommended molecular genetic testing approaches include use of a
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 Spinocerebellar Ataxia Type 38
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
Only two pathogenic variants have been identified to date:
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
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Spinocerebellar ataxia type 38 (SCA38) is characterized as a pure cerebellar ataxia with symptoms typically becoming apparent in the fourth decade of life (age range 26-50 years) [
The most common presenting features are nystagmus (21/21; 100%) and slowly progressive gait ataxia (20/21; 95%).
With disease progression, cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and diplopia on the horizontal line may develop.
In the later stages, ophthalmoparesis followed by ophthalmoplegia may become apparent.
However, visual evoked potentials performed in eight affected individuals were unremarkable [
Peripheral nervous system involvement is present in the last phase of disease with sensory loss.
Dementia or extrapyramidal signs are not detected.
Significant loss of abilities of daily living is reported only after 20 years of disease. In a study by
All affected individuals were able to participate in activities of daily living during the first decade after symptom onset.
During the second decade of symptoms, of 13 affected individuals:
Nine (70%) had difficulties with ambulation that required the use of a cane.
Four (30%) required assistance with washing and dressing.
During the third decade of symptoms, of eight affected individuals:
Seven (87%) required the use of a wheelchair and required assistance with activities of daily living.
Four (50%) required assistance with feeding.
Four (50%) developed dysphagia.
One (12%) developed incontinence.
Features that help distinguish SCA38 from other spinocerebellar ataxia conditions are
Other signs and symptoms may include the following:
Hearing loss (7/21; 33%), the basis of which has not been systematically studied
Auditory evoked potentials were abnormal in 11/12 (92%) of individuals assessed.
Anxiety disorder (7/21; 33%)
No genotype-phenotype correlations are known.
Disease penetrance appears to be 100% in both males and females but is age dependent. In individuals with the
This disease is likely extremely rare. A study of 346 individuals with spinocerebellar ataxia in China found no individuals with a pathogenic variant in
Anticipation has not been observed in families with SCA38.
• The most common presenting features are nystagmus (21/21; 100%) and slowly progressive gait ataxia (20/21; 95%).
• With disease progression, cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and diplopia on the horizontal line may develop.
• In the later stages, ophthalmoparesis followed by ophthalmoplegia may become apparent.
• However, visual evoked potentials performed in eight affected individuals were unremarkable [
• Peripheral nervous system involvement is present in the last phase of disease with sensory loss.
• Dementia or extrapyramidal signs are not detected.
• All affected individuals were able to participate in activities of daily living during the first decade after symptom onset.
• During the second decade of symptoms, of 13 affected individuals:
• Nine (70%) had difficulties with ambulation that required the use of a cane.
• Four (30%) required assistance with washing and dressing.
• Nine (70%) had difficulties with ambulation that required the use of a cane.
• Four (30%) required assistance with washing and dressing.
• During the third decade of symptoms, of eight affected individuals:
• Seven (87%) required the use of a wheelchair and required assistance with activities of daily living.
• Four (50%) required assistance with feeding.
• Four (50%) developed dysphagia.
• One (12%) developed incontinence.
• Seven (87%) required the use of a wheelchair and required assistance with activities of daily living.
• Four (50%) required assistance with feeding.
• Four (50%) developed dysphagia.
• One (12%) developed incontinence.
• Nine (70%) had difficulties with ambulation that required the use of a cane.
• Four (30%) required assistance with washing and dressing.
• Seven (87%) required the use of a wheelchair and required assistance with activities of daily living.
• Four (50%) required assistance with feeding.
• Four (50%) developed dysphagia.
• One (12%) developed incontinence.
• Hearing loss (7/21; 33%), the basis of which has not been systematically studied
• Auditory evoked potentials were abnormal in 11/12 (92%) of individuals assessed.
• Anxiety disorder (7/21; 33%)
## Clinical Description
Spinocerebellar ataxia type 38 (SCA38) is characterized as a pure cerebellar ataxia with symptoms typically becoming apparent in the fourth decade of life (age range 26-50 years) [
The most common presenting features are nystagmus (21/21; 100%) and slowly progressive gait ataxia (20/21; 95%).
With disease progression, cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and diplopia on the horizontal line may develop.
In the later stages, ophthalmoparesis followed by ophthalmoplegia may become apparent.
However, visual evoked potentials performed in eight affected individuals were unremarkable [
Peripheral nervous system involvement is present in the last phase of disease with sensory loss.
Dementia or extrapyramidal signs are not detected.
Significant loss of abilities of daily living is reported only after 20 years of disease. In a study by
All affected individuals were able to participate in activities of daily living during the first decade after symptom onset.
During the second decade of symptoms, of 13 affected individuals:
Nine (70%) had difficulties with ambulation that required the use of a cane.
Four (30%) required assistance with washing and dressing.
During the third decade of symptoms, of eight affected individuals:
Seven (87%) required the use of a wheelchair and required assistance with activities of daily living.
Four (50%) required assistance with feeding.
Four (50%) developed dysphagia.
One (12%) developed incontinence.
Features that help distinguish SCA38 from other spinocerebellar ataxia conditions are
Other signs and symptoms may include the following:
Hearing loss (7/21; 33%), the basis of which has not been systematically studied
Auditory evoked potentials were abnormal in 11/12 (92%) of individuals assessed.
Anxiety disorder (7/21; 33%)
• The most common presenting features are nystagmus (21/21; 100%) and slowly progressive gait ataxia (20/21; 95%).
• With disease progression, cerebellar symptoms such as limb ataxia, dysarthria, dysphagia, and diplopia on the horizontal line may develop.
• In the later stages, ophthalmoparesis followed by ophthalmoplegia may become apparent.
• However, visual evoked potentials performed in eight affected individuals were unremarkable [
• Peripheral nervous system involvement is present in the last phase of disease with sensory loss.
• Dementia or extrapyramidal signs are not detected.
• All affected individuals were able to participate in activities of daily living during the first decade after symptom onset.
• During the second decade of symptoms, of 13 affected individuals:
• Nine (70%) had difficulties with ambulation that required the use of a cane.
• Four (30%) required assistance with washing and dressing.
• Nine (70%) had difficulties with ambulation that required the use of a cane.
• Four (30%) required assistance with washing and dressing.
• During the third decade of symptoms, of eight affected individuals:
• Seven (87%) required the use of a wheelchair and required assistance with activities of daily living.
• Four (50%) required assistance with feeding.
• Four (50%) developed dysphagia.
• One (12%) developed incontinence.
• Seven (87%) required the use of a wheelchair and required assistance with activities of daily living.
• Four (50%) required assistance with feeding.
• Four (50%) developed dysphagia.
• One (12%) developed incontinence.
• Nine (70%) had difficulties with ambulation that required the use of a cane.
• Four (30%) required assistance with washing and dressing.
• Seven (87%) required the use of a wheelchair and required assistance with activities of daily living.
• Four (50%) required assistance with feeding.
• Four (50%) developed dysphagia.
• One (12%) developed incontinence.
• Hearing loss (7/21; 33%), the basis of which has not been systematically studied
• Auditory evoked potentials were abnormal in 11/12 (92%) of individuals assessed.
• Anxiety disorder (7/21; 33%)
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
## Penetrance
Disease penetrance appears to be 100% in both males and females but is age dependent. In individuals with the
## Prevalence
This disease is likely extremely rare. A study of 346 individuals with spinocerebellar ataxia in China found no individuals with a pathogenic variant in
## Anticipation
Anticipation has not been observed in families with SCA38.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The inherited spinocerebellar ataxias (SCAs) are a heterogeneous group of neurologic disorders that defy easy differentiation on the basis of clinical criteria alone [
The most commonly occurring SCAs – those caused by polyglutamine expansions (i.e.,
• The most commonly occurring SCAs – those caused by polyglutamine expansions (i.e.,
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 38 (SCA38), the evaluations in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 38
Management of individuals remains supportive, as no known therapy to delay or halt the progression of the disease exists.
The American Academy of Neurology has developed guidelines for the treatment of motor dysfunction in individuals with ataxia [
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 38
Appropriate social work involvement to connect families w/local resources, respite, & support
Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
Vitamin supplements may be recommended, particularly if caloric intake is reduced.
Affected individuals should be examined at least annually by a physician experienced in movement disorders and ataxia.
Alcohol and medications known to affect cerebellar function should be avoided.
See
A double-blind, randomized, placebo-controlled study followed by an open-label extension phase demonstrated the usefulness of docosahexaenoic acid (DHA) supplementation (600 mg/day) as a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism [
No data on the effectiveness of DHA in postponing the signs and symptoms of SCA38 in asymptomatic individuals who have a heterozygous pathogenic variant in
Search
• Appropriate social work involvement to connect families w/local resources, respite, & support
• Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 38 (SCA38), the evaluations in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 38
## Treatment of Manifestations
Management of individuals remains supportive, as no known therapy to delay or halt the progression of the disease exists.
The American Academy of Neurology has developed guidelines for the treatment of motor dysfunction in individuals with ataxia [
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 38
Appropriate social work involvement to connect families w/local resources, respite, & support
Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
• Appropriate social work involvement to connect families w/local resources, respite, & support
• Care coordination to manage multiple subspecialty appointments, equipment, medications, & supplies
## Prevention of Secondary Complications
Weight control is important because obesity can exacerbate difficulties with ambulation and mobility.
Vitamin supplements may be recommended, particularly if caloric intake is reduced.
## Surveillance
Affected individuals should be examined at least annually by a physician experienced in movement disorders and ataxia.
## Agents/Circumstances to Avoid
Alcohol and medications known to affect cerebellar function should be avoided.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
A double-blind, randomized, placebo-controlled study followed by an open-label extension phase demonstrated the usefulness of docosahexaenoic acid (DHA) supplementation (600 mg/day) as a safe and effective treatment for SCA38, showing an improvement of clinical symptoms and cerebellar hypometabolism [
No data on the effectiveness of DHA in postponing the signs and symptoms of SCA38 in asymptomatic individuals who have a heterozygous pathogenic variant in
Search
## Genetic Counseling
Spinocerebellar ataxia type 38 (SCA38) is inherited in an autosomal dominant manner.
All reported individuals diagnosed with SCA38 have an affected parent.
SCA38 resulting from a
Symptom onset is age dependent (see
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 SCA38 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to have the
If 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 SCA38, 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.
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.
• All reported individuals diagnosed with SCA38 have an affected parent.
• SCA38 resulting from a
• Symptom onset is age dependent (see
• 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 SCA38 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to have the
• If 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
Spinocerebellar ataxia type 38 (SCA38) is inherited in an autosomal dominant manner.
## Risk to Family Members
All reported individuals diagnosed with SCA38 have an affected parent.
SCA38 resulting from a
Symptom onset is age dependent (see
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 SCA38 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to have the
If the
• All reported individuals diagnosed with SCA38 have an affected parent.
• SCA38 resulting from a
• Symptom onset is age dependent (see
• 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 SCA38 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to have the
• If 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 SCA38, 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
• 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, 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
Via Sara 12
16039
Italy
United Kingdom
•
• Via Sara 12
• 16039
• Italy
•
•
• United Kingdom
•
•
•
•
•
## Molecular Genetics
Spinocerebellar Ataxia Type 38: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 38 (
ELOVL5 is a protein that is involved in the elongation of long-chain polyunsaturated fatty acids. It is a membrane protein located in the endoplasmic reticulum and expressed in human cerebellum.
Notable
Variants listed in the table have been provided by the authors.
Variant transcript with additional in-frame exon compared to predominant transcript
Predominant transcript
Described in three Italian families
## Molecular Pathogenesis
ELOVL5 is a protein that is involved in the elongation of long-chain polyunsaturated fatty acids. It is a membrane protein located in the endoplasmic reticulum and expressed in human cerebellum.
Notable
Variants listed in the table have been provided by the authors.
Variant transcript with additional in-frame exon compared to predominant transcript
Predominant transcript
Described in three Italian families
## Chapter Notes
A Brusco and E Di Gregorio are involved in the study of the genetic bases of spinocerebellar ataxia and the molecular pathogenesis of SCA28 and SCA38.
B Borroni is involved in the study of ataxias and dementia.
All the authors recently worked on the development of a therapy for SCA38 based on DHA administration.
Work supported by Telethon Foundation grant GGP14225.
11 July 2019 (ma) Review posted live
31 December 2017 (ab) Original submission
• 11 July 2019 (ma) Review posted live
• 31 December 2017 (ab) Original submission
## Author Notes
A Brusco and E Di Gregorio are involved in the study of the genetic bases of spinocerebellar ataxia and the molecular pathogenesis of SCA28 and SCA38.
B Borroni is involved in the study of ataxias and dementia.
All the authors recently worked on the development of a therapy for SCA38 based on DHA administration.
## Acknowledgments
Work supported by Telethon Foundation grant GGP14225.
## Revision History
11 July 2019 (ma) Review posted live
31 December 2017 (ab) Original submission
• 11 July 2019 (ma) Review posted live
• 31 December 2017 (ab) Original submission
## References
## Literature Cited
|
[] |
11/7/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sca4
|
sca4
|
[
"SCA4",
"Spinocerebellar Ataxia 4",
"SCA4",
"Spinocerebellar Ataxia 4",
"Zinc finger homeobox protein 3",
"ZFHX3",
"Spinocerebellar Ataxia Type 4"
] |
Spinocerebellar Ataxia Type 4
|
Andreas Puschmann, Sigurd Dobloug, Joel Wallenius, Klas Wictorin, Sorina Gorcenco
|
Summary Spinocerebellar ataxia type 4 (SCA4) is a progressive neurologic disease characterized by cerebellar involvement (gait ataxia, balance disturbances, eye movement abnormalities), brain stem involvement (dysarthria, dysphagia), sensory neuropathy, motor neuron involvement (muscle wasting and spasticity), autonomic dysfunction (especially orthostatic hypotension), and cognition and/or behavior manifestations. Age of onset ranges from 12 to 65 years. In the approximately 10% of individuals whose onset is before age 25 years disease manifestations are more severe and often different from those with later-onset disease. As the disease progresses, particularly in those with early-onset disease, eye movement abnormalities, dysarthria, dysphagia, sensory neuropathy, upper and lower motor neuron involvement, and orthostatic hypotension can further aggravate balance and gait problems. Most individuals eventually require a walker or wheelchair. Reduced life expectancy in individuals with earlier-onset severe SCA4 is associated with weight loss, infections, and cardiac arrhythmia. Life expectancy is normal or near normal in individuals with later-onset SCA4. The diagnosis of SCA4 is established in a proband with suggestive findings by the identification of a heterozygous abnormal trinucleotide GGC repeat expansion in the terminal exon of SCA4 is inherited in an autosomal dominant manner. Most individuals diagnosed with SCA4 have an affected parent. As anticipation is common in SCA4, the affected parent frequently has milder disease with a later age of onset than their affected offspring. Each child of an individual with SCA4 has a 50% chance of inheriting an abnormal GGC repeat expansion in
|
## Diagnosis
No consensus diagnostic criteria for spinocerebellar ataxia type 4 (SCA4) have been published.
Spinocerebellar ataxia type 4 (SCA4)
Age of onset ranges from 12 to 65 years. About 10% of individuals have early onset (i.e., before age 25 years).
Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
Rarely, distal extremity sensory impairment can be the presenting manifestation or the one that predominates early in the disease course. Almost all individuals develop sensory neuropathy with disease progression.
Examination reveals reduced vibration sense in all individuals and reduction in other sensory modalities (pinprick, temperature, light touch, proprioception) in some. Romberg test may be positive.
Neurophysiologic signs (a reduction in amplitude or complete loss of sensory nerve action potentials) may predate the onset of balance and gait impairment or of other clinical manifestations [
Examination reveals UMN involvement including extensor plantar reflexes in about 85%.
Signs and symptoms of LMN involvement occur in 30%-100% of individuals with disease progression and can include weakness and muscle wasting that is often mild. Tendon reflexes are absent or diminished in most individuals when balance and gait disturbances become manifest.
Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Of note, anticipation (earlier disease onset in successive generations) is commonly observed. Absence of a known family history does not preclude the diagnosis.
The diagnosis of SCA4
Note: Pathogenic GGC repeat expansions in
Note: (1) Normal alleles always contain interruptions in the regularly repeated GGC sequence that encodes glycine. The most common normal allele includes one AGT triplet (encoding serine, or a "serine interruption") and two GAC triplets (also encoding glycine); however, many different variations have been observed in normal alleles [
Short-read whole-genome sequencing. Short-read whole-genome sequencing-based tools developed for the detection of nucleotide repeat expansions have led to the identification of exonic GGC repeats in the terminal exon of
Long-read sequencing or PCR fragment analysis. Long-read sequencing is likely the most reliable method for the detection of
For further information, see
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 4
See
Long-read sequencing can detect the presence of a pathogenic repeat expansion and has accurately quantified repeat length for all repeat expansions identified to date [
GGC repeat expansions in
• Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
• Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
• Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
• Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
• Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
• Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
• Rarely, distal extremity sensory impairment can be the presenting manifestation or the one that predominates early in the disease course. Almost all individuals develop sensory neuropathy with disease progression.
• Examination reveals reduced vibration sense in all individuals and reduction in other sensory modalities (pinprick, temperature, light touch, proprioception) in some. Romberg test may be positive.
• Neurophysiologic signs (a reduction in amplitude or complete loss of sensory nerve action potentials) may predate the onset of balance and gait impairment or of other clinical manifestations [
• Examination reveals UMN involvement including extensor plantar reflexes in about 85%.
• Signs and symptoms of LMN involvement occur in 30%-100% of individuals with disease progression and can include weakness and muscle wasting that is often mild. Tendon reflexes are absent or diminished in most individuals when balance and gait disturbances become manifest.
• Short-read whole-genome sequencing. Short-read whole-genome sequencing-based tools developed for the detection of nucleotide repeat expansions have led to the identification of exonic GGC repeats in the terminal exon of
• Long-read sequencing or PCR fragment analysis. Long-read sequencing is likely the most reliable method for the detection of
## Suggestive Findings
Spinocerebellar ataxia type 4 (SCA4)
Age of onset ranges from 12 to 65 years. About 10% of individuals have early onset (i.e., before age 25 years).
Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
Rarely, distal extremity sensory impairment can be the presenting manifestation or the one that predominates early in the disease course. Almost all individuals develop sensory neuropathy with disease progression.
Examination reveals reduced vibration sense in all individuals and reduction in other sensory modalities (pinprick, temperature, light touch, proprioception) in some. Romberg test may be positive.
Neurophysiologic signs (a reduction in amplitude or complete loss of sensory nerve action potentials) may predate the onset of balance and gait impairment or of other clinical manifestations [
Examination reveals UMN involvement including extensor plantar reflexes in about 85%.
Signs and symptoms of LMN involvement occur in 30%-100% of individuals with disease progression and can include weakness and muscle wasting that is often mild. Tendon reflexes are absent or diminished in most individuals when balance and gait disturbances become manifest.
Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Of note, anticipation (earlier disease onset in successive generations) is commonly observed. Absence of a known family history does not preclude the diagnosis.
• Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
• Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
• Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
• Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
• Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
• Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
• Rarely, distal extremity sensory impairment can be the presenting manifestation or the one that predominates early in the disease course. Almost all individuals develop sensory neuropathy with disease progression.
• Examination reveals reduced vibration sense in all individuals and reduction in other sensory modalities (pinprick, temperature, light touch, proprioception) in some. Romberg test may be positive.
• Neurophysiologic signs (a reduction in amplitude or complete loss of sensory nerve action potentials) may predate the onset of balance and gait impairment or of other clinical manifestations [
• Examination reveals UMN involvement including extensor plantar reflexes in about 85%.
• Signs and symptoms of LMN involvement occur in 30%-100% of individuals with disease progression and can include weakness and muscle wasting that is often mild. Tendon reflexes are absent or diminished in most individuals when balance and gait disturbances become manifest.
## Clinical Findings
Age of onset ranges from 12 to 65 years. About 10% of individuals have early onset (i.e., before age 25 years).
Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
Rarely, distal extremity sensory impairment can be the presenting manifestation or the one that predominates early in the disease course. Almost all individuals develop sensory neuropathy with disease progression.
Examination reveals reduced vibration sense in all individuals and reduction in other sensory modalities (pinprick, temperature, light touch, proprioception) in some. Romberg test may be positive.
Neurophysiologic signs (a reduction in amplitude or complete loss of sensory nerve action potentials) may predate the onset of balance and gait impairment or of other clinical manifestations [
Examination reveals UMN involvement including extensor plantar reflexes in about 85%.
Signs and symptoms of LMN involvement occur in 30%-100% of individuals with disease progression and can include weakness and muscle wasting that is often mild. Tendon reflexes are absent or diminished in most individuals when balance and gait disturbances become manifest.
• Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
• Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
• Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
• Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
• Although affected individuals may report dizziness when walking and difficulty in rapidly directing their gaze in different directions (such as when crossing a street as a pedestrian), this concern often is only elicited on specific questioning (as these issues are often attributed to cerebellar and sensory involvement and gait disturbances). Examination usually reveals the ability to slowly direct the gaze vertically and/or horizontally in a normal or restricted range. With long-standing disease horizontal, vertical, or total gaze restriction may occur.
• Other eye movement abnormalities include head eye lag, saccadic pursuit, saccadic intrusions, hypermetric saccades, and, in a few individuals, nystagmus or impaired suppression of vestibulo-ocular reflex.
• Rarely, distal extremity sensory impairment can be the presenting manifestation or the one that predominates early in the disease course. Almost all individuals develop sensory neuropathy with disease progression.
• Examination reveals reduced vibration sense in all individuals and reduction in other sensory modalities (pinprick, temperature, light touch, proprioception) in some. Romberg test may be positive.
• Neurophysiologic signs (a reduction in amplitude or complete loss of sensory nerve action potentials) may predate the onset of balance and gait impairment or of other clinical manifestations [
• Examination reveals UMN involvement including extensor plantar reflexes in about 85%.
• Signs and symptoms of LMN involvement occur in 30%-100% of individuals with disease progression and can include weakness and muscle wasting that is often mild. Tendon reflexes are absent or diminished in most individuals when balance and gait disturbances become manifest.
## Imaging Findings
## Family History
Family history is consistent with autosomal dominant inheritance (e.g., affected males and females in multiple generations). Of note, anticipation (earlier disease onset in successive generations) is commonly observed. Absence of a known family history does not preclude the diagnosis.
## Establishing the Diagnosis
The diagnosis of SCA4
Note: Pathogenic GGC repeat expansions in
Note: (1) Normal alleles always contain interruptions in the regularly repeated GGC sequence that encodes glycine. The most common normal allele includes one AGT triplet (encoding serine, or a "serine interruption") and two GAC triplets (also encoding glycine); however, many different variations have been observed in normal alleles [
Short-read whole-genome sequencing. Short-read whole-genome sequencing-based tools developed for the detection of nucleotide repeat expansions have led to the identification of exonic GGC repeats in the terminal exon of
Long-read sequencing or PCR fragment analysis. Long-read sequencing is likely the most reliable method for the detection of
For further information, see
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 4
See
Long-read sequencing can detect the presence of a pathogenic repeat expansion and has accurately quantified repeat length for all repeat expansions identified to date [
GGC repeat expansions in
• Short-read whole-genome sequencing. Short-read whole-genome sequencing-based tools developed for the detection of nucleotide repeat expansions have led to the identification of exonic GGC repeats in the terminal exon of
• Long-read sequencing or PCR fragment analysis. Long-read sequencing is likely the most reliable method for the detection of
## Clinical Characteristics
Spinocerebellar ataxia type 4 (SCA4) is a progressive neurologic disease characterized over time by cerebellar / brain stem involvement, sensory neuropathy, upper and lower motor neuron involvement, and autonomic dysfunction as well as less common signs and symptoms including weight loss.
To date, more than 200 affected individuals have been identified in families with SCA4. For many reports only historical information is available; however, several publications have provided information on modern genetic studies and more detailed clinical information on individuals and kindreds described previously [
Age of onset of initial manifestations of SCA4 reported to date ranges from 12 to 65 years. Compared to individuals with milder, later-onset disease, those with early-onset disease (i.e., before age 25 years) develop more severe and often different manifestations.
While the range of reported eye movement abnormalities is compatible with radiologic and neuropathologic evidence that the disease process affects both the cerebellum and the brain stem, it may also reflect differences in the assessment or reporting of neuro-ophthalmologic findings.
Some individuals may have a predominantly nasal or hypernasal speech [A Puschmann, personal observation].
Paresthesias with tingling or burning sensations in the feet or hands are common, with a distal-to-proximal gradient; symptoms of restless legs also occur. Affected individuals may experience worsening of their balance and gait disturbances in darkness, as observed in sensory ataxia [
Neurophysiologic signs (a reduction in amplitude or complete loss of sensory nerve action potentials) may predate the onset of balance and gait impairment or other clinical manifestations [
UMN involvement, observed in about 85% of individuals, includes extensor plantar reflex responses usually without foot clonus or spasticity.
Later in the disease course, LMN involvement, including weakness and muscle wasting that occurs in 30%-100% of individuals, may contribute to difficulties standing and walking [
In individuals with earlier-onset disease or in advanced disease stages, autonomic dysfunction can become very disabling.
In individuals with more severe disease, orthostatic hypotension can become so pronounced that in extreme cases, individuals cannot be erect or even in a sitting position (despite intensive pharmacologic treatment) because marked drops in blood pressure cause fainting [
In individuals with later-onset disease, orthostatic hypotension may remain subclinical and may not cause impairment because affected individuals tend to start using a wheelchair when their gait and balance problems occur, thus avoiding the frequent postural changes that occur in individuals who are ambulatory.
Other manifestations of autonomic dysfunction can include the following:
Neurogenic urinary bladder disturbances often lead to urinary incontinence.
Increased bowel movements may cause diarrhea; decreased bowel movements may cause constipation. Both can be either mild or severe. When severe either can cause significant distress.
Esophageal hypomobility and atony may occur [
Erectile dysfunction has been reported; the authors suspect that similar dysfunction occurs in females.
Abnormal sweating or hot flashes may either be an independent phenomenon or due to decreases in blood pressure.
Sleep disturbances and acrocyanosis have been reported in some.
Cardiac arrhythmias, a cause of death in severely affected individuals, may be related to cardiac autonomic denervation.
Dystonia manifesting as cervical or exercise-induced dystonia, foot or limb dystonia, or affecting the diaphragm, eyelids, or larynx (i.e., laryngospasm)
Mirror movements of the hands
Overflow movements in which ipsilateral facial grimacing accompanies attempts to lateral gaze
Tremor, choreatic movements, and myoclonic jerks
Parkinsonism has not been reported to date.
Learning difficulties and manifestations of autism spectrum disorder were evident in one individual with very early onset at age 15 years [
One individual with very severe disease declined to see a neurologist for unknown reasons. Other individuals declined gastrostomy tube placement for feeding despite worsening severe weight loss [
Some of the most severely affected individuals develop depression, whereas other persons with SCA4 do not [A Puschmann, personal observations].
The authors suspect these behaviors might indicate cognitive changes; however, this has not been studied in more detail. Nonetheless, these findings in some individuals suggest cognitive or neurobehavioral/psychiatric manifestations, perhaps within the cerebellar cognitive affective syndrome [
Genotype-phenotype correlations to date are preliminary as data are only available on 35 individuals with SCA4 whose repeat sizes have been studied by long-read sequencing [
The longest pathogenic repeat, 74 GGC repeats, was observed in an individual whose balance disturbances started at age 15 years.
The shortest pathogenic repeat, 44 GGC repeats, was observed in an individual whose disease onset was at age 60 years.
Some disease manifestations have only been observed in individuals with younger-onset disease who have longer repeat expansions, including very severe orthostatic hypotension that make erect or seated positions impossible, clinically relevant cognitive or behavioral changes that may remain mild or might include autism spectrum disorder [
To date,
Penetrance is age dependent, with onset between ages 12 and 65 years in all individuals with SCA4 reported to date.
In five families for which individual-level data on age at onset was published, affected children developed manifestations of SCA4 one to 30 years earlier (mean: 10.1 years; standard deviation: 7.5 years) than their affected parents; two children developed manifestations seven and nine years later than their affected parent [
No difference in anticipation between maternal and paternal transmission was observed.
Increasing repeat length with parent-to-child transmission has been described in several instances [
SCA4 was previously referred to as "spinocerebellar ataxia, autosomal dominant, with sensory axonal neuropathy" or "autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism." These terms are no longer in use.
To date,
To date, all reported families with
No pathogenic
To date, no pathogenic
• Neurogenic urinary bladder disturbances often lead to urinary incontinence.
• Increased bowel movements may cause diarrhea; decreased bowel movements may cause constipation. Both can be either mild or severe. When severe either can cause significant distress.
• Esophageal hypomobility and atony may occur [
• Erectile dysfunction has been reported; the authors suspect that similar dysfunction occurs in females.
• Abnormal sweating or hot flashes may either be an independent phenomenon or due to decreases in blood pressure.
• Sleep disturbances and acrocyanosis have been reported in some.
• Cardiac arrhythmias, a cause of death in severely affected individuals, may be related to cardiac autonomic denervation.
• Dystonia manifesting as cervical or exercise-induced dystonia, foot or limb dystonia, or affecting the diaphragm, eyelids, or larynx (i.e., laryngospasm)
• Mirror movements of the hands
• Overflow movements in which ipsilateral facial grimacing accompanies attempts to lateral gaze
• Tremor, choreatic movements, and myoclonic jerks
• Learning difficulties and manifestations of autism spectrum disorder were evident in one individual with very early onset at age 15 years [
• One individual with very severe disease declined to see a neurologist for unknown reasons. Other individuals declined gastrostomy tube placement for feeding despite worsening severe weight loss [
• Some of the most severely affected individuals develop depression, whereas other persons with SCA4 do not [A Puschmann, personal observations].
• The longest pathogenic repeat, 74 GGC repeats, was observed in an individual whose balance disturbances started at age 15 years.
• The shortest pathogenic repeat, 44 GGC repeats, was observed in an individual whose disease onset was at age 60 years.
## Clinical Description
Spinocerebellar ataxia type 4 (SCA4) is a progressive neurologic disease characterized over time by cerebellar / brain stem involvement, sensory neuropathy, upper and lower motor neuron involvement, and autonomic dysfunction as well as less common signs and symptoms including weight loss.
To date, more than 200 affected individuals have been identified in families with SCA4. For many reports only historical information is available; however, several publications have provided information on modern genetic studies and more detailed clinical information on individuals and kindreds described previously [
Age of onset of initial manifestations of SCA4 reported to date ranges from 12 to 65 years. Compared to individuals with milder, later-onset disease, those with early-onset disease (i.e., before age 25 years) develop more severe and often different manifestations.
While the range of reported eye movement abnormalities is compatible with radiologic and neuropathologic evidence that the disease process affects both the cerebellum and the brain stem, it may also reflect differences in the assessment or reporting of neuro-ophthalmologic findings.
Some individuals may have a predominantly nasal or hypernasal speech [A Puschmann, personal observation].
Paresthesias with tingling or burning sensations in the feet or hands are common, with a distal-to-proximal gradient; symptoms of restless legs also occur. Affected individuals may experience worsening of their balance and gait disturbances in darkness, as observed in sensory ataxia [
Neurophysiologic signs (a reduction in amplitude or complete loss of sensory nerve action potentials) may predate the onset of balance and gait impairment or other clinical manifestations [
UMN involvement, observed in about 85% of individuals, includes extensor plantar reflex responses usually without foot clonus or spasticity.
Later in the disease course, LMN involvement, including weakness and muscle wasting that occurs in 30%-100% of individuals, may contribute to difficulties standing and walking [
In individuals with earlier-onset disease or in advanced disease stages, autonomic dysfunction can become very disabling.
In individuals with more severe disease, orthostatic hypotension can become so pronounced that in extreme cases, individuals cannot be erect or even in a sitting position (despite intensive pharmacologic treatment) because marked drops in blood pressure cause fainting [
In individuals with later-onset disease, orthostatic hypotension may remain subclinical and may not cause impairment because affected individuals tend to start using a wheelchair when their gait and balance problems occur, thus avoiding the frequent postural changes that occur in individuals who are ambulatory.
Other manifestations of autonomic dysfunction can include the following:
Neurogenic urinary bladder disturbances often lead to urinary incontinence.
Increased bowel movements may cause diarrhea; decreased bowel movements may cause constipation. Both can be either mild or severe. When severe either can cause significant distress.
Esophageal hypomobility and atony may occur [
Erectile dysfunction has been reported; the authors suspect that similar dysfunction occurs in females.
Abnormal sweating or hot flashes may either be an independent phenomenon or due to decreases in blood pressure.
Sleep disturbances and acrocyanosis have been reported in some.
Cardiac arrhythmias, a cause of death in severely affected individuals, may be related to cardiac autonomic denervation.
Dystonia manifesting as cervical or exercise-induced dystonia, foot or limb dystonia, or affecting the diaphragm, eyelids, or larynx (i.e., laryngospasm)
Mirror movements of the hands
Overflow movements in which ipsilateral facial grimacing accompanies attempts to lateral gaze
Tremor, choreatic movements, and myoclonic jerks
Parkinsonism has not been reported to date.
Learning difficulties and manifestations of autism spectrum disorder were evident in one individual with very early onset at age 15 years [
One individual with very severe disease declined to see a neurologist for unknown reasons. Other individuals declined gastrostomy tube placement for feeding despite worsening severe weight loss [
Some of the most severely affected individuals develop depression, whereas other persons with SCA4 do not [A Puschmann, personal observations].
The authors suspect these behaviors might indicate cognitive changes; however, this has not been studied in more detail. Nonetheless, these findings in some individuals suggest cognitive or neurobehavioral/psychiatric manifestations, perhaps within the cerebellar cognitive affective syndrome [
• Neurogenic urinary bladder disturbances often lead to urinary incontinence.
• Increased bowel movements may cause diarrhea; decreased bowel movements may cause constipation. Both can be either mild or severe. When severe either can cause significant distress.
• Esophageal hypomobility and atony may occur [
• Erectile dysfunction has been reported; the authors suspect that similar dysfunction occurs in females.
• Abnormal sweating or hot flashes may either be an independent phenomenon or due to decreases in blood pressure.
• Sleep disturbances and acrocyanosis have been reported in some.
• Cardiac arrhythmias, a cause of death in severely affected individuals, may be related to cardiac autonomic denervation.
• Dystonia manifesting as cervical or exercise-induced dystonia, foot or limb dystonia, or affecting the diaphragm, eyelids, or larynx (i.e., laryngospasm)
• Mirror movements of the hands
• Overflow movements in which ipsilateral facial grimacing accompanies attempts to lateral gaze
• Tremor, choreatic movements, and myoclonic jerks
• Learning difficulties and manifestations of autism spectrum disorder were evident in one individual with very early onset at age 15 years [
• One individual with very severe disease declined to see a neurologist for unknown reasons. Other individuals declined gastrostomy tube placement for feeding despite worsening severe weight loss [
• Some of the most severely affected individuals develop depression, whereas other persons with SCA4 do not [A Puschmann, personal observations].
## Cerebellar / Brain Stem Involvement
While the range of reported eye movement abnormalities is compatible with radiologic and neuropathologic evidence that the disease process affects both the cerebellum and the brain stem, it may also reflect differences in the assessment or reporting of neuro-ophthalmologic findings.
Some individuals may have a predominantly nasal or hypernasal speech [A Puschmann, personal observation].
## Sensory Neuropathy
Paresthesias with tingling or burning sensations in the feet or hands are common, with a distal-to-proximal gradient; symptoms of restless legs also occur. Affected individuals may experience worsening of their balance and gait disturbances in darkness, as observed in sensory ataxia [
Neurophysiologic signs (a reduction in amplitude or complete loss of sensory nerve action potentials) may predate the onset of balance and gait impairment or other clinical manifestations [
## Upper Motor Neuron (UMN) and/or Lower Motor Neuron (LMN) Involvement
UMN involvement, observed in about 85% of individuals, includes extensor plantar reflex responses usually without foot clonus or spasticity.
Later in the disease course, LMN involvement, including weakness and muscle wasting that occurs in 30%-100% of individuals, may contribute to difficulties standing and walking [
## Autonomic Dysfunction
In individuals with earlier-onset disease or in advanced disease stages, autonomic dysfunction can become very disabling.
In individuals with more severe disease, orthostatic hypotension can become so pronounced that in extreme cases, individuals cannot be erect or even in a sitting position (despite intensive pharmacologic treatment) because marked drops in blood pressure cause fainting [
In individuals with later-onset disease, orthostatic hypotension may remain subclinical and may not cause impairment because affected individuals tend to start using a wheelchair when their gait and balance problems occur, thus avoiding the frequent postural changes that occur in individuals who are ambulatory.
Other manifestations of autonomic dysfunction can include the following:
Neurogenic urinary bladder disturbances often lead to urinary incontinence.
Increased bowel movements may cause diarrhea; decreased bowel movements may cause constipation. Both can be either mild or severe. When severe either can cause significant distress.
Esophageal hypomobility and atony may occur [
Erectile dysfunction has been reported; the authors suspect that similar dysfunction occurs in females.
Abnormal sweating or hot flashes may either be an independent phenomenon or due to decreases in blood pressure.
Sleep disturbances and acrocyanosis have been reported in some.
Cardiac arrhythmias, a cause of death in severely affected individuals, may be related to cardiac autonomic denervation.
• Neurogenic urinary bladder disturbances often lead to urinary incontinence.
• Increased bowel movements may cause diarrhea; decreased bowel movements may cause constipation. Both can be either mild or severe. When severe either can cause significant distress.
• Esophageal hypomobility and atony may occur [
• Erectile dysfunction has been reported; the authors suspect that similar dysfunction occurs in females.
• Abnormal sweating or hot flashes may either be an independent phenomenon or due to decreases in blood pressure.
• Sleep disturbances and acrocyanosis have been reported in some.
• Cardiac arrhythmias, a cause of death in severely affected individuals, may be related to cardiac autonomic denervation.
## Other Findings
Dystonia manifesting as cervical or exercise-induced dystonia, foot or limb dystonia, or affecting the diaphragm, eyelids, or larynx (i.e., laryngospasm)
Mirror movements of the hands
Overflow movements in which ipsilateral facial grimacing accompanies attempts to lateral gaze
Tremor, choreatic movements, and myoclonic jerks
Parkinsonism has not been reported to date.
Learning difficulties and manifestations of autism spectrum disorder were evident in one individual with very early onset at age 15 years [
One individual with very severe disease declined to see a neurologist for unknown reasons. Other individuals declined gastrostomy tube placement for feeding despite worsening severe weight loss [
Some of the most severely affected individuals develop depression, whereas other persons with SCA4 do not [A Puschmann, personal observations].
The authors suspect these behaviors might indicate cognitive changes; however, this has not been studied in more detail. Nonetheless, these findings in some individuals suggest cognitive or neurobehavioral/psychiatric manifestations, perhaps within the cerebellar cognitive affective syndrome [
• Dystonia manifesting as cervical or exercise-induced dystonia, foot or limb dystonia, or affecting the diaphragm, eyelids, or larynx (i.e., laryngospasm)
• Mirror movements of the hands
• Overflow movements in which ipsilateral facial grimacing accompanies attempts to lateral gaze
• Tremor, choreatic movements, and myoclonic jerks
• Learning difficulties and manifestations of autism spectrum disorder were evident in one individual with very early onset at age 15 years [
• One individual with very severe disease declined to see a neurologist for unknown reasons. Other individuals declined gastrostomy tube placement for feeding despite worsening severe weight loss [
• Some of the most severely affected individuals develop depression, whereas other persons with SCA4 do not [A Puschmann, personal observations].
## Genotype-Phenotype Correlations
Genotype-phenotype correlations to date are preliminary as data are only available on 35 individuals with SCA4 whose repeat sizes have been studied by long-read sequencing [
The longest pathogenic repeat, 74 GGC repeats, was observed in an individual whose balance disturbances started at age 15 years.
The shortest pathogenic repeat, 44 GGC repeats, was observed in an individual whose disease onset was at age 60 years.
Some disease manifestations have only been observed in individuals with younger-onset disease who have longer repeat expansions, including very severe orthostatic hypotension that make erect or seated positions impossible, clinically relevant cognitive or behavioral changes that may remain mild or might include autism spectrum disorder [
• The longest pathogenic repeat, 74 GGC repeats, was observed in an individual whose balance disturbances started at age 15 years.
• The shortest pathogenic repeat, 44 GGC repeats, was observed in an individual whose disease onset was at age 60 years.
## Penetrance
To date,
Penetrance is age dependent, with onset between ages 12 and 65 years in all individuals with SCA4 reported to date.
## Intergenerational Instability
In five families for which individual-level data on age at onset was published, affected children developed manifestations of SCA4 one to 30 years earlier (mean: 10.1 years; standard deviation: 7.5 years) than their affected parents; two children developed manifestations seven and nine years later than their affected parent [
No difference in anticipation between maternal and paternal transmission was observed.
Increasing repeat length with parent-to-child transmission has been described in several instances [
## Nomenclature
SCA4 was previously referred to as "spinocerebellar ataxia, autosomal dominant, with sensory axonal neuropathy" or "autosomal dominant cerebellar ataxia with slow ocular saccades, neuropathy and orthostatism." These terms are no longer in use.
## Prevalence
To date,
To date, all reported families with
No pathogenic
To date, no pathogenic
## Genetically Related (Allelic) Disorders
Pathogenic predominantly
Heterozygous
Biallelic pathogenic variants were identified in eight (2.1%) unrelated Chinese children with focal (partial) epilepsy and infantile spasms with or without neurodevelopmental features in a group of 378 individuals with focal epilepsy [
• Heterozygous
• Biallelic pathogenic variants were identified in eight (2.1%) unrelated Chinese children with focal (partial) epilepsy and infantile spasms with or without neurodevelopmental features in a group of 378 individuals with focal epilepsy [
## Differential Diagnosis
Although spinocerebellar ataxia type 4 (SCA4) is characterized by sensory impairment, slow saccades, and autonomic dysfunction, it is difficult and often impossible to distinguish SCA4 from other hereditary ataxias based on clinical examination alone. Molecular genetic testing is highly recommended to make an accurate diagnosis. (See
Genetic Disorders with Ataxia, Sensory Neuropathy, and/or Slow or Hypermetric Ocular Saccades in the Differential Diagnosis of Spinocerebellar Ataxia Type 4
Progressive cerebellar ataxia
Slow or hypermetric ocular saccades
Sensory neuropathy
Spasticity
More prominent/earlier bulbar dysfunction (speech, swallowing)
Cognitive dysfunction
Usually mixed sensorimotor neuropathy
Progressive cerebellar ataxia
Slow or hypermetric ocular saccades
Predominantly sensory neuropathy in many persons
Parkinsonism, tremor
↓ muscle tone
Not all persons have neuropathy
Progressive cerebellar ataxia
Slow or hypermetric ocular saccades
Predominantly sensory neuro(no)pathy in some individuals
Amyotrophy
Parkinsonism
Action-induced facial & lingual fasciculations
Bulging eyes
May have motor or sensorimotor neuro(no)pathy
Progressive cerebellar ataxia
Sensory neuropathy
Autonomic dysfunction
Abnormal or absent vestibulo-ocular reflex
Chronic cough
Prominent neuropathic pain
Progressive cerebellar ataxia
↓ vibration sense
Muscular weakness
Bladder dysfunction
Neuropathy
Usually sensorimotor neuropathy
Scoliosis
Hearing & vision loss
Cardiomyopathy
Usually earlier onset
Progressive cerebellar ataxia
Distal sensory impairment
More commonly early onset in late childhood to adolescence
Develop motor neuropathy & peripheral weakness
Nystagmus
No saccadic slowing described
Progressive ataxia
Upper & lower motor neuron signs
Purely sensory neuropathy in subset of persons
Manifests more commonly in childhood
Retinopathy
Very low plasma vitamin E concentration
Neuropathy may be purely motor or sensorimotor
Based on
AD = autosomal dominant; AR = autosomal recessive; CANVAS = cerebellar ataxia with neuropathy and vestibular areflexia syndrome; MOI = mode of inheritance; SCA = spinocerebellar ataxia
• Progressive cerebellar ataxia
• Slow or hypermetric ocular saccades
• Sensory neuropathy
• Spasticity
• More prominent/earlier bulbar dysfunction (speech, swallowing)
• Cognitive dysfunction
• Usually mixed sensorimotor neuropathy
• Progressive cerebellar ataxia
• Slow or hypermetric ocular saccades
• Predominantly sensory neuropathy in many persons
• Parkinsonism, tremor
• ↓ muscle tone
• Not all persons have neuropathy
• Progressive cerebellar ataxia
• Slow or hypermetric ocular saccades
• Predominantly sensory neuro(no)pathy in some individuals
• Amyotrophy
• Parkinsonism
• Action-induced facial & lingual fasciculations
• Bulging eyes
• May have motor or sensorimotor neuro(no)pathy
• Progressive cerebellar ataxia
• Sensory neuropathy
• Autonomic dysfunction
• Abnormal or absent vestibulo-ocular reflex
• Chronic cough
• Prominent neuropathic pain
• Progressive cerebellar ataxia
• ↓ vibration sense
• Muscular weakness
• Bladder dysfunction
• Neuropathy
• Usually sensorimotor neuropathy
• Scoliosis
• Hearing & vision loss
• Cardiomyopathy
• Usually earlier onset
• Progressive cerebellar ataxia
• Distal sensory impairment
• More commonly early onset in late childhood to adolescence
• Develop motor neuropathy & peripheral weakness
• Nystagmus
• No saccadic slowing described
• Progressive ataxia
• Upper & lower motor neuron signs
• Purely sensory neuropathy in subset of persons
• Manifests more commonly in childhood
• Retinopathy
• Very low plasma vitamin E concentration
• Neuropathy may be purely motor or sensorimotor
## Management
No clinical practice guidelines for spinocerebellar ataxia type 4 (SCA4) 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 and needs in an individual diagnosed with SCA4, the evaluations summarized in
Spinocerebellar Ataxia Type 4: Recommended Evaluations Following Initial Diagnosis
Use clinical neurologic eval
Consider nerve conduction studies to establish presence & severity of sensory neuropathy.
Dizziness, lightheadedness, fainting, falls when standing up
Urinary dysfunction
Sexual dysfunction
Constipation, diarrhea, fecal incontinence
Flushing, abnormal sweating
Use standardized measurement of orthostatic blood pressure.
Consider tilt table testing.
Consider urology eval.
Consider additional autonomic testing in persons who are symptomatic.
Assess saccades, gaze restriction, & smooth pursuit.
Use standardized eye movement exam for ocular pursuit & saccades, apraxia, & gaze restriction.
Consider objective/instrumental recordings of eye movements.
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).
Speech-language therapy;
Methods of augmentative & alternative communication.
Swallowing eval
Measure & record body weight.
Calculate BMI.
Consider VFSS 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; ASD = autism spectrum disorder; BMI = body mass index; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; VFSS = videofluoroscopic swallowing study
See
Medical geneticist, certified genetic counselor, certified advanced genetic nurse, other health practitioners performing genetic counseling in specific health care systems
There is no cure for SCA4. 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
Spinocerebellar Ataxia Type 4: Treatment of Manifestations
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)
No specific pharmacologic treatment has been studied in SCA4.
Consider treatments (e.g., riluzole) as recommended in published consensus guidelines
Counsel on how to minimize impact of slow/limited eye movements in daily life situations.
Consider emerging pharmacotherapies for eye movement disturbances.
Consider nutritional & vitamin supplementation to meet dietary needs.
Consider timing of gastrostomy tube placement.
For orthostatic hypotension, consider ↑ fluid intake, bolus fluid intake, ↑ sodium intake, abdominal & lower extremity compression &/or treatment w/medications (e.g., midodrine, droxydopa, fludrocortisone, or others).
Consider treatment for urinary urgency/frequency (e.g., bladder / pelvic floor muscle training, mirabegron, solifenacin, self-catheterization).
Consider treatment for erectile dysfunction, constipation, diarrhea (loperamide).
Exercise as feasible re motor symptoms, stimulation-based OT
Psychodynamic therapy, cognitive behavioral therapy
SSRI, buspirone
Non-pharmacologic supportive treatment
Pharmacologic treatment as indicated
Psychological support
ASD = autism spectrum disorder; OT = occupational therapy/therapist; PT = physical therapy/therapist; SSRI = selective serotonin reuptake inhibitor
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Spinocerebellar Ataxia Type 4: Recommended Surveillance
Neurologic eval to assess progression & need for pharmacotherapy
Monitor ataxia progression w/standardized scale (SARA).
Measurement of body weight
Calculation of BMI
Initially, at least annually
When weight loss occurs, at least every 3 mos
Assess relevant eye movements (see
Assess for dizziness when turning head, looking sideways.
OT = occupational therapy/therapist; PT = physical therapy/therapist; SARA = Scale for the Assessment and Rating of Ataxia
Persons with SCA4 can be advised to avoid the following:
Drinking alcohol, which can further reduce cerebellar function, especially if excessive
Sedating drugs, which may reduce cerebellar function
Any other agents that may impair balance or lower blood pressure
Large carbohydrate-rich meals, as they may cause postprandial hypotension and exacerbate orthostatic decreases in blood pressure
Dehydration, especially in high ambient temperatures, as it may exacerbate hypotension
The benefit of the use of diuretics or antihypertensive agents needs to be balanced against the risk of increasing orthostatic hypotension [
See
Search
• Use clinical neurologic eval
• Consider nerve conduction studies to establish presence & severity of sensory neuropathy.
• Dizziness, lightheadedness, fainting, falls when standing up
• Urinary dysfunction
• Sexual dysfunction
• Constipation, diarrhea, fecal incontinence
• Flushing, abnormal sweating
• Use standardized measurement of orthostatic blood pressure.
• Consider tilt table testing.
• Consider urology eval.
• Consider additional autonomic testing in persons who are symptomatic.
• Assess saccades, gaze restriction, & smooth pursuit.
• Use standardized eye movement exam for ocular pursuit & saccades, apraxia, & gaze restriction.
• Consider objective/instrumental recordings of eye movements.
• 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).
• Speech-language therapy;
• Methods of augmentative & alternative communication.
• Swallowing eval
• Measure & record body weight.
• Calculate BMI.
• Consider VFSS 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)
• No specific pharmacologic treatment has been studied in SCA4.
• Consider treatments (e.g., riluzole) as recommended in published consensus guidelines
• Counsel on how to minimize impact of slow/limited eye movements in daily life situations.
• Consider emerging pharmacotherapies for eye movement disturbances.
• Consider nutritional & vitamin supplementation to meet dietary needs.
• Consider timing of gastrostomy tube placement.
• For orthostatic hypotension, consider ↑ fluid intake, bolus fluid intake, ↑ sodium intake, abdominal & lower extremity compression &/or treatment w/medications (e.g., midodrine, droxydopa, fludrocortisone, or others).
• Consider treatment for urinary urgency/frequency (e.g., bladder / pelvic floor muscle training, mirabegron, solifenacin, self-catheterization).
• Consider treatment for erectile dysfunction, constipation, diarrhea (loperamide).
• Exercise as feasible re motor symptoms, stimulation-based OT
• Psychodynamic therapy, cognitive behavioral therapy
• SSRI, buspirone
• Non-pharmacologic supportive treatment
• Pharmacologic treatment as indicated
• Psychological support
• Neurologic eval to assess progression & need for pharmacotherapy
• Monitor ataxia progression w/standardized scale (SARA).
• Measurement of body weight
• Calculation of BMI
• Initially, at least annually
• When weight loss occurs, at least every 3 mos
• Assess relevant eye movements (see
• Assess for dizziness when turning head, looking sideways.
• Drinking alcohol, which can further reduce cerebellar function, especially if excessive
• Sedating drugs, which may reduce cerebellar function
• Any other agents that may impair balance or lower blood pressure
• Large carbohydrate-rich meals, as they may cause postprandial hypotension and exacerbate orthostatic decreases in blood pressure
• Dehydration, especially in high ambient temperatures, as it may exacerbate hypotension
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SCA4, the evaluations summarized in
Spinocerebellar Ataxia Type 4: Recommended Evaluations Following Initial Diagnosis
Use clinical neurologic eval
Consider nerve conduction studies to establish presence & severity of sensory neuropathy.
Dizziness, lightheadedness, fainting, falls when standing up
Urinary dysfunction
Sexual dysfunction
Constipation, diarrhea, fecal incontinence
Flushing, abnormal sweating
Use standardized measurement of orthostatic blood pressure.
Consider tilt table testing.
Consider urology eval.
Consider additional autonomic testing in persons who are symptomatic.
Assess saccades, gaze restriction, & smooth pursuit.
Use standardized eye movement exam for ocular pursuit & saccades, apraxia, & gaze restriction.
Consider objective/instrumental recordings of eye movements.
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).
Speech-language therapy;
Methods of augmentative & alternative communication.
Swallowing eval
Measure & record body weight.
Calculate BMI.
Consider VFSS 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; ASD = autism spectrum disorder; BMI = body mass index; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; VFSS = videofluoroscopic swallowing study
See
Medical geneticist, certified genetic counselor, certified advanced genetic nurse, other health practitioners performing genetic counseling in specific health care systems
• Use clinical neurologic eval
• Consider nerve conduction studies to establish presence & severity of sensory neuropathy.
• Dizziness, lightheadedness, fainting, falls when standing up
• Urinary dysfunction
• Sexual dysfunction
• Constipation, diarrhea, fecal incontinence
• Flushing, abnormal sweating
• Use standardized measurement of orthostatic blood pressure.
• Consider tilt table testing.
• Consider urology eval.
• Consider additional autonomic testing in persons who are symptomatic.
• Assess saccades, gaze restriction, & smooth pursuit.
• Use standardized eye movement exam for ocular pursuit & saccades, apraxia, & gaze restriction.
• Consider objective/instrumental recordings of eye movements.
• 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).
• Speech-language therapy;
• Methods of augmentative & alternative communication.
• Swallowing eval
• Measure & record body weight.
• Calculate BMI.
• Consider VFSS 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 SCA4. 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
Spinocerebellar Ataxia Type 4: Treatment of Manifestations
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)
No specific pharmacologic treatment has been studied in SCA4.
Consider treatments (e.g., riluzole) as recommended in published consensus guidelines
Counsel on how to minimize impact of slow/limited eye movements in daily life situations.
Consider emerging pharmacotherapies for eye movement disturbances.
Consider nutritional & vitamin supplementation to meet dietary needs.
Consider timing of gastrostomy tube placement.
For orthostatic hypotension, consider ↑ fluid intake, bolus fluid intake, ↑ sodium intake, abdominal & lower extremity compression &/or treatment w/medications (e.g., midodrine, droxydopa, fludrocortisone, or others).
Consider treatment for urinary urgency/frequency (e.g., bladder / pelvic floor muscle training, mirabegron, solifenacin, self-catheterization).
Consider treatment for erectile dysfunction, constipation, diarrhea (loperamide).
Exercise as feasible re motor symptoms, stimulation-based OT
Psychodynamic therapy, cognitive behavioral therapy
SSRI, buspirone
Non-pharmacologic supportive treatment
Pharmacologic treatment as indicated
Psychological support
ASD = autism spectrum disorder; OT = occupational therapy/therapist; PT = physical therapy/therapist; SSRI = selective serotonin reuptake inhibitor
• 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)
• No specific pharmacologic treatment has been studied in SCA4.
• Consider treatments (e.g., riluzole) as recommended in published consensus guidelines
• Counsel on how to minimize impact of slow/limited eye movements in daily life situations.
• Consider emerging pharmacotherapies for eye movement disturbances.
• Consider nutritional & vitamin supplementation to meet dietary needs.
• Consider timing of gastrostomy tube placement.
• For orthostatic hypotension, consider ↑ fluid intake, bolus fluid intake, ↑ sodium intake, abdominal & lower extremity compression &/or treatment w/medications (e.g., midodrine, droxydopa, fludrocortisone, or others).
• Consider treatment for urinary urgency/frequency (e.g., bladder / pelvic floor muscle training, mirabegron, solifenacin, self-catheterization).
• Consider treatment for erectile dysfunction, constipation, diarrhea (loperamide).
• Exercise as feasible re motor symptoms, stimulation-based OT
• Psychodynamic therapy, cognitive behavioral therapy
• SSRI, buspirone
• Non-pharmacologic supportive treatment
• Pharmacologic treatment as indicated
• Psychological support
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Spinocerebellar Ataxia Type 4: Recommended Surveillance
Neurologic eval to assess progression & need for pharmacotherapy
Monitor ataxia progression w/standardized scale (SARA).
Measurement of body weight
Calculation of BMI
Initially, at least annually
When weight loss occurs, at least every 3 mos
Assess relevant eye movements (see
Assess for dizziness when turning head, looking sideways.
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).
• Measurement of body weight
• Calculation of BMI
• Initially, at least annually
• When weight loss occurs, at least every 3 mos
• Assess relevant eye movements (see
• Assess for dizziness when turning head, looking sideways.
## Agents/Circumstances to Avoid
Persons with SCA4 can be advised to avoid the following:
Drinking alcohol, which can further reduce cerebellar function, especially if excessive
Sedating drugs, which may reduce cerebellar function
Any other agents that may impair balance or lower blood pressure
Large carbohydrate-rich meals, as they may cause postprandial hypotension and exacerbate orthostatic decreases in blood pressure
Dehydration, especially in high ambient temperatures, as it may exacerbate hypotension
The benefit of the use of diuretics or antihypertensive agents needs to be balanced against the risk of increasing orthostatic hypotension [
• Drinking alcohol, which can further reduce cerebellar function, especially if excessive
• Sedating drugs, which may reduce cerebellar function
• Any other agents that may impair balance or lower blood pressure
• Large carbohydrate-rich meals, as they may cause postprandial hypotension and exacerbate orthostatic decreases in blood pressure
• Dehydration, especially in high ambient temperatures, as it may exacerbate hypotension
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Spinocerebellar ataxia type 4 (SCA4) is inherited in an autosomal dominant manner.
Anticipation (earlier disease onset in successive generations) has been observed in many families and is an important issue to address when counseling family members of individuals with SCA4 (see
Most individuals diagnosed with SCA4 have an affected parent. As anticipation is common in SCA4, the affected parent frequently has milder disease with a later age of onset than their affected offspring.
To date, only one individual diagnosed with SCA4 represents a simplex case (i.e., the only affected family member) [
A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
If a parent has an abnormal GGC repeat expansion in
If a parent has an intermediate number of repeats (i.e., approximately 31-41 GGC repeats), the parent is not likely to display manifestations of SCA4; however, the repeat size may expand on transmission to offspring and the risk to each sib is increased (see
If the genetic status of the parents is unknown and:
There is more than one affected family member, the risk to each sib is presumed to be 50%.
The proband represents a simplex case (rare in SCA4 and most likely observed in individuals who develop SCA4 late in their lives), the risk to sibs cannot be quantified but is presumed to be increased.
Each child of an individual with SCA4 has a 50% chance of inheriting an abnormal GGC repeat expansion in
The likelihood that an abnormal
Predictive testing for at-risk relatives is possible once an abnormal
Such testing should be performed in the context of formal genetic counseling and is not useful in reliably predicting age of onset, severity, type of manifestations, or rate of progression in asymptomatic individuals.
Potential consequences of such testing (including, but not limited to, psychological consequences and the perceived 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. Such counseling needs to take into account that there may be wide individual, societal, and legislative differences with regard to which consequences might arise after genetic testing of asymptomatic individuals.
In a family with an established diagnosis of SCA4, 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.
Once a pathogenic
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 diagnosed with SCA4 have an affected parent. As anticipation is common in SCA4, the affected parent frequently has milder disease with a later age of onset than their affected offspring.
• To date, only one individual diagnosed with SCA4 represents a simplex case (i.e., the only affected family member) [
• A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
• If a parent has an abnormal GGC repeat expansion in
• If a parent has an intermediate number of repeats (i.e., approximately 31-41 GGC repeats), the parent is not likely to display manifestations of SCA4; however, the repeat size may expand on transmission to offspring and the risk to each sib is increased (see
• If the genetic status of the parents is unknown and:
• There is more than one affected family member, the risk to each sib is presumed to be 50%.
• The proband represents a simplex case (rare in SCA4 and most likely observed in individuals who develop SCA4 late in their lives), the risk to sibs cannot be quantified but is presumed to be increased.
• There is more than one affected family member, the risk to each sib is presumed to be 50%.
• The proband represents a simplex case (rare in SCA4 and most likely observed in individuals who develop SCA4 late in their lives), the risk to sibs cannot be quantified but is presumed to be increased.
• There is more than one affected family member, the risk to each sib is presumed to be 50%.
• The proband represents a simplex case (rare in SCA4 and most likely observed in individuals who develop SCA4 late in their lives), the risk to sibs cannot be quantified but is presumed to be increased.
• Each child of an individual with SCA4 has a 50% chance of inheriting an abnormal GGC repeat expansion in
• The likelihood that an abnormal
• Predictive testing for at-risk relatives is possible once an abnormal
• Such testing should be performed in the context of formal genetic counseling and is not useful in reliably predicting age of onset, severity, type of manifestations, or rate of progression in asymptomatic individuals.
• Potential consequences of such testing (including, but not limited to, psychological consequences and the perceived 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. Such counseling needs to take into account that there may be wide individual, societal, and legislative differences with regard to which consequences might arise after genetic testing of asymptomatic 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 young adults who are affected or at risk.
## Mode of Inheritance
Spinocerebellar ataxia type 4 (SCA4) is inherited in an autosomal dominant manner.
Anticipation (earlier disease onset in successive generations) has been observed in many families and is an important issue to address when counseling family members of individuals with SCA4 (see
## Risk to Family Members
Most individuals diagnosed with SCA4 have an affected parent. As anticipation is common in SCA4, the affected parent frequently has milder disease with a later age of onset than their affected offspring.
To date, only one individual diagnosed with SCA4 represents a simplex case (i.e., the only affected family member) [
A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
If a parent has an abnormal GGC repeat expansion in
If a parent has an intermediate number of repeats (i.e., approximately 31-41 GGC repeats), the parent is not likely to display manifestations of SCA4; however, the repeat size may expand on transmission to offspring and the risk to each sib is increased (see
If the genetic status of the parents is unknown and:
There is more than one affected family member, the risk to each sib is presumed to be 50%.
The proband represents a simplex case (rare in SCA4 and most likely observed in individuals who develop SCA4 late in their lives), the risk to sibs cannot be quantified but is presumed to be increased.
Each child of an individual with SCA4 has a 50% chance of inheriting an abnormal GGC repeat expansion in
The likelihood that an abnormal
• Most individuals diagnosed with SCA4 have an affected parent. As anticipation is common in SCA4, the affected parent frequently has milder disease with a later age of onset than their affected offspring.
• To date, only one individual diagnosed with SCA4 represents a simplex case (i.e., the only affected family member) [
• A proband may appear to be the only affected family member because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent. Therefore,
• If a parent has an abnormal GGC repeat expansion in
• If a parent has an intermediate number of repeats (i.e., approximately 31-41 GGC repeats), the parent is not likely to display manifestations of SCA4; however, the repeat size may expand on transmission to offspring and the risk to each sib is increased (see
• If the genetic status of the parents is unknown and:
• There is more than one affected family member, the risk to each sib is presumed to be 50%.
• The proband represents a simplex case (rare in SCA4 and most likely observed in individuals who develop SCA4 late in their lives), the risk to sibs cannot be quantified but is presumed to be increased.
• There is more than one affected family member, the risk to each sib is presumed to be 50%.
• The proband represents a simplex case (rare in SCA4 and most likely observed in individuals who develop SCA4 late in their lives), the risk to sibs cannot be quantified but is presumed to be increased.
• There is more than one affected family member, the risk to each sib is presumed to be 50%.
• The proband represents a simplex case (rare in SCA4 and most likely observed in individuals who develop SCA4 late in their lives), the risk to sibs cannot be quantified but is presumed to be increased.
• Each child of an individual with SCA4 has a 50% chance of inheriting an abnormal GGC repeat expansion in
• The likelihood that an abnormal
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once an abnormal
Such testing should be performed in the context of formal genetic counseling and is not useful in reliably predicting age of onset, severity, type of manifestations, or rate of progression in asymptomatic individuals.
Potential consequences of such testing (including, but not limited to, psychological consequences and the perceived 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. Such counseling needs to take into account that there may be wide individual, societal, and legislative differences with regard to which consequences might arise after genetic testing of asymptomatic individuals.
In a family with an established diagnosis of SCA4, 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 an abnormal
• Such testing should be performed in the context of formal genetic counseling and is not useful in reliably predicting age of onset, severity, type of manifestations, or rate of progression in asymptomatic individuals.
• Potential consequences of such testing (including, but not limited to, psychological consequences and the perceived 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. Such counseling needs to take into account that there may be wide individual, societal, and legislative differences with regard to which consequences might arise after genetic testing of asymptomatic 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 young adults who are affected or at risk.
## Prenatal Testing and Preimplantation Genetic Testing
Once a pathogenic
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
United Kingdom
United Kingdom
Sweden
•
• Canada
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
• Sweden
•
## Molecular Genetics
Spinocerebellar Ataxia Type 4: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 4 (
Many affected neurons have p62-positive inclusions, mostly in the nucleus but also in the cytoplasm [
Note: Some of the oldest generations in SCA4 families were not known to have neurologic manifestations (molecular data are not available for these individuals). However, these families are known to share a common founder, suggesting that the founder event may have been the elimination of non-GGC interruptions in
Repeats in the normal range (below 31 GGC repeats) can often be detected in short-read exome and genome data.
Methods to detect and approximate the size of expanded repeats (42 or more GGC repeats) include the following methods [
Whole-genome sequencing (short-read sequencing with customized analytic tools)
Exome sequencing or sequencing-based multigene panels including
Long-read sequencing has been shown to reliably detect the presence of a pathogenic repeat expansion and accurately quantify repeat length for all repeat expansions identified to date.
PCR fragment analysis has recently been shown to accurately determine repeat lengths [
Normal-length alleles can be confirmed in whole-genome, exome, and sequence-based multigene panels that include
By contrast, automated analytic pipelines can be insufficient to analyze for
A crucial factor in the detection ability of standard sequencing-based methods is a read length of at least 100 bp or more to ensure accurate mapping of expanded alleles. Although such testing can detect an expanded GGC repeat, it is typically unable to accurately determine the number of repeats. To date, sequencing methods with read lengths below 150 bp have not been able to reliably detect an expansion, although the loss of non-GGC interruptions is reliably detected.
The detection of non-GGC interruptions can probably exclude the diagnosis of SCA4 even when the exact number of repeat units has not been accurately determined. Conversely, lack of non-GGC interruptions may indicate a possible diagnosis of SCA4 and may prompt validation with additional methods.
Detailed evaluation of all available data from single-molecule long-read sequencing suggests that the exact length of expanded repeats may differ slightly between blood cells of an individual with SCA4 (due to either mosaicism or technical reasons). This can make it impossible to define one single repeat length for an individual; rather, one individual may have a range of repeat lengths in a blood sample. However, this range is relatively narrow, and in all 35 individuals with SCA4 analyzed by long-read sequencing to date, it was possible to determine clearly if repeats were pathogenically expanded or not [
Variants listed in the table have been provided by the authors.
• Note: Some of the oldest generations in SCA4 families were not known to have neurologic manifestations (molecular data are not available for these individuals). However, these families are known to share a common founder, suggesting that the founder event may have been the elimination of non-GGC interruptions in
• Repeats in the normal range (below 31 GGC repeats) can often be detected in short-read exome and genome data.
• Methods to detect and approximate the size of expanded repeats (42 or more GGC repeats) include the following methods [
• Whole-genome sequencing (short-read sequencing with customized analytic tools)
• Exome sequencing or sequencing-based multigene panels including
• Long-read sequencing has been shown to reliably detect the presence of a pathogenic repeat expansion and accurately quantify repeat length for all repeat expansions identified to date.
• PCR fragment analysis has recently been shown to accurately determine repeat lengths [
• Whole-genome sequencing (short-read sequencing with customized analytic tools)
• Exome sequencing or sequencing-based multigene panels including
• Long-read sequencing has been shown to reliably detect the presence of a pathogenic repeat expansion and accurately quantify repeat length for all repeat expansions identified to date.
• PCR fragment analysis has recently been shown to accurately determine repeat lengths [
• Whole-genome sequencing (short-read sequencing with customized analytic tools)
• Exome sequencing or sequencing-based multigene panels including
• Long-read sequencing has been shown to reliably detect the presence of a pathogenic repeat expansion and accurately quantify repeat length for all repeat expansions identified to date.
• PCR fragment analysis has recently been shown to accurately determine repeat lengths [
## Molecular Pathogenesis
Many affected neurons have p62-positive inclusions, mostly in the nucleus but also in the cytoplasm [
Note: Some of the oldest generations in SCA4 families were not known to have neurologic manifestations (molecular data are not available for these individuals). However, these families are known to share a common founder, suggesting that the founder event may have been the elimination of non-GGC interruptions in
Repeats in the normal range (below 31 GGC repeats) can often be detected in short-read exome and genome data.
Methods to detect and approximate the size of expanded repeats (42 or more GGC repeats) include the following methods [
Whole-genome sequencing (short-read sequencing with customized analytic tools)
Exome sequencing or sequencing-based multigene panels including
Long-read sequencing has been shown to reliably detect the presence of a pathogenic repeat expansion and accurately quantify repeat length for all repeat expansions identified to date.
PCR fragment analysis has recently been shown to accurately determine repeat lengths [
Normal-length alleles can be confirmed in whole-genome, exome, and sequence-based multigene panels that include
By contrast, automated analytic pipelines can be insufficient to analyze for
A crucial factor in the detection ability of standard sequencing-based methods is a read length of at least 100 bp or more to ensure accurate mapping of expanded alleles. Although such testing can detect an expanded GGC repeat, it is typically unable to accurately determine the number of repeats. To date, sequencing methods with read lengths below 150 bp have not been able to reliably detect an expansion, although the loss of non-GGC interruptions is reliably detected.
The detection of non-GGC interruptions can probably exclude the diagnosis of SCA4 even when the exact number of repeat units has not been accurately determined. Conversely, lack of non-GGC interruptions may indicate a possible diagnosis of SCA4 and may prompt validation with additional methods.
Detailed evaluation of all available data from single-molecule long-read sequencing suggests that the exact length of expanded repeats may differ slightly between blood cells of an individual with SCA4 (due to either mosaicism or technical reasons). This can make it impossible to define one single repeat length for an individual; rather, one individual may have a range of repeat lengths in a blood sample. However, this range is relatively narrow, and in all 35 individuals with SCA4 analyzed by long-read sequencing to date, it was possible to determine clearly if repeats were pathogenically expanded or not [
Variants listed in the table have been provided by the authors.
• Note: Some of the oldest generations in SCA4 families were not known to have neurologic manifestations (molecular data are not available for these individuals). However, these families are known to share a common founder, suggesting that the founder event may have been the elimination of non-GGC interruptions in
• Repeats in the normal range (below 31 GGC repeats) can often be detected in short-read exome and genome data.
• Methods to detect and approximate the size of expanded repeats (42 or more GGC repeats) include the following methods [
• Whole-genome sequencing (short-read sequencing with customized analytic tools)
• Exome sequencing or sequencing-based multigene panels including
• Long-read sequencing has been shown to reliably detect the presence of a pathogenic repeat expansion and accurately quantify repeat length for all repeat expansions identified to date.
• PCR fragment analysis has recently been shown to accurately determine repeat lengths [
• Whole-genome sequencing (short-read sequencing with customized analytic tools)
• Exome sequencing or sequencing-based multigene panels including
• Long-read sequencing has been shown to reliably detect the presence of a pathogenic repeat expansion and accurately quantify repeat length for all repeat expansions identified to date.
• PCR fragment analysis has recently been shown to accurately determine repeat lengths [
• Whole-genome sequencing (short-read sequencing with customized analytic tools)
• Exome sequencing or sequencing-based multigene panels including
• Long-read sequencing has been shown to reliably detect the presence of a pathogenic repeat expansion and accurately quantify repeat length for all repeat expansions identified to date.
• PCR fragment analysis has recently been shown to accurately determine repeat lengths [
## Chapter Notes
The authors work within the
Dr Andreas Puschmann (
Contact Dr Andreas Puschmann to discuss any findings of intermediate
We are grateful to the families with SCA4 from Skåne, Sweden, who have participated in our research studies. Many neurologists at our center have through the years contributed valuable clinical information on the phenotype of SCA4 in these individuals. Bioinformatician and medical geneticist Efthymia Kafantari has contributed to many bioinformatic analyses that ruled out alternative causes for the disorder in our SCA4 families. We thank Region Skåne, Lund University, and MultiPark, a strategic research area at Lund University, as well as others, for financial and institutional support.
12 December 2024 (bp) Review posted live
18 June 2024 (ap) Original submission
• 12 December 2024 (bp) Review posted live
• 18 June 2024 (ap) Original submission
## Author Notes
The authors work within the
Dr Andreas Puschmann (
Contact Dr Andreas Puschmann to discuss any findings of intermediate
## Acknowledgments
We are grateful to the families with SCA4 from Skåne, Sweden, who have participated in our research studies. Many neurologists at our center have through the years contributed valuable clinical information on the phenotype of SCA4 in these individuals. Bioinformatician and medical geneticist Efthymia Kafantari has contributed to many bioinformatic analyses that ruled out alternative causes for the disorder in our SCA4 families. We thank Region Skåne, Lund University, and MultiPark, a strategic research area at Lund University, as well as others, for financial and institutional support.
## Revision History
12 December 2024 (bp) Review posted live
18 June 2024 (ap) Original submission
• 12 December 2024 (bp) Review posted live
• 18 June 2024 (ap) Original submission
## References
## Literature Cited
|
[] |
12/12/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sca6
|
sca6
|
[
"SCA6",
"SCA6",
"Voltage-dependent P/Q-type calcium channel subunit alpha-1A",
"CACNA1A",
"Spinocerebellar Ataxia Type 6"
] |
Spinocerebellar Ataxia Type 6
|
Hannah L Casey, Christopher M Gomez
|
Summary Spinocerebellar ataxia type 6 (SCA6) is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The age of onset ranges from 19 to 73 years; mean age of onset is between 43 and 52 years. Initial symptoms are gait unsteadiness, stumbling, and imbalance (in ~90%) and dysarthria (in ~10%). Eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common. Visual disturbances may result from diplopia, difficulty fixating on moving objects, horizontal gaze-evoked nystagmus, and vertical nystagmus. Hyperreflexia and extensor plantar responses occur in up to 40%-50%. Basal ganglia signs, including dystonia and blepharospasm, occur in up to 25%. Mentation is generally preserved. The diagnosis of SCA6 rests on the use of molecular genetic testing to detect an abnormal CAG trinucleotide repeat expansion in SCA6 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting an abnormal CAG trinucleotide repeat expansion in
|
## Diagnosis
Formal diagnostic criteria for spinocerebellar ataxia type 6 (SCA6) have not been established.
SCA6
The diagnosis of SCA6
Meiotic expansion of a 19-CAG repeat allele into the known pathogenic range [
Elderly asymptomatic individuals [
An individual with atypical features of SCA6 [
An ataxic individual homozygous for the 19-CAG repeat allele [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 6
See
See
PCR amplification can detect CAG trinucleotide repeat expansions up to ~100 repeats.
• Meiotic expansion of a 19-CAG repeat allele into the known pathogenic range [
• Elderly asymptomatic individuals [
• An individual with atypical features of SCA6 [
• An ataxic individual homozygous for the 19-CAG repeat allele [
• Meiotic expansion of a 19-CAG repeat allele into the known pathogenic range [
• Elderly asymptomatic individuals [
• An individual with atypical features of SCA6 [
• An ataxic individual homozygous for the 19-CAG repeat allele [
• Meiotic expansion of a 19-CAG repeat allele into the known pathogenic range [
• Elderly asymptomatic individuals [
• An individual with atypical features of SCA6 [
• An ataxic individual homozygous for the 19-CAG repeat allele [
• For an introduction to multigene panels click
## Suggestive Findings
SCA6
## Establishing the Diagnosis
The diagnosis of SCA6
Meiotic expansion of a 19-CAG repeat allele into the known pathogenic range [
Elderly asymptomatic individuals [
An individual with atypical features of SCA6 [
An ataxic individual homozygous for the 19-CAG repeat allele [
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 6
See
See
PCR amplification can detect CAG trinucleotide repeat expansions up to ~100 repeats.
• Meiotic expansion of a 19-CAG repeat allele into the known pathogenic range [
• Elderly asymptomatic individuals [
• An individual with atypical features of SCA6 [
• An ataxic individual homozygous for the 19-CAG repeat allele [
• Meiotic expansion of a 19-CAG repeat allele into the known pathogenic range [
• Elderly asymptomatic individuals [
• An individual with atypical features of SCA6 [
• An ataxic individual homozygous for the 19-CAG repeat allele [
• Meiotic expansion of a 19-CAG repeat allele into the known pathogenic range [
• Elderly asymptomatic individuals [
• An individual with atypical features of SCA6 [
• An ataxic individual homozygous for the 19-CAG repeat allele [
• For an introduction to multigene panels click
## Clinical Characteristics
To date, fewer than 10,000 individuals with spinocerebellar ataxia type 6 (SCA6) have been identified. The following description of the phenotypic features associated with this condition is based on these reported individuals.
Features of Spinocerebellar Ataxia Type 6
SCA6 is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The range in age of onset is from 19 to 73 years. The mean age of onset is between 43 and 52 years. Age of onset and clinical picture vary even within the same family; sibs with the same size full-penetrance allele may differ in age of onset by as much as 12 years, or exhibit, at least initially, an episodic course [
Initial symptoms are gait unsteadiness, stumbling, and imbalance in approximately 90% of individuals; the remainder present with dysarthria. Symptoms progress slowly, and eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common.
Diplopia occurs in approximately 50% of individuals. Others experience visual disturbances related to difficulty fixating on moving objects, as well as horizontal gaze-evoked nystagmus (70%-100%) [
Hyperreflexia and extensor plantar responses occur in up to 40%-50% of individuals with SCA6.
Basal ganglia signs, such as dystonia and blepharospasm, are noted in up to 25% of individuals.
Mentation is generally preserved. Formal neuropsychological testing in one series revealed no significant cognitive deficits [
Individuals with SCA6 do not have sensory complaints, restless legs, stiffness, migraine, primary visual disturbances, or muscle atrophy.
Life span is not shortened.
Penetrance is nearly 100%, although symptoms may not appear until the seventh decade.
Expansions of
Hereditary forms of ataxia once known as Holmes type of cerebellar cortical degeneration, and later as autosomal dominant cerebellar ataxia type III (pure cerebellar ataxia), may have included SCA6.
The prevalence of SCA6 appears to vary by geographic area, presumably relating to founder effects. Estimated as the fraction of all kindreds with autosomal dominant spinocerebellar ataxia, rates for SCA6 are 1%-2% in Spain and France, 3% in China, 12% in the US, 13% in Germany, and 31% in Japan.
The overall prevalence of autosomal dominant ataxia is estimated at 1:100,000, and the prevalence of SCA6 at 0.02:100,000 to 0.31:100,000 [
The frequency of
## Clinical Description
To date, fewer than 10,000 individuals with spinocerebellar ataxia type 6 (SCA6) have been identified. The following description of the phenotypic features associated with this condition is based on these reported individuals.
Features of Spinocerebellar Ataxia Type 6
SCA6 is characterized by adult-onset, slowly progressive cerebellar ataxia, dysarthria, and nystagmus. The range in age of onset is from 19 to 73 years. The mean age of onset is between 43 and 52 years. Age of onset and clinical picture vary even within the same family; sibs with the same size full-penetrance allele may differ in age of onset by as much as 12 years, or exhibit, at least initially, an episodic course [
Initial symptoms are gait unsteadiness, stumbling, and imbalance in approximately 90% of individuals; the remainder present with dysarthria. Symptoms progress slowly, and eventually all persons have gait ataxia, upper-limb incoordination, intention tremor, and dysarthria. Dysphagia and choking are common.
Diplopia occurs in approximately 50% of individuals. Others experience visual disturbances related to difficulty fixating on moving objects, as well as horizontal gaze-evoked nystagmus (70%-100%) [
Hyperreflexia and extensor plantar responses occur in up to 40%-50% of individuals with SCA6.
Basal ganglia signs, such as dystonia and blepharospasm, are noted in up to 25% of individuals.
Mentation is generally preserved. Formal neuropsychological testing in one series revealed no significant cognitive deficits [
Individuals with SCA6 do not have sensory complaints, restless legs, stiffness, migraine, primary visual disturbances, or muscle atrophy.
Life span is not shortened.
## Genotype-Phenotype Correlations
## Penetrance
Penetrance is nearly 100%, although symptoms may not appear until the seventh decade.
## Anticipation
Expansions of
## Nomenclature
Hereditary forms of ataxia once known as Holmes type of cerebellar cortical degeneration, and later as autosomal dominant cerebellar ataxia type III (pure cerebellar ataxia), may have included SCA6.
## Prevalence
The prevalence of SCA6 appears to vary by geographic area, presumably relating to founder effects. Estimated as the fraction of all kindreds with autosomal dominant spinocerebellar ataxia, rates for SCA6 are 1%-2% in Spain and France, 3% in China, 12% in the US, 13% in Germany, and 31% in Japan.
The overall prevalence of autosomal dominant ataxia is estimated at 1:100,000, and the prevalence of SCA6 at 0.02:100,000 to 0.31:100,000 [
The frequency of
## Genetically Related (Allelic) Disorders
Heterozygous
Allelic Autosomal Dominant Disorders to Consider in the Differential Diagnosis of Spinocerebellar Ataxia Type 6
Onset typically in childhood or early adolescence
Attacks of ataxia, vertigo, & nausea lasting hrs to days
Attacks can be assoc w/dysarthria, diplopia, tinnitus, dystonia, hemiplegia, & headache.
Between attacks, individuals may initially be normal but eventually develop interictal findings incl nystagmus & ataxia.
After years of episodic ataxia, a condition of interictal ataxia indistinguishable from SCA6 may develop.
Individuals w/SCA6 may present w/EA.
1 family w/a
2 families w/a
Severe progressive ataxia
Cerebellar atrophy
Aura of hemiplegia assoc w/at least 1 other aura symptom (e.g., hemianopsia, hemisensory deficit, aphasia) followed by moderate-to-severe headache
Coma & seizures (can be triggered by minor head injury or angiography)
Trauma-triggered delayed cerebral edema
In a family w/EA2, affected members also had hemiplegia & 1 affected member had migraine during episodes of ataxia.
In a family w/a
EA = episodic ataxia
In one study, up to 33% of individuals with ≥21 CAG repeats in
As these pathogenic variants do not act through nuclear translocation of an expanded polyglutamine tract in the C terminus, the disease presumably occurs through perturbed calcium channel function caused by the abnormal allele [
The two clinical forms of FMH are: (1) pure FHM (found in 80% of affected families), in which interictal examination is normal in all family members, and (2) FHM with permanent cerebellar symptoms (found in 20% of affected families), in which some family members show interictal nystagmus and/or ataxia.
Trauma-triggered delayed cerebral edema has been associated with the
Heterozygous pathogenic variants in
• Onset typically in childhood or early adolescence
• Attacks of ataxia, vertigo, & nausea lasting hrs to days
• Attacks can be assoc w/dysarthria, diplopia, tinnitus, dystonia, hemiplegia, & headache.
• Between attacks, individuals may initially be normal but eventually develop interictal findings incl nystagmus & ataxia.
• After years of episodic ataxia, a condition of interictal ataxia indistinguishable from SCA6 may develop.
• Individuals w/SCA6 may present w/EA.
• 1 family w/a
• 2 families w/a
• Severe progressive ataxia
• Cerebellar atrophy
• Aura of hemiplegia assoc w/at least 1 other aura symptom (e.g., hemianopsia, hemisensory deficit, aphasia) followed by moderate-to-severe headache
• Coma & seizures (can be triggered by minor head injury or angiography)
• Trauma-triggered delayed cerebral edema
• In a family w/EA2, affected members also had hemiplegia & 1 affected member had migraine during episodes of ataxia.
• In a family w/a
## Differential Diagnosis
Individuals with spinocerebellar ataxia type 6 (SCA6) may present with unexplained ataxia that is part of the larger differential diagnosis of hereditary and acquired ataxias (see
It is difficult and often impossible to distinguish spinocerebellar ataxia type 6 (SCA6) from the other hereditary ataxias (see
SCA6-related
Proportion of Individuals with SCA6 Manifesting Phenotypic Features Compared with Individuals with SCA1, SCA3, and SCA2
Percentages modified from
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 6 (SCA6), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 6
Management for individuals with SCA6 is supportive.
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 6
Canes, walking sticks, & walkers help prevent falling.
Modification of home w/aids incl grab bars, raised toilet seats, & ramps to accommodate motorized chairs may be necessary.
Weighted eating utensils & dressing hooks help maintain sense of independence.
Regular physical activity
PT & exercises enhancing balance & core strength
May reduce vertigo &/or osscilopsia
Some literature supports 4-aminopyridine for vestibular symptoms.
OT = occupational therapist/therapy; PT = physical therapist/therapy
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 6
Nutrition evaluation
Video esophagram
Feeding assessment when dysphagia becomes troublesome
Agents with sedative/hypnotic properties such as ethanol or certain medications may produce marked increases in incoordination.
See
Although the disease rarely manifests during years of fertility, measures to support imbalance should be enhanced in symptomatic pregnant women.
Search
Tremor-controlling drugs are not usually effective in reducing cerebellar tremors.
The growing interest in cannabidiol (CBD) requires further empiric experience or clinical trials.
• Canes, walking sticks, & walkers help prevent falling.
• Modification of home w/aids incl grab bars, raised toilet seats, & ramps to accommodate motorized chairs may be necessary.
• Weighted eating utensils & dressing hooks help maintain sense of independence.
• Regular physical activity
• PT & exercises enhancing balance & core strength
• May reduce vertigo &/or osscilopsia
• Some literature supports 4-aminopyridine for vestibular symptoms.
• Nutrition evaluation
• Video esophagram
• Feeding assessment when dysphagia becomes troublesome
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 6 (SCA6), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 6
## Treatment of Manifestations
Management for individuals with SCA6 is supportive.
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 6
Canes, walking sticks, & walkers help prevent falling.
Modification of home w/aids incl grab bars, raised toilet seats, & ramps to accommodate motorized chairs may be necessary.
Weighted eating utensils & dressing hooks help maintain sense of independence.
Regular physical activity
PT & exercises enhancing balance & core strength
May reduce vertigo &/or osscilopsia
Some literature supports 4-aminopyridine for vestibular symptoms.
OT = occupational therapist/therapy; PT = physical therapist/therapy
• Canes, walking sticks, & walkers help prevent falling.
• Modification of home w/aids incl grab bars, raised toilet seats, & ramps to accommodate motorized chairs may be necessary.
• Weighted eating utensils & dressing hooks help maintain sense of independence.
• Regular physical activity
• PT & exercises enhancing balance & core strength
• May reduce vertigo &/or osscilopsia
• Some literature supports 4-aminopyridine for vestibular symptoms.
## Surveillance
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 6
Nutrition evaluation
Video esophagram
Feeding assessment when dysphagia becomes troublesome
• Nutrition evaluation
• Video esophagram
• Feeding assessment when dysphagia becomes troublesome
## Agents/Circumstances to Avoid
Agents with sedative/hypnotic properties such as ethanol or certain medications may produce marked increases in incoordination.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Although the disease rarely manifests during years of fertility, measures to support imbalance should be enhanced in symptomatic pregnant women.
## Therapies Under Investigation
Search
## Other
Tremor-controlling drugs are not usually effective in reducing cerebellar tremors.
The growing interest in cannabidiol (CBD) requires further empiric experience or clinical trials.
## Genetic Counseling
Spinocerebellar ataxia type 6 (SCA6) is inherited in an autosomal dominant manner.
Because penetrance of SCA6 is 100%, most individuals diagnosed with SCA6 have an affected parent.
A proband with SCA6 may have the disorder as the result of an expansion of an intermediate or mutable normal allele inherited from an unaffected parent [
Recommendations for the evaluation of parents of an individual with SCA6 and no known family history of SCA6 include clinical evaluation and molecular genetic testing.
Although most individuals diagnosed with SCA6 have an affected parent, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
If one parent has a full-penetrance
If one parent has an intermediate or mutable normal
If an expanded
If the parents have not been tested for an expanded
Each child of an individual with SCA6 has a 50% chance of inheriting the expanded
Although repeat-size changes can occur in SCA6 alleles in subsequent generations, they are much rarer than those in other repeat expansion disorders.
Predictive testing for at-risk relatives is possible once molecular genetic testing has identified a
This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
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 SCA6, 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.
Once 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.
• Because penetrance of SCA6 is 100%, most individuals diagnosed with SCA6 have an affected parent.
• A proband with SCA6 may have the disorder as the result of an expansion of an intermediate or mutable normal allele inherited from an unaffected parent [
• Recommendations for the evaluation of parents of an individual with SCA6 and no known family history of SCA6 include clinical evaluation and molecular genetic testing.
• Although most individuals diagnosed with SCA6 have an affected parent, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• If one parent has a full-penetrance
• If one parent has an intermediate or mutable normal
• If an expanded
• If the parents have not been tested for an expanded
• Each child of an individual with SCA6 has a 50% chance of inheriting the expanded
• Although repeat-size changes can occur in SCA6 alleles in subsequent generations, they are much rarer than those in other repeat expansion disorders.
• Predictive testing for at-risk relatives is possible once molecular genetic testing has identified a
• This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• 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
Spinocerebellar ataxia type 6 (SCA6) is inherited in an autosomal dominant manner.
## Risk to Family Members
Because penetrance of SCA6 is 100%, most individuals diagnosed with SCA6 have an affected parent.
A proband with SCA6 may have the disorder as the result of an expansion of an intermediate or mutable normal allele inherited from an unaffected parent [
Recommendations for the evaluation of parents of an individual with SCA6 and no known family history of SCA6 include clinical evaluation and molecular genetic testing.
Although most individuals diagnosed with SCA6 have an affected parent, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
If one parent has a full-penetrance
If one parent has an intermediate or mutable normal
If an expanded
If the parents have not been tested for an expanded
Each child of an individual with SCA6 has a 50% chance of inheriting the expanded
Although repeat-size changes can occur in SCA6 alleles in subsequent generations, they are much rarer than those in other repeat expansion disorders.
• Because penetrance of SCA6 is 100%, most individuals diagnosed with SCA6 have an affected parent.
• A proband with SCA6 may have the disorder as the result of an expansion of an intermediate or mutable normal allele inherited from an unaffected parent [
• Recommendations for the evaluation of parents of an individual with SCA6 and no known family history of SCA6 include clinical evaluation and molecular genetic testing.
• Although most individuals diagnosed with SCA6 have an affected parent, the family history 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 late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has been performed on the parents of the proband.
• If one parent has a full-penetrance
• If one parent has an intermediate or mutable normal
• If an expanded
• If the parents have not been tested for an expanded
• Each child of an individual with SCA6 has a 50% chance of inheriting the expanded
• Although repeat-size changes can occur in SCA6 alleles in subsequent generations, they are much rarer than those in other repeat expansion disorders.
## Related Genetic Counseling Issues
Predictive testing for at-risk relatives is possible once molecular genetic testing has identified a
This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
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 SCA6, 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 molecular genetic testing has identified a
• This testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals.
• 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 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
United Kingdom
United Kingdom
Spain
Sanford Research
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• United Kingdom
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• United Kingdom
•
•
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• Spain
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• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia Type 6: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 6 (
P/Q-type calcium channels are high-voltage-activated calcium channels found primarily on neurons and expressed at high levels in granule cells and Purkinje cells of the cerebellar cortex. Their principal role is believed to be in synaptic transmission. α1A subunits are membrane glycoproteins approximately 2,400 amino acids in length that are the major pore-forming subunit of the P/Q-type voltage-gated calcium channel.
The discovery of the polymorphic CAG repeat in the 3' end
The α1ACT protein is encoded as a separate protein within the 3' portion of the long splice form of α1A subunit mRNA. The α1ACT polypeptide is translated from the α1A mRNA as a separate protein under the control of a cellular internal ribosomal entry site. α1ACT is a transcriptional protein that is translocated to nuclei and binds and enhances expression via a conserved AT-rich motif on several genes expressed in Purkinje cells. α1ACT expressed without α1A subunits accelerates neurite outgrowth in cultured neuronal cells and normalizes Purkinje cell dendrites and innervation when expressed in α1A knockout mice. α1ACT polypeptide bears the polymorphic polyglutamine tract [
The expanded CAG repeat in
## Molecular Pathogenesis
P/Q-type calcium channels are high-voltage-activated calcium channels found primarily on neurons and expressed at high levels in granule cells and Purkinje cells of the cerebellar cortex. Their principal role is believed to be in synaptic transmission. α1A subunits are membrane glycoproteins approximately 2,400 amino acids in length that are the major pore-forming subunit of the P/Q-type voltage-gated calcium channel.
The discovery of the polymorphic CAG repeat in the 3' end
The α1ACT protein is encoded as a separate protein within the 3' portion of the long splice form of α1A subunit mRNA. The α1ACT polypeptide is translated from the α1A mRNA as a separate protein under the control of a cellular internal ribosomal entry site. α1ACT is a transcriptional protein that is translocated to nuclei and binds and enhances expression via a conserved AT-rich motif on several genes expressed in Purkinje cells. α1ACT expressed without α1A subunits accelerates neurite outgrowth in cultured neuronal cells and normalizes Purkinje cell dendrites and innervation when expressed in α1A knockout mice. α1ACT polypeptide bears the polymorphic polyglutamine tract [
The expanded CAG repeat in
## References
## Published Guidelines / Consensus Statements
## Literature Cited
## Chapter Notes
21 November 2019 (sw) Comprehensive update posted live
18 July 2013 (me) Comprehensive update posted live
16 June 2008 (cd) Revision: mutation scanning/sequence analysis no longer available clinically
21 September 2007 (me) Comprehensive update posted live
8 January 2007 (cd) Revision: errata, Genotype-Phenotype Correlations, Heterozygous individuals
12 May 2005 (me) Comprehensive update posted live
11 April 2003 (me) Comprehensive update posted live
25 July 2000 (me) Comprehensive update posted live
23 October 1998 (pb) Review posted live
7 April 1998 (cg) Original submission
• 21 November 2019 (sw) Comprehensive update posted live
• 18 July 2013 (me) Comprehensive update posted live
• 16 June 2008 (cd) Revision: mutation scanning/sequence analysis no longer available clinically
• 21 September 2007 (me) Comprehensive update posted live
• 8 January 2007 (cd) Revision: errata, Genotype-Phenotype Correlations, Heterozygous individuals
• 12 May 2005 (me) Comprehensive update posted live
• 11 April 2003 (me) Comprehensive update posted live
• 25 July 2000 (me) Comprehensive update posted live
• 23 October 1998 (pb) Review posted live
• 7 April 1998 (cg) Original submission
## Revision History
21 November 2019 (sw) Comprehensive update posted live
18 July 2013 (me) Comprehensive update posted live
16 June 2008 (cd) Revision: mutation scanning/sequence analysis no longer available clinically
21 September 2007 (me) Comprehensive update posted live
8 January 2007 (cd) Revision: errata, Genotype-Phenotype Correlations, Heterozygous individuals
12 May 2005 (me) Comprehensive update posted live
11 April 2003 (me) Comprehensive update posted live
25 July 2000 (me) Comprehensive update posted live
23 October 1998 (pb) Review posted live
7 April 1998 (cg) Original submission
• 21 November 2019 (sw) Comprehensive update posted live
• 18 July 2013 (me) Comprehensive update posted live
• 16 June 2008 (cd) Revision: mutation scanning/sequence analysis no longer available clinically
• 21 September 2007 (me) Comprehensive update posted live
• 8 January 2007 (cd) Revision: errata, Genotype-Phenotype Correlations, Heterozygous individuals
• 12 May 2005 (me) Comprehensive update posted live
• 11 April 2003 (me) Comprehensive update posted live
• 25 July 2000 (me) Comprehensive update posted live
• 23 October 1998 (pb) Review posted live
• 7 April 1998 (cg) Original submission
|
[] |
23/10/1998
|
21/11/2019
|
16/6/2008
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sca7
|
sca7
|
[
"SCA7",
"SCA7",
"Ataxin-7",
"ATXN7",
"Spinocerebellar Ataxia Type 7"
] |
Spinocerebellar Ataxia Type 7
|
Albert R La Spada
|
Summary Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death. Anticipation in this nucleotide repeat disorder may be so dramatic that within a family a child with infantile or early-childhood onset may be diagnosed with what is thought to be an unrelated neurodegenerative disorder years before a parent or grandparent with a CAG repeat expansion becomes symptomatic. In adolescent-onset SCA7, the initial manifestation is typically impaired vision, followed by cerebellar ataxia. In those with adult onset, progressive cerebellar ataxia usually precedes the onset of visual manifestations. While the rate of progression varies in these two age groups, the eventual result for almost all affected individuals is loss of vision, severe dysarthria and dysphagia, and a bedridden state with loss of motor control. The diagnosis of SCA7 is established in a proband by the identification of a heterozygous abnormal CAG trinucleotide repeat expansion in SCA7 is inherited in an autosomal dominant manner. Offspring of an affected individual have a 50% chance of inheriting an abnormal CAG repeat expansion in
|
## Diagnosis
Spinocerebellar ataxia type 7 (SCA7)
Progressive incoordination caused by cerebellar ataxia, including dysarthria/dysphagia, dysmetria, and dysdiadochokinesia.
Cone-rod retinal dystrophy with the following:
Loss of central vision
A tritan-axis (blue/yellow) defect on detailed color vision testing
Macular changes on fundoscopic examination
Paracentral scotoma on visual field testing
On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
Failure to thrive and loss of motor milestones (may be the earliest findings)
Rapid deterioration with early death
Ataxia and visual loss not obvious
Family history is consistent with autosomal dominant inheritance (i.e., multiple affected family members in successive generations or a single occurrence in a family). Note that in this nucleotide repeat disorder, anticipation in a family may be so dramatic that a child may be diagnosed with what is thought to be an unrelated neurodegenerative disease years before a parent or grandparent with a CAG repeat expansion becomes symptomatic [
The diagnosis of SCA7
Note: Pathogenic (CAG)
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 7
See
See
Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene.
• Progressive incoordination caused by cerebellar ataxia, including dysarthria/dysphagia, dysmetria, and dysdiadochokinesia.
• Cone-rod retinal dystrophy with the following:
• Loss of central vision
• A tritan-axis (blue/yellow) defect on detailed color vision testing
• Macular changes on fundoscopic examination
• Paracentral scotoma on visual field testing
• On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
• Loss of central vision
• A tritan-axis (blue/yellow) defect on detailed color vision testing
• Macular changes on fundoscopic examination
• Paracentral scotoma on visual field testing
• On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
• Loss of central vision
• A tritan-axis (blue/yellow) defect on detailed color vision testing
• Macular changes on fundoscopic examination
• Paracentral scotoma on visual field testing
• On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
• Failure to thrive and loss of motor milestones (may be the earliest findings)
• Rapid deterioration with early death
• Ataxia and visual loss not obvious
## Suggestive Findings
Spinocerebellar ataxia type 7 (SCA7)
Progressive incoordination caused by cerebellar ataxia, including dysarthria/dysphagia, dysmetria, and dysdiadochokinesia.
Cone-rod retinal dystrophy with the following:
Loss of central vision
A tritan-axis (blue/yellow) defect on detailed color vision testing
Macular changes on fundoscopic examination
Paracentral scotoma on visual field testing
On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
Failure to thrive and loss of motor milestones (may be the earliest findings)
Rapid deterioration with early death
Ataxia and visual loss not obvious
Family history is consistent with autosomal dominant inheritance (i.e., multiple affected family members in successive generations or a single occurrence in a family). Note that in this nucleotide repeat disorder, anticipation in a family may be so dramatic that a child may be diagnosed with what is thought to be an unrelated neurodegenerative disease years before a parent or grandparent with a CAG repeat expansion becomes symptomatic [
• Progressive incoordination caused by cerebellar ataxia, including dysarthria/dysphagia, dysmetria, and dysdiadochokinesia.
• Cone-rod retinal dystrophy with the following:
• Loss of central vision
• A tritan-axis (blue/yellow) defect on detailed color vision testing
• Macular changes on fundoscopic examination
• Paracentral scotoma on visual field testing
• On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
• Loss of central vision
• A tritan-axis (blue/yellow) defect on detailed color vision testing
• Macular changes on fundoscopic examination
• Paracentral scotoma on visual field testing
• On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
• Loss of central vision
• A tritan-axis (blue/yellow) defect on detailed color vision testing
• Macular changes on fundoscopic examination
• Paracentral scotoma on visual field testing
• On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
• Failure to thrive and loss of motor milestones (may be the earliest findings)
• Rapid deterioration with early death
• Ataxia and visual loss not obvious
## Clinical Findings
Progressive incoordination caused by cerebellar ataxia, including dysarthria/dysphagia, dysmetria, and dysdiadochokinesia.
Cone-rod retinal dystrophy with the following:
Loss of central vision
A tritan-axis (blue/yellow) defect on detailed color vision testing
Macular changes on fundoscopic examination
Paracentral scotoma on visual field testing
On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
Failure to thrive and loss of motor milestones (may be the earliest findings)
Rapid deterioration with early death
Ataxia and visual loss not obvious
• Progressive incoordination caused by cerebellar ataxia, including dysarthria/dysphagia, dysmetria, and dysdiadochokinesia.
• Cone-rod retinal dystrophy with the following:
• Loss of central vision
• A tritan-axis (blue/yellow) defect on detailed color vision testing
• Macular changes on fundoscopic examination
• Paracentral scotoma on visual field testing
• On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
• Loss of central vision
• A tritan-axis (blue/yellow) defect on detailed color vision testing
• Macular changes on fundoscopic examination
• Paracentral scotoma on visual field testing
• On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
• Loss of central vision
• A tritan-axis (blue/yellow) defect on detailed color vision testing
• Macular changes on fundoscopic examination
• Paracentral scotoma on visual field testing
• On electroretinogram (ERG), abnormalities of cone function initially, followed by abnormalities of rod function
• Failure to thrive and loss of motor milestones (may be the earliest findings)
• Rapid deterioration with early death
• Ataxia and visual loss not obvious
## Family History
Family history is consistent with autosomal dominant inheritance (i.e., multiple affected family members in successive generations or a single occurrence in a family). Note that in this nucleotide repeat disorder, anticipation in a family may be so dramatic that a child may be diagnosed with what is thought to be an unrelated neurodegenerative disease years before a parent or grandparent with a CAG repeat expansion becomes symptomatic [
## Establishing the Diagnosis
The diagnosis of SCA7
Note: Pathogenic (CAG)
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 7
See
See
Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in this gene.
## Clinical Characteristics
Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy with progressive central visual loss to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death [
One important aspect of SCA7 clinical manifestations is their extreme variability with respect to age of onset and rate of progression. Affected individuals may present in infancy, childhood, adolescence, young adulthood, middle age, or old age.
When onset is at or before adolescence, initial manifestations are typically impaired vision, ultimately progressing to blindness from retinal degeneration. Individuals with manifestations in their teens may be blind within a decade or less.
In adults, the progressive cerebellar ataxia (i.e., dysmetria, dysdiadochokinesia, and poor coordination) usually precedes the onset of visual manifestations. The age of onset inversely correlates with rate of progression and extent of symptomatology, as onset in or after the fifth decade of life gives a predominant cerebellar ataxia without progression to significant visual impairment, whereas onset prior to middle age often features progression to vision loss.
Progression to severe disability resulting in death varies based on age of onset, ranging from months in infants to fewer than ten years in older children to two to three decades in adolescents and adults. While the rate of progression varies, the eventual result for almost all affected individuals is severe dysarthria, dysphagia, and a bedridden state with loss of motor control.
To date, more than 1,000 individuals with SCA7 have been identified worldwide. Frequency of select features in adolescent- or adult-onset disease are summarized in
Select Features of Adolescent- or Adult-Onset SCA7
Slowed ocular saccades
Ophthalmoplegia
Upper motor neuron involvement (hyperreflexia, spasticity); may resemble hereditary spastic paraplegia.
Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
Altered mentation
Impaired reality testing
Loss of central vision & color vision
Abnormal fundoscopic exam
Involvement of the corticospinal tracts, resulting in brisk tendon reflexes and spasticity, may become evident as the disease progresses.
Cognitive decline and psychosis have been reported [
Early signs of cone-rod dystrophy are subtle granular changes in the macula. Electroretinogram is consistently abnormal early in the disease course, showing a decrease in the photopic (cone) response initially, followed by a decrease in the scotopic (rod) response [
In infancy or early childhood disease, progression is always more rapid and aggressive than in adults. In infants, the clinical diagnosis may be elusive because ataxia and visual loss are not obvious; failure to thrive and loss of motor milestones may be the earliest findings. Other findings include progressive hypotonia, poor feeding, dysphagia, and congestive heart failure [
Affected infants usually die within months of initial presentation and never survive into early childhood [
A correlation between CAG repeat sizes and disease severity exists: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease.
Infantile onset may be associated with CAG repeat sizes ranging from 200 to 400; however, technical limitations of genetic testing utilizing PCR amplification of the
Childhood onset is usually associated with CAG repeat sizes greater than 100.
Juvenile onset is often associated with CAG repeat sizes 60-100.
A correlation between CAG repeat size and initial clinical manifestation exists [
CAG repeat sizes greater than 59 are typically associated with adolescent or young-adult onset (age <30 years) and visual impairment as the initial manifestation.
CAG repeat sizes smaller than 59 are often associated with adult onset (age >30 years) and cerebellar findings as the initial manifestation.
Despite observations correlating CAG repeat length with age of onset, disease severity, and course, CAG repeat size cannot provide sufficient predictive value for clinical prognosis within the classic adult-onset CAG repeat size range of 38 to 50 repeats [
A woman with 34 CAG repeats had "very mild symptoms" at age 65 years [
An individual with 35 CAG repeats was symptomatic [
An individual with 36 CAG repeats developed relatively mild symptoms at age 63 years [
See
In families with a pathogenic (full-penetrance) CAG repeat expansion, the repeat size tends to expand with transmission to successive generations, with more marked expansions seen in affected offspring of affected males [
Anticipation in a family may be so dramatic that a child may be diagnosed with what is thought to be an unrelated neurodegenerative disease years before a parent or grandparent with pathogenic CAG repeat expansion becomes symptomatic [
Repeat contraction has not been reported.
Terms used in the past to designate SCA7 include olivopontocerebellar ataxia (OPCA) type III and ADCA type II.
The prevalence is fewer than 1:300,000. In several studies, SCA7 represented 2% of all SCAs [
SCA7 occurs predominantly in two racial population groups: northern Europeans and Africans. Indeed, SCA7 is the only repeat expansion disease, with the exception of
As a result of a founder effect in Mexico dating back to the colonial era, a very large concentration of individuals with SCA7 have been ascertained in the state of Veracruz in Mexico, with well over 150 documented affected individuals.
• Slowed ocular saccades
• Ophthalmoplegia
• Upper motor neuron involvement (hyperreflexia, spasticity); may resemble hereditary spastic paraplegia.
• Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
• Altered mentation
• Impaired reality testing
• Loss of central vision & color vision
• Abnormal fundoscopic exam
• Infantile onset may be associated with CAG repeat sizes ranging from 200 to 400; however, technical limitations of genetic testing utilizing PCR amplification of the
• Childhood onset is usually associated with CAG repeat sizes greater than 100.
• Juvenile onset is often associated with CAG repeat sizes 60-100.
• CAG repeat sizes greater than 59 are typically associated with adolescent or young-adult onset (age <30 years) and visual impairment as the initial manifestation.
• CAG repeat sizes smaller than 59 are often associated with adult onset (age >30 years) and cerebellar findings as the initial manifestation.
• A woman with 34 CAG repeats had "very mild symptoms" at age 65 years [
• An individual with 35 CAG repeats was symptomatic [
• An individual with 36 CAG repeats developed relatively mild symptoms at age 63 years [
## Clinical Description
Spinocerebellar ataxia type 7 (SCA7) comprises a phenotypic spectrum ranging from adolescent- or adult-onset progressive cerebellar ataxia and cone-rod retinal dystrophy with progressive central visual loss to infantile or early-childhood onset with multiorgan failure, an accelerated course, and early death [
One important aspect of SCA7 clinical manifestations is their extreme variability with respect to age of onset and rate of progression. Affected individuals may present in infancy, childhood, adolescence, young adulthood, middle age, or old age.
When onset is at or before adolescence, initial manifestations are typically impaired vision, ultimately progressing to blindness from retinal degeneration. Individuals with manifestations in their teens may be blind within a decade or less.
In adults, the progressive cerebellar ataxia (i.e., dysmetria, dysdiadochokinesia, and poor coordination) usually precedes the onset of visual manifestations. The age of onset inversely correlates with rate of progression and extent of symptomatology, as onset in or after the fifth decade of life gives a predominant cerebellar ataxia without progression to significant visual impairment, whereas onset prior to middle age often features progression to vision loss.
Progression to severe disability resulting in death varies based on age of onset, ranging from months in infants to fewer than ten years in older children to two to three decades in adolescents and adults. While the rate of progression varies, the eventual result for almost all affected individuals is severe dysarthria, dysphagia, and a bedridden state with loss of motor control.
To date, more than 1,000 individuals with SCA7 have been identified worldwide. Frequency of select features in adolescent- or adult-onset disease are summarized in
Select Features of Adolescent- or Adult-Onset SCA7
Slowed ocular saccades
Ophthalmoplegia
Upper motor neuron involvement (hyperreflexia, spasticity); may resemble hereditary spastic paraplegia.
Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
Altered mentation
Impaired reality testing
Loss of central vision & color vision
Abnormal fundoscopic exam
Involvement of the corticospinal tracts, resulting in brisk tendon reflexes and spasticity, may become evident as the disease progresses.
Cognitive decline and psychosis have been reported [
Early signs of cone-rod dystrophy are subtle granular changes in the macula. Electroretinogram is consistently abnormal early in the disease course, showing a decrease in the photopic (cone) response initially, followed by a decrease in the scotopic (rod) response [
In infancy or early childhood disease, progression is always more rapid and aggressive than in adults. In infants, the clinical diagnosis may be elusive because ataxia and visual loss are not obvious; failure to thrive and loss of motor milestones may be the earliest findings. Other findings include progressive hypotonia, poor feeding, dysphagia, and congestive heart failure [
Affected infants usually die within months of initial presentation and never survive into early childhood [
• Slowed ocular saccades
• Ophthalmoplegia
• Upper motor neuron involvement (hyperreflexia, spasticity); may resemble hereditary spastic paraplegia.
• Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
• Altered mentation
• Impaired reality testing
• Loss of central vision & color vision
• Abnormal fundoscopic exam
## Adolescent- or Adult-Onset SCA7
Select Features of Adolescent- or Adult-Onset SCA7
Slowed ocular saccades
Ophthalmoplegia
Upper motor neuron involvement (hyperreflexia, spasticity); may resemble hereditary spastic paraplegia.
Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
Altered mentation
Impaired reality testing
Loss of central vision & color vision
Abnormal fundoscopic exam
Involvement of the corticospinal tracts, resulting in brisk tendon reflexes and spasticity, may become evident as the disease progresses.
Cognitive decline and psychosis have been reported [
Early signs of cone-rod dystrophy are subtle granular changes in the macula. Electroretinogram is consistently abnormal early in the disease course, showing a decrease in the photopic (cone) response initially, followed by a decrease in the scotopic (rod) response [
• Slowed ocular saccades
• Ophthalmoplegia
• Upper motor neuron involvement (hyperreflexia, spasticity); may resemble hereditary spastic paraplegia.
• Lower motor neuron involvement (fasciculations, weakness w/muscle wasting, areflexia, distal sensory loss)
• Altered mentation
• Impaired reality testing
• Loss of central vision & color vision
• Abnormal fundoscopic exam
## Infantile- or Early Childhood-Onset SCA7
In infancy or early childhood disease, progression is always more rapid and aggressive than in adults. In infants, the clinical diagnosis may be elusive because ataxia and visual loss are not obvious; failure to thrive and loss of motor milestones may be the earliest findings. Other findings include progressive hypotonia, poor feeding, dysphagia, and congestive heart failure [
Affected infants usually die within months of initial presentation and never survive into early childhood [
## Genotype-Phenotype Correlations
A correlation between CAG repeat sizes and disease severity exists: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease.
Infantile onset may be associated with CAG repeat sizes ranging from 200 to 400; however, technical limitations of genetic testing utilizing PCR amplification of the
Childhood onset is usually associated with CAG repeat sizes greater than 100.
Juvenile onset is often associated with CAG repeat sizes 60-100.
A correlation between CAG repeat size and initial clinical manifestation exists [
CAG repeat sizes greater than 59 are typically associated with adolescent or young-adult onset (age <30 years) and visual impairment as the initial manifestation.
CAG repeat sizes smaller than 59 are often associated with adult onset (age >30 years) and cerebellar findings as the initial manifestation.
Despite observations correlating CAG repeat length with age of onset, disease severity, and course, CAG repeat size cannot provide sufficient predictive value for clinical prognosis within the classic adult-onset CAG repeat size range of 38 to 50 repeats [
A woman with 34 CAG repeats had "very mild symptoms" at age 65 years [
An individual with 35 CAG repeats was symptomatic [
An individual with 36 CAG repeats developed relatively mild symptoms at age 63 years [
• Infantile onset may be associated with CAG repeat sizes ranging from 200 to 400; however, technical limitations of genetic testing utilizing PCR amplification of the
• Childhood onset is usually associated with CAG repeat sizes greater than 100.
• Juvenile onset is often associated with CAG repeat sizes 60-100.
• CAG repeat sizes greater than 59 are typically associated with adolescent or young-adult onset (age <30 years) and visual impairment as the initial manifestation.
• CAG repeat sizes smaller than 59 are often associated with adult onset (age >30 years) and cerebellar findings as the initial manifestation.
• A woman with 34 CAG repeats had "very mild symptoms" at age 65 years [
• An individual with 35 CAG repeats was symptomatic [
• An individual with 36 CAG repeats developed relatively mild symptoms at age 63 years [
## Penetrance
See
## Anticipation
In families with a pathogenic (full-penetrance) CAG repeat expansion, the repeat size tends to expand with transmission to successive generations, with more marked expansions seen in affected offspring of affected males [
Anticipation in a family may be so dramatic that a child may be diagnosed with what is thought to be an unrelated neurodegenerative disease years before a parent or grandparent with pathogenic CAG repeat expansion becomes symptomatic [
Repeat contraction has not been reported.
## Nomenclature
Terms used in the past to designate SCA7 include olivopontocerebellar ataxia (OPCA) type III and ADCA type II.
## Prevalence
The prevalence is fewer than 1:300,000. In several studies, SCA7 represented 2% of all SCAs [
SCA7 occurs predominantly in two racial population groups: northern Europeans and Africans. Indeed, SCA7 is the only repeat expansion disease, with the exception of
As a result of a founder effect in Mexico dating back to the colonial era, a very large concentration of individuals with SCA7 have been ascertained in the state of Veracruz in Mexico, with well over 150 documented affected individuals.
## Genetically Related (Allelic) Disorders
No phenotypes other than those described in this
## Differential Diagnosis
While many of the neurologic and pathologic findings of the other spinocerebellar ataxias (SCAs) overlap with SCA7, retinal degeneration is the distinguishing feature of SCA7 (see
Disorders with Retinal Degeneration in the Differential Diagnosis of Spinocerebellar Ataxia Type 7
Optic atrophy in childhood (age <10 yrs)
Common in persons of Iraqi Jewish origin due to founder variant
AD = autosomal dominant; AR = autosomal recessive; Mat = maternal; MOI = mode of inheritance
Three common mtDNA pathogenic variants in the listed genes account for 90%-95% of Leber hereditary optic neuropathy (LHON). Pathogenic variants in other mitochondrial genes (
• Optic atrophy in childhood (age <10 yrs)
• Common in persons of Iraqi Jewish origin due to founder variant
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 7 (SCA7) of adolescent or adult onset, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of SCA7: Adolescent or Adult Onset
BCVA
Extraocular movement
Refractive error
Color vision testing
Full-field ERG
Spectral-domain OCT
Nutritional status;
Aspiration risk.
Referral to urologist
Consider urodynamic eval.
CCAS scale
Psychiatrist, psychologist, neuropsychologist if needed.
Community or online
Social work involvement for caregiver support;
Home nursing referral.
BARS = Brief Ataxia Rating Scale; BCVA = best-corrected visual acuity; CCAS = cerebellar cognitive affective syndrome; ERG = electroretinogram; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; MOI = mode of inheritance; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
Management of affected individuals remains supportive, as no known therapy to delay or halt the progression of the disease exists.
Treatment of Manifestations of SCA 7: Adolescent or Adult Onset
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADLs (incl use of adaptive devices, e.g., weighted eating utensils & dressing hooks)
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
Inpatient rehab w/OT/PT may improve ataxia & functional abilities.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
Therapies intended to ↓ symptoms work variably well in different individuals.
Most commonly used drugs: amantadine, buspirone, riluzole
Consider nutritional & vitamin supplementation to meet dietary needs.
Avoid obesity (which can exacerbate difficulties with ambulation & mobility).
If physical rehab or biofeedback do not remedy problem, consider anticholinergic drugs for overactive bladder.
Anticholinergic agents are also indicated for neurogenic bladder.
Botulinum toxin injections should be reserved for severe or unresponsive bladder dysfunction.
ADLs = activities of daily living; LMN = lower motor neuron; OT = occupational therapy/therapist; PT = physical therapy/therapist; TMS = transcranial magnetic stimulation; UMN = upper motor neuron
Recommended Surveillance for Individuals with SCA7
Neurologic assessment for progression of ataxia; UMN or LMN signs; dystonia & parkinsonism; autonomic dysfunction
Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
BARS = Brief Ataxia Rating Scale; BCVA = best-corrected visual acuity; ERG = electroretinogram; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Avoid drinking alcoholic beverages, as alcohol intake can further impair cerebellar function, especially if excessive.
Avoid foods identified by a registered dietician as potentially causing dizziness or disorientation.
See
Ongoing clinical trials for SCA7 include a study of:
Troriluzole in adults as a treatment for ataxia in the United States (ClinicalTrials.gov:
Riluzole in adults as a treatment for ataxia in Italy (ClinicalTrials.gov:
Ionis Pharmaceuticals™ is developing an antisense oligonucleotide for dosage reduction of ataxin-7 in the retina and brain, as a preclinical trial of this strategy was found to be an effective treatment for retinal degeneration in an SCA7 mouse model [
Search
• BCVA
• Extraocular movement
• Refractive error
• Color vision testing
• Full-field ERG
• Spectral-domain OCT
• Nutritional status;
• Aspiration risk.
• Referral to urologist
• Consider urodynamic eval.
• CCAS scale
• Psychiatrist, psychologist, neuropsychologist if needed.
• Community or online
• Social work involvement for caregiver support;
• Home nursing referral.
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADLs (incl use of adaptive devices, e.g., weighted eating utensils & dressing hooks)
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
• Inpatient rehab w/OT/PT may improve ataxia & functional abilities.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
• Therapies intended to ↓ symptoms work variably well in different individuals.
• Most commonly used drugs: amantadine, buspirone, riluzole
• Consider nutritional & vitamin supplementation to meet dietary needs.
• Avoid obesity (which can exacerbate difficulties with ambulation & mobility).
• If physical rehab or biofeedback do not remedy problem, consider anticholinergic drugs for overactive bladder.
• Anticholinergic agents are also indicated for neurogenic bladder.
• Botulinum toxin injections should be reserved for severe or unresponsive bladder dysfunction.
• Neurologic assessment for progression of ataxia; UMN or LMN signs; dystonia & parkinsonism; autonomic dysfunction
• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
• Troriluzole in adults as a treatment for ataxia in the United States (ClinicalTrials.gov:
• Riluzole in adults as a treatment for ataxia in Italy (ClinicalTrials.gov:
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 7 (SCA7) of adolescent or adult onset, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis of SCA7: Adolescent or Adult Onset
BCVA
Extraocular movement
Refractive error
Color vision testing
Full-field ERG
Spectral-domain OCT
Nutritional status;
Aspiration risk.
Referral to urologist
Consider urodynamic eval.
CCAS scale
Psychiatrist, psychologist, neuropsychologist if needed.
Community or online
Social work involvement for caregiver support;
Home nursing referral.
BARS = Brief Ataxia Rating Scale; BCVA = best-corrected visual acuity; CCAS = cerebellar cognitive affective syndrome; ERG = electroretinogram; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; MOI = mode of inheritance; OCT = optical coherence tomography; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, or certified advanced genetic nurse
• BCVA
• Extraocular movement
• Refractive error
• Color vision testing
• Full-field ERG
• Spectral-domain OCT
• Nutritional status;
• Aspiration risk.
• Referral to urologist
• Consider urodynamic eval.
• CCAS scale
• Psychiatrist, psychologist, neuropsychologist if needed.
• Community or online
• Social work involvement for caregiver support;
• Home nursing referral.
## Treatment of Manifestations
Management of affected individuals remains supportive, as no known therapy to delay or halt the progression of the disease exists.
Treatment of Manifestations of SCA 7: Adolescent or Adult Onset
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADLs (incl use of adaptive devices, e.g., weighted eating utensils & dressing hooks)
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
Inpatient rehab w/OT/PT may improve ataxia & functional abilities.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
Therapies intended to ↓ symptoms work variably well in different individuals.
Most commonly used drugs: amantadine, buspirone, riluzole
Consider nutritional & vitamin supplementation to meet dietary needs.
Avoid obesity (which can exacerbate difficulties with ambulation & mobility).
If physical rehab or biofeedback do not remedy problem, consider anticholinergic drugs for overactive bladder.
Anticholinergic agents are also indicated for neurogenic bladder.
Botulinum toxin injections should be reserved for severe or unresponsive bladder dysfunction.
ADLs = activities of daily living; LMN = lower motor neuron; OT = occupational therapy/therapist; PT = physical therapy/therapist; TMS = transcranial magnetic stimulation; UMN = upper motor neuron
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADLs (incl use of adaptive devices, e.g., weighted eating utensils & dressing hooks)
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, motorized chairs).
• Inpatient rehab w/OT/PT may improve ataxia & functional abilities.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats) & improve mobility (e.g., ramps to accommodate motorized chairs)
• Therapies intended to ↓ symptoms work variably well in different individuals.
• Most commonly used drugs: amantadine, buspirone, riluzole
• Consider nutritional & vitamin supplementation to meet dietary needs.
• Avoid obesity (which can exacerbate difficulties with ambulation & mobility).
• If physical rehab or biofeedback do not remedy problem, consider anticholinergic drugs for overactive bladder.
• Anticholinergic agents are also indicated for neurogenic bladder.
• Botulinum toxin injections should be reserved for severe or unresponsive bladder dysfunction.
## Surveillance
Recommended Surveillance for Individuals with SCA7
Neurologic assessment for progression of ataxia; UMN or LMN signs; dystonia & parkinsonism; autonomic dysfunction
Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
BARS = Brief Ataxia Rating Scale; BCVA = best-corrected visual acuity; ERG = electroretinogram; ICARS = International Co-operative Ataxia Rating Scale; LMN = lower motor neuron; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
• Neurologic assessment for progression of ataxia; UMN or LMN signs; dystonia & parkinsonism; autonomic dysfunction
• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
## Agents/Circumstances to Avoid
Avoid drinking alcoholic beverages, as alcohol intake can further impair cerebellar function, especially if excessive.
Avoid foods identified by a registered dietician as potentially causing dizziness or disorientation.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Ongoing clinical trials for SCA7 include a study of:
Troriluzole in adults as a treatment for ataxia in the United States (ClinicalTrials.gov:
Riluzole in adults as a treatment for ataxia in Italy (ClinicalTrials.gov:
Ionis Pharmaceuticals™ is developing an antisense oligonucleotide for dosage reduction of ataxin-7 in the retina and brain, as a preclinical trial of this strategy was found to be an effective treatment for retinal degeneration in an SCA7 mouse model [
Search
• Troriluzole in adults as a treatment for ataxia in the United States (ClinicalTrials.gov:
• Riluzole in adults as a treatment for ataxia in Italy (ClinicalTrials.gov:
## Genetic Counseling
Spinocerebellar ataxia type 7 (SCA7) is inherited in an autosomal dominant manner.
Most individuals diagnosed with SCA7 have an affected parent. Note: Anticipation in a family may be so dramatic that a child may be diagnosed with SCA7 years before a parent or grandparent with pathogenic CAG repeat expansion becomes symptomatic [
A proband with SCA7 may have the disorder as the result of expansion of a pathogenic reduced-penetrance CAG repeat (34-36 CAG repeats) or a mutable normal CAG repeat (28-33 CAG repeats) inherited from an unaffected parent.
If neither of the parents of the proband is known to have SCA7, recommendations for the evaluation of parents include physical examination and consideration of
The family history of some individuals diagnosed with SCA7 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to have an abnormal CAG repeat, the risk to each sib of inheriting the CAG repeat expansion is 50%. Pathogenic full-penetrance CAG repeat expansions tend to expand on transmission from parent to offspring (more marked expansions are seen when the transmitting parent is male) and often result in an earlier age of onset and more severe disease manifestations in offspring (see
Clinical presentation in sibs who inherit an abnormal CAG repeat usually correlates with their CAG repeat size: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease (see
If the parents of a proband are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for SCA7 because of the possibility of late onset of SCA7 in a heterozygous parent.
Each child of an affected individual has a 50% chance of inheriting the CAG repeat expansion.
Pathogenic full-penetrance CAG repeat expansions tend to expand on transmission from parent to offspring (more marked expansions are seen when the transmitting parent is male) and often result in an earlier age of onset and more severe disease manifestations in offspring (see
Note: If neither parent of a proband with SCA7 has a CAG repeat expansion, nonmedical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 molecular genetic testing has identified a CAG repeat expansion 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.
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 SCA7, it is appropriate to consider testing of symptomatic individuals regardless of age.
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 individuals diagnosed with SCA7 have an affected parent. Note: Anticipation in a family may be so dramatic that a child may be diagnosed with SCA7 years before a parent or grandparent with pathogenic CAG repeat expansion becomes symptomatic [
• A proband with SCA7 may have the disorder as the result of expansion of a pathogenic reduced-penetrance CAG repeat (34-36 CAG repeats) or a mutable normal CAG repeat (28-33 CAG repeats) inherited from an unaffected parent.
• If neither of the parents of the proband is known to have SCA7, recommendations for the evaluation of parents include physical examination and consideration of
• The family history of some individuals diagnosed with SCA7 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to have an abnormal CAG repeat, the risk to each sib of inheriting the CAG repeat expansion is 50%. Pathogenic full-penetrance CAG repeat expansions tend to expand on transmission from parent to offspring (more marked expansions are seen when the transmitting parent is male) and often result in an earlier age of onset and more severe disease manifestations in offspring (see
• Clinical presentation in sibs who inherit an abnormal CAG repeat usually correlates with their CAG repeat size: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease (see
• If the parents of a proband are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for SCA7 because of the possibility of late onset of SCA7 in a heterozygous parent.
• Each child of an affected individual has a 50% chance of inheriting the CAG repeat expansion.
• Pathogenic full-penetrance CAG repeat expansions tend to expand on transmission from parent to offspring (more marked expansions are seen when the transmitting parent is male) and often result in an earlier age of onset and more severe disease manifestations in offspring (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.
• Predictive testing for at-risk relatives is possible once molecular genetic testing has identified a CAG repeat expansion 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.
• 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
Spinocerebellar ataxia type 7 (SCA7) is inherited in an autosomal dominant manner.
## Risk to Family Members
Most individuals diagnosed with SCA7 have an affected parent. Note: Anticipation in a family may be so dramatic that a child may be diagnosed with SCA7 years before a parent or grandparent with pathogenic CAG repeat expansion becomes symptomatic [
A proband with SCA7 may have the disorder as the result of expansion of a pathogenic reduced-penetrance CAG repeat (34-36 CAG repeats) or a mutable normal CAG repeat (28-33 CAG repeats) inherited from an unaffected parent.
If neither of the parents of the proband is known to have SCA7, recommendations for the evaluation of parents include physical examination and consideration of
The family history of some individuals diagnosed with SCA7 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
If a parent of the proband is affected and/or is known to have an abnormal CAG repeat, the risk to each sib of inheriting the CAG repeat expansion is 50%. Pathogenic full-penetrance CAG repeat expansions tend to expand on transmission from parent to offspring (more marked expansions are seen when the transmitting parent is male) and often result in an earlier age of onset and more severe disease manifestations in offspring (see
Clinical presentation in sibs who inherit an abnormal CAG repeat usually correlates with their CAG repeat size: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease (see
If the parents of a proband are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for SCA7 because of the possibility of late onset of SCA7 in a heterozygous parent.
Each child of an affected individual has a 50% chance of inheriting the CAG repeat expansion.
Pathogenic full-penetrance CAG repeat expansions tend to expand on transmission from parent to offspring (more marked expansions are seen when the transmitting parent is male) and often result in an earlier age of onset and more severe disease manifestations in offspring (see
• Most individuals diagnosed with SCA7 have an affected parent. Note: Anticipation in a family may be so dramatic that a child may be diagnosed with SCA7 years before a parent or grandparent with pathogenic CAG repeat expansion becomes symptomatic [
• A proband with SCA7 may have the disorder as the result of expansion of a pathogenic reduced-penetrance CAG repeat (34-36 CAG repeats) or a mutable normal CAG repeat (28-33 CAG repeats) inherited from an unaffected parent.
• If neither of the parents of the proband is known to have SCA7, recommendations for the evaluation of parents include physical examination and consideration of
• The family history of some individuals diagnosed with SCA7 may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless appropriate molecular genetic testing has been performed on the parents of the proband.
• If a parent of the proband is affected and/or is known to have an abnormal CAG repeat, the risk to each sib of inheriting the CAG repeat expansion is 50%. Pathogenic full-penetrance CAG repeat expansions tend to expand on transmission from parent to offspring (more marked expansions are seen when the transmitting parent is male) and often result in an earlier age of onset and more severe disease manifestations in offspring (see
• Clinical presentation in sibs who inherit an abnormal CAG repeat usually correlates with their CAG repeat size: the longer the CAG repeat, the earlier the age of onset and the more severe and rapidly progressive the disease (see
• If the parents of a proband are clinically unaffected but their genetic status is unknown, sibs are still presumed to be at increased risk for SCA7 because of the possibility of late onset of SCA7 in a heterozygous parent.
• Each child of an affected individual has a 50% chance of inheriting the CAG repeat expansion.
• Pathogenic full-penetrance CAG repeat expansions tend to expand on transmission from parent to offspring (more marked expansions are seen when the transmitting parent is male) and often result in an earlier age of onset and more severe disease manifestations in offspring (see
## Related Genetic Counseling Issues
Note: If neither parent of a proband with SCA7 has a CAG repeat expansion, nonmedical explanations including alternate paternity or maternity (e.g., with assisted reproduction) and undisclosed adoption could also be explored.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 molecular genetic testing has identified a CAG repeat expansion 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.
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 SCA7, 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 molecular genetic testing has identified a CAG repeat expansion 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.
• 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 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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Sanford Research
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## Molecular Genetics
Spinocerebellar Ataxia Type 7: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 7 (
In addition, somatic and germline instability of expanded repeats must be considered.
Methods to Characterize
The design of a triplet-primed PCR (TP-PCR) assay may include conventional PCR primers to size normal repeats and detect expanded repeats in a single assay. The TP-PCR assay itself does not determine repeat size, even alleles in the normal range.
Methods to detect and approximate the size of expanded repeats include long-range PCR sized by gel electrophoresis and Southern blotting. The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/or patient as a result of competition by the normal allele during amplification.
Detection of an apparently homozygous repeat does not rule out the presence of an expanded CAG repeat; thus, testing by TP-PCR or expanded repeat analysis is required to detect a repeat expansion.
The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/or patient as a result of competition from the normal allele during amplification.
TP-PCR for the CAG repeat expansion has been described [
Repeats at the lower end of this range may not show the characteristic stutter pattern that indicates an expanded repeat [
Southern blotting for the CAG repeat expansion has been described [
Precise sizing of repeats is not necessary, as clinical utility for determining the exact repeat number has not been demonstrated.
Notable
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
In addition, somatic and germline instability of expanded repeats must be considered.
Methods to Characterize
The design of a triplet-primed PCR (TP-PCR) assay may include conventional PCR primers to size normal repeats and detect expanded repeats in a single assay. The TP-PCR assay itself does not determine repeat size, even alleles in the normal range.
Methods to detect and approximate the size of expanded repeats include long-range PCR sized by gel electrophoresis and Southern blotting. The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/or patient as a result of competition by the normal allele during amplification.
Detection of an apparently homozygous repeat does not rule out the presence of an expanded CAG repeat; thus, testing by TP-PCR or expanded repeat analysis is required to detect a repeat expansion.
The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/or patient as a result of competition from the normal allele during amplification.
TP-PCR for the CAG repeat expansion has been described [
Repeats at the lower end of this range may not show the characteristic stutter pattern that indicates an expanded repeat [
Southern blotting for the CAG repeat expansion has been described [
Precise sizing of repeats is not necessary, as clinical utility for determining the exact repeat number has not been demonstrated.
Notable
Variants listed in the table have been provided by the author.
## References
## Published Guidelines / Consensus Statements
## Literature Cited
## Chapter Notes
Thomas D Bird, MD; University of Washington (2007-2012)Gwenn Garden, MD, PhD; University of Washington (2012-2020)Launce G-C Gouw, MD, PhD; University of Utah School of Medicine (1998-2007)Albert R La Spada, MD, PhD (2007-2012; 2020-present)Roberta A Pagon, MD; University of Washington (2007-2012)Louis J Ptacek, MD; University of California, San Francisco (1998-2007)
23 July 2020 (bp) Comprehensive update posted live
20 December 2012 (me) Comprehensive update posted live
6 September 2007 (tb) Revision: Natural History (Clinical Description)
9 February 2007 (me) Comprehensive update posted live
11 December 2003 (me) Comprehensive update posted live
20 June 2001 (me) Comprehensive update posted live
27 August 1998 (pb) Review posted live
1 June 1998 (lg) Original submission
• 23 July 2020 (bp) Comprehensive update posted live
• 20 December 2012 (me) Comprehensive update posted live
• 6 September 2007 (tb) Revision: Natural History (Clinical Description)
• 9 February 2007 (me) Comprehensive update posted live
• 11 December 2003 (me) Comprehensive update posted live
• 20 June 2001 (me) Comprehensive update posted live
• 27 August 1998 (pb) Review posted live
• 1 June 1998 (lg) Original submission
## Author History
Thomas D Bird, MD; University of Washington (2007-2012)Gwenn Garden, MD, PhD; University of Washington (2012-2020)Launce G-C Gouw, MD, PhD; University of Utah School of Medicine (1998-2007)Albert R La Spada, MD, PhD (2007-2012; 2020-present)Roberta A Pagon, MD; University of Washington (2007-2012)Louis J Ptacek, MD; University of California, San Francisco (1998-2007)
## Revision History
23 July 2020 (bp) Comprehensive update posted live
20 December 2012 (me) Comprehensive update posted live
6 September 2007 (tb) Revision: Natural History (Clinical Description)
9 February 2007 (me) Comprehensive update posted live
11 December 2003 (me) Comprehensive update posted live
20 June 2001 (me) Comprehensive update posted live
27 August 1998 (pb) Review posted live
1 June 1998 (lg) Original submission
• 23 July 2020 (bp) Comprehensive update posted live
• 20 December 2012 (me) Comprehensive update posted live
• 6 September 2007 (tb) Revision: Natural History (Clinical Description)
• 9 February 2007 (me) Comprehensive update posted live
• 11 December 2003 (me) Comprehensive update posted live
• 20 June 2001 (me) Comprehensive update posted live
• 27 August 1998 (pb) Review posted live
• 1 June 1998 (lg) Original submission
Funduscopic photo shows extreme macular degeneration of late-stage SCA7.
|
[] |
27/8/1998
|
23/7/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sca8
|
sca8
|
[
"SCA8",
"SCA8",
"Ataxin-8",
"ATXN8",
"ATXN8OS",
"Spinocerebellar Ataxia Type 8"
] |
Spinocerebellar Ataxia Type 8
|
John Douglas Cleary, SH Subramony, Laura PW Ranum
|
Summary SCA8 is a slowly progressive ataxia with onset typically in the third to fifth decade but with a range from before age one year to after age 60 years. Common initial manifestations are scanning dysarthria with a characteristic drawn-out slowness of speech and gait instability. Over the disease course other findings can include eye movement abnormalities (nystagmus, abnormal pursuit and abnormal saccades, and, rarely, ophthalmoplegia); upper motor neuron involvement; extrapyramidal signs; brain stem signs (dysphagia and poor cough reflex); sensory neuropathy; and cognitive impairment (e.g., executive dysfunction, psychomotor slowing and other features of cerebellar cognitive-affective disorder in some). Life span is typically not shortened. The diagnosis of SCA8 is established in a proband with suggestive findings and a heterozygous abnormal (CTG SCA8 is inherited in an autosomal dominant manner with reduced penetrance. To date, all individuals diagnosed with SCA8 whose parents have been evaluated with molecular genetic testing have one parent with an
|
## Diagnosis
Spinocerebellar ataxia type 8 (SCA8)
Gait and limb ataxia
Scanning dysarthria characterized by a drawn-out slowness of speech
Eye movement abnormalities (e.g., nystagmus, abnormal pursuit and abnormal saccades)
Often "extracerebellar signs" including:
Upper motor neuron findings (e.g., brisk tendon reflexes, spasticity, and Babinski sign)
Extrapyramidal signs (e.g., tremor, dystonia and occasionally parkinson-like features)
Brain stem signs (e.g., dysphagia and poor cough reflex)
Sensory neuropathy (e.g., loss of sensation and loss of tendon reflexes in distal limbs)
Cognitive features (e.g., executive dysfunction, psychomotor slowing, and other features of cerebellar cognitive-affective disorder in some)
The absence of an autosomal dominant family history of disease should not be used to rule out a diagnosis of SCA8.
Note: Affected individuals homozygous for repeat expansions have also been reported in the literature, suggesting that two expansion alleles may further increase risk.
The diagnosis of SCA8
Molecular genetic testing relies on targeted analysis to characterize the number of
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 8
See
See
Note: Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in these genes.
Trinucleotide repeat expansion located within two overlapping genes: an untranslated portion of
• Gait and limb ataxia
• Scanning dysarthria characterized by a drawn-out slowness of speech
• Eye movement abnormalities (e.g., nystagmus, abnormal pursuit and abnormal saccades)
• Often "extracerebellar signs" including:
• Upper motor neuron findings (e.g., brisk tendon reflexes, spasticity, and Babinski sign)
• Extrapyramidal signs (e.g., tremor, dystonia and occasionally parkinson-like features)
• Brain stem signs (e.g., dysphagia and poor cough reflex)
• Sensory neuropathy (e.g., loss of sensation and loss of tendon reflexes in distal limbs)
• Cognitive features (e.g., executive dysfunction, psychomotor slowing, and other features of cerebellar cognitive-affective disorder in some)
• Upper motor neuron findings (e.g., brisk tendon reflexes, spasticity, and Babinski sign)
• Extrapyramidal signs (e.g., tremor, dystonia and occasionally parkinson-like features)
• Brain stem signs (e.g., dysphagia and poor cough reflex)
• Sensory neuropathy (e.g., loss of sensation and loss of tendon reflexes in distal limbs)
• Cognitive features (e.g., executive dysfunction, psychomotor slowing, and other features of cerebellar cognitive-affective disorder in some)
• Upper motor neuron findings (e.g., brisk tendon reflexes, spasticity, and Babinski sign)
• Extrapyramidal signs (e.g., tremor, dystonia and occasionally parkinson-like features)
• Brain stem signs (e.g., dysphagia and poor cough reflex)
• Sensory neuropathy (e.g., loss of sensation and loss of tendon reflexes in distal limbs)
• Cognitive features (e.g., executive dysfunction, psychomotor slowing, and other features of cerebellar cognitive-affective disorder in some)
## Suggestive Findings
Spinocerebellar ataxia type 8 (SCA8)
Gait and limb ataxia
Scanning dysarthria characterized by a drawn-out slowness of speech
Eye movement abnormalities (e.g., nystagmus, abnormal pursuit and abnormal saccades)
Often "extracerebellar signs" including:
Upper motor neuron findings (e.g., brisk tendon reflexes, spasticity, and Babinski sign)
Extrapyramidal signs (e.g., tremor, dystonia and occasionally parkinson-like features)
Brain stem signs (e.g., dysphagia and poor cough reflex)
Sensory neuropathy (e.g., loss of sensation and loss of tendon reflexes in distal limbs)
Cognitive features (e.g., executive dysfunction, psychomotor slowing, and other features of cerebellar cognitive-affective disorder in some)
The absence of an autosomal dominant family history of disease should not be used to rule out a diagnosis of SCA8.
Note: Affected individuals homozygous for repeat expansions have also been reported in the literature, suggesting that two expansion alleles may further increase risk.
• Gait and limb ataxia
• Scanning dysarthria characterized by a drawn-out slowness of speech
• Eye movement abnormalities (e.g., nystagmus, abnormal pursuit and abnormal saccades)
• Often "extracerebellar signs" including:
• Upper motor neuron findings (e.g., brisk tendon reflexes, spasticity, and Babinski sign)
• Extrapyramidal signs (e.g., tremor, dystonia and occasionally parkinson-like features)
• Brain stem signs (e.g., dysphagia and poor cough reflex)
• Sensory neuropathy (e.g., loss of sensation and loss of tendon reflexes in distal limbs)
• Cognitive features (e.g., executive dysfunction, psychomotor slowing, and other features of cerebellar cognitive-affective disorder in some)
• Upper motor neuron findings (e.g., brisk tendon reflexes, spasticity, and Babinski sign)
• Extrapyramidal signs (e.g., tremor, dystonia and occasionally parkinson-like features)
• Brain stem signs (e.g., dysphagia and poor cough reflex)
• Sensory neuropathy (e.g., loss of sensation and loss of tendon reflexes in distal limbs)
• Cognitive features (e.g., executive dysfunction, psychomotor slowing, and other features of cerebellar cognitive-affective disorder in some)
• Upper motor neuron findings (e.g., brisk tendon reflexes, spasticity, and Babinski sign)
• Extrapyramidal signs (e.g., tremor, dystonia and occasionally parkinson-like features)
• Brain stem signs (e.g., dysphagia and poor cough reflex)
• Sensory neuropathy (e.g., loss of sensation and loss of tendon reflexes in distal limbs)
• Cognitive features (e.g., executive dysfunction, psychomotor slowing, and other features of cerebellar cognitive-affective disorder in some)
## Establishing the Diagnosis
The diagnosis of SCA8
Molecular genetic testing relies on targeted analysis to characterize the number of
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 8
See
See
Note: Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in these genes.
Trinucleotide repeat expansion located within two overlapping genes: an untranslated portion of
## Repeat Sizes
## Molecular Genetic Testing
Molecular genetic testing relies on targeted analysis to characterize the number of
Molecular Genetic Testing Used in Spinocerebellar Ataxia Type 8
See
See
Note: Sequence-based multigene panels, exome sequencing, and genome sequencing cannot detect pathogenic repeat expansions in these genes.
Trinucleotide repeat expansion located within two overlapping genes: an untranslated portion of
## Clinical Characteristics
SCA8 is a slowly progressive ataxia with onset typically in adulthood (range: neonatal period to age 73 years) [
Persons with adult onset typically exhibit cerebellar signs (e.g., nystagmus, abnormal pursuit and saccadic eye movement) and gait and limb ataxia indicated by a broad-based gait and abnormal finger-to-nose, finger-chase, and heel-to-shin maneuvers. These are often associated with additional neurologic signs [unpublished data and
Dysphagia can be a significant complication [
Select Features of Spinocerebellar Ataxia Type 8
++ = feature present in >80% of individuals; ++ = present in 30%-50% of individuals; + = present in <20% of individuals
Although a number of atypical findings have been reported in individuals with (CTG
Parkinson-like features [
Multiple-system atrophy [
Severe childhood onset (<20 years) including neonatal onset with cognitive difficulties associated with ataxia and cerebellar atrophy on brain imaging observed in a proportion of individuals without other identified disorders [
Amyotrophic lateral sclerosis [
Oromandibular and lingual dystonia (in 1 individual). Persons with oromandibular or lingual dystonia may have increased chewing and swallowing problems.
Respiratory muscle weakness (uncommon) [
Seizure-like episodes (highly unusual; reported in 1 individual) [
In one individual in whom serial MRI scans were performed nine years apart, little progression in the cerebellar atrophy was observed [
Mild cerebellar atrophy was observed in an asymptomatic male age 71 years with a (CTG
Compared to the ages of onset of individuals heterozygous for a (CTG
The true penetrance of the combined (CTA
A number of independent studies have shown that greater than 90 combined (CTA
In a large family (MN-A [
Analysis of additional families showed that the pathogenic repeat expansion range varied substantially among families, and that repeat length could not be used to predict whether an asymptomatic individual would subsequently develop disease manifestations [
There are no epidemiologic studies of the frequency of (CTA
SCA8 is thought to account for 2%-5% of autosomal dominant inherited ataxia. Because of reduced penetrance, the prevalence of SCA8 is far lower than expected based on observed frequency of (CTA
The frequency of expansions greater than ~90 repeats is higher in persons with ataxia than in the general population [
The prevalence of a (CTG
• Parkinson-like features [
• Multiple-system atrophy [
• Severe childhood onset (<20 years) including neonatal onset with cognitive difficulties associated with ataxia and cerebellar atrophy on brain imaging observed in a proportion of individuals without other identified disorders [
• Amyotrophic lateral sclerosis [
• Oromandibular and lingual dystonia (in 1 individual). Persons with oromandibular or lingual dystonia may have increased chewing and swallowing problems.
• Respiratory muscle weakness (uncommon) [
• Seizure-like episodes (highly unusual; reported in 1 individual) [
• A number of independent studies have shown that greater than 90 combined (CTA
• In a large family (MN-A [
## Clinical Description
SCA8 is a slowly progressive ataxia with onset typically in adulthood (range: neonatal period to age 73 years) [
Persons with adult onset typically exhibit cerebellar signs (e.g., nystagmus, abnormal pursuit and saccadic eye movement) and gait and limb ataxia indicated by a broad-based gait and abnormal finger-to-nose, finger-chase, and heel-to-shin maneuvers. These are often associated with additional neurologic signs [unpublished data and
Dysphagia can be a significant complication [
Select Features of Spinocerebellar Ataxia Type 8
++ = feature present in >80% of individuals; ++ = present in 30%-50% of individuals; + = present in <20% of individuals
Although a number of atypical findings have been reported in individuals with (CTG
Parkinson-like features [
Multiple-system atrophy [
Severe childhood onset (<20 years) including neonatal onset with cognitive difficulties associated with ataxia and cerebellar atrophy on brain imaging observed in a proportion of individuals without other identified disorders [
Amyotrophic lateral sclerosis [
Oromandibular and lingual dystonia (in 1 individual). Persons with oromandibular or lingual dystonia may have increased chewing and swallowing problems.
Respiratory muscle weakness (uncommon) [
Seizure-like episodes (highly unusual; reported in 1 individual) [
In one individual in whom serial MRI scans were performed nine years apart, little progression in the cerebellar atrophy was observed [
Mild cerebellar atrophy was observed in an asymptomatic male age 71 years with a (CTG
• Parkinson-like features [
• Multiple-system atrophy [
• Severe childhood onset (<20 years) including neonatal onset with cognitive difficulties associated with ataxia and cerebellar atrophy on brain imaging observed in a proportion of individuals without other identified disorders [
• Amyotrophic lateral sclerosis [
• Oromandibular and lingual dystonia (in 1 individual). Persons with oromandibular or lingual dystonia may have increased chewing and swallowing problems.
• Respiratory muscle weakness (uncommon) [
• Seizure-like episodes (highly unusual; reported in 1 individual) [
## Genotype-Phenotype Correlations
Compared to the ages of onset of individuals heterozygous for a (CTG
## Penetrance
The true penetrance of the combined (CTA
A number of independent studies have shown that greater than 90 combined (CTA
In a large family (MN-A [
Analysis of additional families showed that the pathogenic repeat expansion range varied substantially among families, and that repeat length could not be used to predict whether an asymptomatic individual would subsequently develop disease manifestations [
• A number of independent studies have shown that greater than 90 combined (CTA
• In a large family (MN-A [
## Anticipation
## Prevalence
There are no epidemiologic studies of the frequency of (CTA
SCA8 is thought to account for 2%-5% of autosomal dominant inherited ataxia. Because of reduced penetrance, the prevalence of SCA8 is far lower than expected based on observed frequency of (CTA
The frequency of expansions greater than ~90 repeats is higher in persons with ataxia than in the general population [
The prevalence of a (CTG
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Individuals with spinocerebellar ataxia type 8 (SCA8) may present with unexplained ataxia that is part of the larger differential diagnosis of hereditary and acquired ataxias (see
## Management
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 8 (SCA8) the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 8
CCAS scale
Psychiatrist, psychologist, neuropsychologist if needed.
Knowledge & availability of local community support or
Need for social work involvement for parental support;
Need for home nursing referral.
BARS = Brief Ataxia Rating Scale; CCAS = cerebellar cognitive affective syndrome; ICARS = International Co-operative Ataxia Rating Scale; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no specific treatment for SCA8. The goals of treatment are to maximize function and reduce complications.
It is recommended that affected individuals be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech and language therapists, and psychologists depending on the clinical manifestations.
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 8
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADL
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs).
Inpatient rehab w/OT/PT may improve ataxia & functional abilities in those w/degenerative ataxias.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Abnormal eye movements may respond to 4-aminopyridine, baclofen, or memantine.
Prisms may be used to obviate diplopia.
Video esophagram may help define best food consistency.
Sensory stimulation (e.g., putting an item such as a straw in the mouth) may ↓ involuntary movements & improve articulation, chewing &/or swallowing.
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist; UMN = upper motor neuron
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 8
Neurologic assessment for progression of ataxia, UMN signs
Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia & spasticity
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Alcohol should be avoided because it can exacerbate problems with incoordination.
See
Troriluzole is in a Phase III clinical trial (
Ongoing preclinical studies are being performed in SCA8 animal models to assess possible benefits of therapies that target the pathogenic (CTA
Because it is possible that therapeutic strategies successful for one spinocerebellar ataxia caused by an abnormal nucleotide repeat expansion could apply to other SCAs, it is important to prepare for eventual clinical trial studies by establishing key outcome measures for affected individuals.
Search
• CCAS scale
• Psychiatrist, psychologist, neuropsychologist if needed.
• Knowledge & availability of local community support or
• Need for social work involvement for parental support;
• Need for home nursing referral.
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs).
• Inpatient rehab w/OT/PT may improve ataxia & functional abilities in those w/degenerative ataxias.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Abnormal eye movements may respond to 4-aminopyridine, baclofen, or memantine.
• Prisms may be used to obviate diplopia.
• Video esophagram may help define best food consistency.
• Sensory stimulation (e.g., putting an item such as a straw in the mouth) may ↓ involuntary movements & improve articulation, chewing &/or swallowing.
• Neurologic assessment for progression of ataxia, UMN signs
• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
• Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia & spasticity
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with spinocerebellar ataxia type 8 (SCA8) the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Spinocerebellar Ataxia Type 8
CCAS scale
Psychiatrist, psychologist, neuropsychologist if needed.
Knowledge & availability of local community support or
Need for social work involvement for parental support;
Need for home nursing referral.
BARS = Brief Ataxia Rating Scale; CCAS = cerebellar cognitive affective syndrome; ICARS = International Co-operative Ataxia Rating Scale; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• CCAS scale
• Psychiatrist, psychologist, neuropsychologist if needed.
• Knowledge & availability of local community support or
• Need for social work involvement for parental support;
• Need for home nursing referral.
## Treatment of Manifestations
There is no specific treatment for SCA8. The goals of treatment are to maximize function and reduce complications.
It is recommended that affected individuals be managed by a multidisciplinary team of relevant specialists such as neurologists, occupational therapists, physical therapists, physiatrists, orthopedists, nutritionists, speech and language therapists, and psychologists depending on the clinical manifestations.
Treatment of Manifestations in Individuals with Spinocerebellar Ataxia Type 8
PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
OT to optimize ADL
Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs).
Inpatient rehab w/OT/PT may improve ataxia & functional abilities in those w/degenerative ataxias.
Weight control to avoid obesity
Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
Abnormal eye movements may respond to 4-aminopyridine, baclofen, or memantine.
Prisms may be used to obviate diplopia.
Video esophagram may help define best food consistency.
Sensory stimulation (e.g., putting an item such as a straw in the mouth) may ↓ involuntary movements & improve articulation, chewing &/or swallowing.
ADL = activities of daily living; OT = occupational therapy/therapist; PT = physical therapy/therapist; UMN = upper motor neuron
• PT (balance exercises, gait training, muscle strengthening) to maintain mobility & function
• OT to optimize ADL
• Consider adaptive devices to maintain/improve independence in mobility (e.g., canes, walkers, ramps to accommodate motorized chairs).
• Inpatient rehab w/OT/PT may improve ataxia & functional abilities in those w/degenerative ataxias.
• Weight control to avoid obesity
• Home adaptations to prevent falls (e.g., grab bars, raised toilet seats)
• Abnormal eye movements may respond to 4-aminopyridine, baclofen, or memantine.
• Prisms may be used to obviate diplopia.
• Video esophagram may help define best food consistency.
• Sensory stimulation (e.g., putting an item such as a straw in the mouth) may ↓ involuntary movements & improve articulation, chewing &/or swallowing.
## Surveillance
Recommended Surveillance for Individuals with Spinocerebellar Ataxia Type 8
Neurologic assessment for progression of ataxia, UMN signs
Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia & spasticity
BARS = Brief Ataxia Rating Scale; ICARS = International Co-operative Ataxia Rating Scale; OT = occupational therapy; PT = physical therapy; SARA = Scale for the Assessment and Rating of Ataxia; UMN = upper motor neuron
• Neurologic assessment for progression of ataxia, UMN signs
• Monitor ataxia progression w/standardized scale (SARA, ICARS, or BARS).
• Physiatry, OT/PT assessment of mobility, self-help skills as they relate to ataxia & spasticity
## Agents/Circumstances to Avoid
Alcohol should be avoided because it can exacerbate problems with incoordination.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Troriluzole is in a Phase III clinical trial (
Ongoing preclinical studies are being performed in SCA8 animal models to assess possible benefits of therapies that target the pathogenic (CTA
Because it is possible that therapeutic strategies successful for one spinocerebellar ataxia caused by an abnormal nucleotide repeat expansion could apply to other SCAs, it is important to prepare for eventual clinical trial studies by establishing key outcome measures for affected individuals.
Search
## Genetic Counseling
Spinocerebellar ataxia type 8 (SCA8) is inherited in an autosomal dominant manner.
Note: Because the penetrance of SCA8 is reduced, it is common for a proband to represent a simplex case (i.e., the only affected family member) or, alternatively, the family history of a proband may appear to be consistent with autosomal recessive inheritance because of multiple affected sibs in a single generation.
To date, all individuals diagnosed with SCA8 whose parents have been evaluated with molecular genetic testing have one parent with an
The transmitting parent may or may not have clinical manifestations of SCA8 depending on the size of the combined (CTA
If neither of the parents of the proband is known to have SCA8, recommendations for the evaluation of parents include targeted analysis for the SCA8 (CTA
The family history of some individuals diagnosed with SCA8 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the (CTG
If a parent of the proband is known to have a (CTG
Sibs who inherit a (CTG
The (CTG
Each child of an individual with a (CTG
If the proband is female, the (CTG
Note: If neither parent of a proband with SCA8 has a (CTG
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
Because of reduced penetrance and disease complexity, the combined (CTA
Predictive testing for at-risk relatives is possible once molecular genetic testing has identified a (CTG
If a (CTG
If a (CTG
The true penetrance of the combined (CTA
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 SCA8, it is appropriate to consider testing of symptomatic individuals regardless of age.
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. For more information, see the National Society of Genetic Counselors
• To date, all individuals diagnosed with SCA8 whose parents have been evaluated with molecular genetic testing have one parent with an
• The transmitting parent may or may not have clinical manifestations of SCA8 depending on the size of the combined (CTA
• If neither of the parents of the proband is known to have SCA8, recommendations for the evaluation of parents include targeted analysis for the SCA8 (CTA
• The family history of some individuals diagnosed with SCA8 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the (CTG
• If a parent of the proband is known to have a (CTG
• Sibs who inherit a (CTG
• The (CTG
• Each child of an individual with a (CTG
• If the proband is female, the (CTG
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
• Because of reduced penetrance and disease complexity, the combined (CTA
• Predictive testing for at-risk relatives is possible once molecular genetic testing has identified a (CTG
• If a (CTG
• If a (CTG
• The true penetrance of the combined (CTA
• If a (CTG
• If a (CTG
• The true penetrance of the combined (CTA
• 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.
• If a (CTG
• If a (CTG
• The true penetrance of the combined (CTA
• 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
Spinocerebellar ataxia type 8 (SCA8) is inherited in an autosomal dominant manner.
Note: Because the penetrance of SCA8 is reduced, it is common for a proband to represent a simplex case (i.e., the only affected family member) or, alternatively, the family history of a proband may appear to be consistent with autosomal recessive inheritance because of multiple affected sibs in a single generation.
## Risk to Family Members
To date, all individuals diagnosed with SCA8 whose parents have been evaluated with molecular genetic testing have one parent with an
The transmitting parent may or may not have clinical manifestations of SCA8 depending on the size of the combined (CTA
If neither of the parents of the proband is known to have SCA8, recommendations for the evaluation of parents include targeted analysis for the SCA8 (CTA
The family history of some individuals diagnosed with SCA8 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the (CTG
If a parent of the proband is known to have a (CTG
Sibs who inherit a (CTG
The (CTG
Each child of an individual with a (CTG
If the proband is female, the (CTG
• To date, all individuals diagnosed with SCA8 whose parents have been evaluated with molecular genetic testing have one parent with an
• The transmitting parent may or may not have clinical manifestations of SCA8 depending on the size of the combined (CTA
• If neither of the parents of the proband is known to have SCA8, recommendations for the evaluation of parents include targeted analysis for the SCA8 (CTA
• The family history of some individuals diagnosed with SCA8 may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance, early death of the parent before the onset of manifestations, or late onset of the disease in the affected parent. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has demonstrated that neither parent is heterozygous for the (CTG
• If a parent of the proband is known to have a (CTG
• Sibs who inherit a (CTG
• The (CTG
• Each child of an individual with a (CTG
• If the proband is female, the (CTG
## Related Genetic Counseling Issues
Note: If neither parent of a proband with SCA8 has a (CTG
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
Because of reduced penetrance and disease complexity, the combined (CTA
Predictive testing for at-risk relatives is possible once molecular genetic testing has identified a (CTG
If a (CTG
If a (CTG
The true penetrance of the combined (CTA
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 SCA8, 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.
• Because of reduced penetrance and disease complexity, the combined (CTA
• Predictive testing for at-risk relatives is possible once molecular genetic testing has identified a (CTG
• If a (CTG
• If a (CTG
• The true penetrance of the combined (CTA
• If a (CTG
• If a (CTG
• The true penetrance of the combined (CTA
• 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.
• If a (CTG
• If a (CTG
• The true penetrance of the combined (CTA
• 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 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. For more information, see the National Society of Genetic Counselors
## Resources
United Kingdom
United Kingdom
Spain
Sanford Research
•
•
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
• Spain
•
•
• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia Type 8: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia Type 8 (
The role of (CTG
This repeat sequence is located in both the 3' untranslated region of
The CTG
CUG expansion transcripts (
CAG expansion transcripts (
CAG expansion transcripts (
CTG
Adjacent CTA
Interruptions w/in CTG
Persons w/SCA8 have been shown to have both pure CTG
The (CTG
The (CTG
Methods to Characterize
CTG
The design of an 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 alleles in the normal range.
Methods of expanded repeat analysis to detect and approximate the size of expanded repeats include long-range PCR sized by gel electrophoresis and Southern blotting.
The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/or patient as a result of competition by the normal allele during amplification.
Detection of an apparently homozygous normal allele does not rule out the presence of an expanded (CTA
Southern blotting for the CAG repeat expansion has been described [
Precise sizing of repeats is not necessary as clinical utility for determining the exact repeat number has not been demonstrated.
The clinical significance of SCA8 alleles in the 51-70 repeat range is currently unclear but repeats in this range appear to be less likely to result in disease.
RP-PCR (referred to as triplet-primed PCR; TP-PCR) for the CAG repeat expansion has been described [
Repeats at the lower end of this range may not show the characteristic stutter pattern that indicates an expanded repeat.
• CUG expansion transcripts (
• CAG expansion transcripts (
• CAG expansion transcripts (
• CTG
• Adjacent CTA
• Interruptions w/in CTG
• Persons w/SCA8 have been shown to have both pure CTG
• The (CTG
• The (CTG
## Molecular Pathogenesis
The role of (CTG
This repeat sequence is located in both the 3' untranslated region of
The CTG
CUG expansion transcripts (
CAG expansion transcripts (
CAG expansion transcripts (
CTG
Adjacent CTA
Interruptions w/in CTG
Persons w/SCA8 have been shown to have both pure CTG
The (CTG
The (CTG
Methods to Characterize
CTG
The design of an 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 alleles in the normal range.
Methods of expanded repeat analysis to detect and approximate the size of expanded repeats include long-range PCR sized by gel electrophoresis and Southern blotting.
The upper limit of repeat size detected will vary by assay design, laboratory, sample, and/or patient as a result of competition by the normal allele during amplification.
Detection of an apparently homozygous normal allele does not rule out the presence of an expanded (CTA
Southern blotting for the CAG repeat expansion has been described [
Precise sizing of repeats is not necessary as clinical utility for determining the exact repeat number has not been demonstrated.
The clinical significance of SCA8 alleles in the 51-70 repeat range is currently unclear but repeats in this range appear to be less likely to result in disease.
RP-PCR (referred to as triplet-primed PCR; TP-PCR) for the CAG repeat expansion has been described [
Repeats at the lower end of this range may not show the characteristic stutter pattern that indicates an expanded repeat.
• CUG expansion transcripts (
• CAG expansion transcripts (
• CAG expansion transcripts (
• CTG
• Adjacent CTA
• Interruptions w/in CTG
• Persons w/SCA8 have been shown to have both pure CTG
• The (CTG
• The (CTG
## Chapter Notes
University of Florida Center for NeuroGenetics:
SH Subramony's web page:
Laura PW Ranum's web page:
John Douglas Cleary's web page:
We would like to acknowledge all the SCA8 families who have donated time, materials, or knowledge to our work over the years. We would also like to acknowledge previous authors, trainees, and colleagues who have contributed to the understanding of this disorder. Our work has been funded and/or supported by the National Ataxia Foundation, National Institutes of Health, the University of Florida Foundation, and many private donors.
Fatma Ayhan, BS; University of Florida (2014-2021)John Douglas Cleary, PhD (2021-present)Joline C Dalton, MS; University of Minnesota (2001-2021)John W Day, MD, PhD; Stanford University (2001-2021)Yoshio Ikeda, MD, PhD; Gunma University Graduate School of Medicine (2001-2021)Laura PW Ranum, PhD (2001-present)SH Subramony, MD, PhD (2021-present)
22 April 2021 (bp) Comprehensive update posted live
3 April 2014 (me) Comprehensive update posted live
7 February 2007 (me) Comprehensive update posted live
15 March 2004 (me) Comprehensive update posted live
27 November 2001 (me) Review posted live
15 February 2001 (jd) Original submission
• 22 April 2021 (bp) Comprehensive update posted live
• 3 April 2014 (me) Comprehensive update posted live
• 7 February 2007 (me) Comprehensive update posted live
• 15 March 2004 (me) Comprehensive update posted live
• 27 November 2001 (me) Review posted live
• 15 February 2001 (jd) Original submission
## Author Notes
University of Florida Center for NeuroGenetics:
SH Subramony's web page:
Laura PW Ranum's web page:
John Douglas Cleary's web page:
## Acknowledgments
We would like to acknowledge all the SCA8 families who have donated time, materials, or knowledge to our work over the years. We would also like to acknowledge previous authors, trainees, and colleagues who have contributed to the understanding of this disorder. Our work has been funded and/or supported by the National Ataxia Foundation, National Institutes of Health, the University of Florida Foundation, and many private donors.
## Author History
Fatma Ayhan, BS; University of Florida (2014-2021)John Douglas Cleary, PhD (2021-present)Joline C Dalton, MS; University of Minnesota (2001-2021)John W Day, MD, PhD; Stanford University (2001-2021)Yoshio Ikeda, MD, PhD; Gunma University Graduate School of Medicine (2001-2021)Laura PW Ranum, PhD (2001-present)SH Subramony, MD, PhD (2021-present)
## Revision History
22 April 2021 (bp) Comprehensive update posted live
3 April 2014 (me) Comprehensive update posted live
7 February 2007 (me) Comprehensive update posted live
15 March 2004 (me) Comprehensive update posted live
27 November 2001 (me) Review posted live
15 February 2001 (jd) Original submission
• 22 April 2021 (bp) Comprehensive update posted live
• 3 April 2014 (me) Comprehensive update posted live
• 7 February 2007 (me) Comprehensive update posted live
• 15 March 2004 (me) Comprehensive update posted live
• 27 November 2001 (me) Review posted live
• 15 February 2001 (jd) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
|
[] |
27/11/2001
|
22/4/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
scad
|
scad
|
[
"SCADD",
"SCAD Deficiency",
"SCAD Deficiency",
"SCADD",
"Short-chain specific acyl-CoA dehydrogenase, mitochondrial",
"ACADS",
"Short-Chain Acyl-CoA Dehydrogenase Deficiency"
] |
Short-Chain Acyl-CoA Dehydrogenase Deficiency
|
Lynne Wolfe, Reena Jethva, Devin Oglesbee, Jerry Vockley
|
Summary Most infants with short-chain acyl-CoA dehydrogenase deficiency (SCADD) identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria are reported. Thus, SCADD is now viewed as a biochemical phenotype rather than a disease. A broad range of clinical findings was originally reported in those with confirmed SCADD, including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported. In a large series of affected individuals detected on metabolic evaluation for developmental delay, 20% had failure to thrive, feeding difficulties, and hypotonia; 22% had seizures; and 30% had hypotonia without seizures. In contrast, the majority of infants with SCADD have been detected by expanded newborn screening, and the great majority of these infants remain asymptomatic. As with other fatty acid oxidation deficiencies, characteristic biochemical findings of SCADD may be absent except during times of physiologic stress such as fasting and illness. A diagnosis of SCADD based on clinical findings should not preclude additional testing to look for other causes. SCADD has been defined as the presence of: Increased butyrylcarnitine (C4) concentrations in plasma and/or increased ethylmalonic acid (EMA) concentrations in urine under non-stressed conditions (on at least two occasions); AND Biallelic SCADD is inherited in an autosomal recessive manner. At conception, each sib of an individual with SCADD has a 25% chance of inheriting biallelic
|
## Diagnosis
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) has been defined as the presence of:
Increased butyrylcarnitine (C4) concentrations in plasma and/or increased ethylmalonic acid (EMA) concentrations in urine under non-stressed conditions (on at least two occasions)
AND
Biallelic
Most infants with SCADD identified through newborn screening programs have remained well, and asymptomatic relatives who meet diagnostic criteria are reported. Thus, SCADD is now viewed as a biochemical phenotype rather than a disease. Some affected individuals have been identified through metabolic evaluation for developmental delay. As with other fatty acid oxidation deficiencies, characteristic biochemical findings of SCADD may be absent except during times of physiologic stress such as fasting and illness.
Short-chain acyl CoA dehydrogenase deficiency (SCADD)
NBS for SCADD is primarily based on acylcarnitine analysis by tandem mass spectrometry to detect elevated blood C4 (butyrylcarnitine).
Note: (1) Normal ranges for isolated C4 vary from state to state, necessitating confirmatory testing consistent with the American College of Medical Genetics (ACMG)
C4 values above the cutoff reported by the screening laboratory are considered positive and require additional biochemical testing and in most cases molecular genetic testing to establish the diagnosis (see
For symptomatic individuals who were not identified on NBS, the following nonspecific clinical features and preliminary laboratory findings support a diagnosis of SCADD:
Note: Because elevations of these metabolites individually are not entirely specific to SCADD, follow-up testing to establish or rule out the diagnosis of SCADD is required (see
The diagnosis of SCADD
Note: Two common variants may lead to the biochemical phenotype, but are not clinically relevant (see
Molecular genetic testing approaches, which depend on the clinical 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. Children with the distinctive laboratory findings of SCADD described in
When NBS results and other laboratory findings suggest the diagnosis of SCADD, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of SCADD has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SCADD
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
In individuals with biochemical findings consistent with the diagnosis of SCADD [
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.
Most studies have performed only sequence analysis; therefore, no data on detection rate of gene-targeted deletion/duplication analysis are available. Given the proposed mechanism of disease, such events are likely to be rare.
• Increased butyrylcarnitine (C4) concentrations in plasma and/or increased ethylmalonic acid (EMA) concentrations in urine under non-stressed conditions (on at least two occasions)
• AND
• Biallelic
• Note: Because elevations of these metabolites individually are not entirely specific to SCADD, follow-up testing to establish or rule out the diagnosis of SCADD is required (see
• For an introduction to multigene panels click
## Suggestive Findings
Short-chain acyl CoA dehydrogenase deficiency (SCADD)
NBS for SCADD is primarily based on acylcarnitine analysis by tandem mass spectrometry to detect elevated blood C4 (butyrylcarnitine).
Note: (1) Normal ranges for isolated C4 vary from state to state, necessitating confirmatory testing consistent with the American College of Medical Genetics (ACMG)
C4 values above the cutoff reported by the screening laboratory are considered positive and require additional biochemical testing and in most cases molecular genetic testing to establish the diagnosis (see
For symptomatic individuals who were not identified on NBS, the following nonspecific clinical features and preliminary laboratory findings support a diagnosis of SCADD:
Note: Because elevations of these metabolites individually are not entirely specific to SCADD, follow-up testing to establish or rule out the diagnosis of SCADD is required (see
• Note: Because elevations of these metabolites individually are not entirely specific to SCADD, follow-up testing to establish or rule out the diagnosis of SCADD is required (see
## Positive Newborn Screening (NBS) Result
NBS for SCADD is primarily based on acylcarnitine analysis by tandem mass spectrometry to detect elevated blood C4 (butyrylcarnitine).
Note: (1) Normal ranges for isolated C4 vary from state to state, necessitating confirmatory testing consistent with the American College of Medical Genetics (ACMG)
C4 values above the cutoff reported by the screening laboratory are considered positive and require additional biochemical testing and in most cases molecular genetic testing to establish the diagnosis (see
## Symptomatic Individuals
For symptomatic individuals who were not identified on NBS, the following nonspecific clinical features and preliminary laboratory findings support a diagnosis of SCADD:
Note: Because elevations of these metabolites individually are not entirely specific to SCADD, follow-up testing to establish or rule out the diagnosis of SCADD is required (see
• Note: Because elevations of these metabolites individually are not entirely specific to SCADD, follow-up testing to establish or rule out the diagnosis of SCADD is required (see
## Establishing the Diagnosis
The diagnosis of SCADD
Note: Two common variants may lead to the biochemical phenotype, but are not clinically relevant (see
Molecular genetic testing approaches, which depend on the clinical 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. Children with the distinctive laboratory findings of SCADD described in
When NBS results and other laboratory findings suggest the diagnosis of SCADD, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the diagnosis of SCADD has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SCADD
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
In individuals with biochemical findings consistent with the diagnosis of SCADD [
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.
Most studies have performed only sequence analysis; therefore, no data on detection rate of gene-targeted deletion/duplication analysis are available. Given the proposed mechanism of disease, such events are likely to be rare.
• For an introduction to multigene panels click
## Option 1
When NBS results and other laboratory findings suggest the diagnosis of SCADD, 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 SCADD has not been considered,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SCADD
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
In individuals with biochemical findings consistent with the diagnosis of SCADD [
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.
Most studies have performed only sequence analysis; therefore, no data on detection rate of gene-targeted deletion/duplication analysis are available. Given the proposed mechanism of disease, such events are likely to be rare.
## Clinical Characteristics
A broad range of clinical findings was originally reported in those with confirmed short-chain acyl-coA dehydrogenase deficiency (SCADD), including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported.
SCADD was first reported in two neonates who had increased urinary ethylmalonic acid (EMA) excretion; the diagnosis was confirmed enzymatically in skin fibroblasts [
Since most infants with SCADD identified through newborn screening programs have been well at the time of diagnosis, the reported relationship of clinical manifestations to the deficiency of SCAD has come into question [
The most convincing study on the clinical relevance of SCADD was reported in 76 babies out of 2,632,058 screened in California over a five-year period [
All older reports on SCADD identified symptomatic individuals retrospectively; many of such reports did not differentiate between true deficiency and the presence of the
23 (20%) with failure to thrive, feeding difficulties, and hypotonia
25 (22%) with seizures
34 (30%) with hypotonia without seizures
Four individuals were asymptomatic, identified either through family studies or newborn screening programs.
In a retrospective study from the Netherlands,
In a study of ten affected individuals of Ashkenazi Jewish ancestry, eight had developmental delay and four had muscle biopsy-proven multiminicore myopathy [
As in other fatty acid oxidation disorders, characteristic biochemical findings of SCADD may be absent in affected individuals except during times of physiologic stress including fasting and illness [
Individuals with biallelic common variants (
No consistent clinical phenotype-genotype correlations have been observed. However, data have suggested a correlation between urinary levels of biomarkers (ethylmalonic acid and methylsuccinic acid) and presence of biallelic pathogenic variants versus one pathogenic and either the
Using fairly strict biochemical and molecular criteria, a birth prevalence of at least 1:50,000 has been estimated in the Netherlands [
• 23 (20%) with failure to thrive, feeding difficulties, and hypotonia
• 25 (22%) with seizures
• 34 (30%) with hypotonia without seizures
## Clinical Description
A broad range of clinical findings was originally reported in those with confirmed short-chain acyl-coA dehydrogenase deficiency (SCADD), including severe dysmorphic facial features, feeding difficulties / failure to thrive, metabolic acidosis, ketotic hypoglycemia, lethargy, developmental delay, seizures, hypotonia, dystonia, and myopathy. However, individuals with no symptoms were also reported.
SCADD was first reported in two neonates who had increased urinary ethylmalonic acid (EMA) excretion; the diagnosis was confirmed enzymatically in skin fibroblasts [
Since most infants with SCADD identified through newborn screening programs have been well at the time of diagnosis, the reported relationship of clinical manifestations to the deficiency of SCAD has come into question [
The most convincing study on the clinical relevance of SCADD was reported in 76 babies out of 2,632,058 screened in California over a five-year period [
All older reports on SCADD identified symptomatic individuals retrospectively; many of such reports did not differentiate between true deficiency and the presence of the
23 (20%) with failure to thrive, feeding difficulties, and hypotonia
25 (22%) with seizures
34 (30%) with hypotonia without seizures
Four individuals were asymptomatic, identified either through family studies or newborn screening programs.
In a retrospective study from the Netherlands,
In a study of ten affected individuals of Ashkenazi Jewish ancestry, eight had developmental delay and four had muscle biopsy-proven multiminicore myopathy [
As in other fatty acid oxidation disorders, characteristic biochemical findings of SCADD may be absent in affected individuals except during times of physiologic stress including fasting and illness [
Individuals with biallelic common variants (
• 23 (20%) with failure to thrive, feeding difficulties, and hypotonia
• 25 (22%) with seizures
• 34 (30%) with hypotonia without seizures
## Genotype-Phenotype Correlations
No consistent clinical phenotype-genotype correlations have been observed. However, data have suggested a correlation between urinary levels of biomarkers (ethylmalonic acid and methylsuccinic acid) and presence of biallelic pathogenic variants versus one pathogenic and either the
## Prevalence
Using fairly strict biochemical and molecular criteria, a birth prevalence of at least 1:50,000 has been estimated in the Netherlands [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Other disorders to consider in the differential diagnosis:
## Management
To establish the extent of disease and needs in an individual diagnosed with short-chain acyl-coA dehydrogenase deficiency (SCADD), the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended.
Once a molecular diagnosis of SCAD deficiency is made, there is no need for additional clinical evaluation or further follow up.
Since SCADD is now viewed as a biochemical phenotype rather than a disease, there is no need for treatment.
Given the paucity of research, especially long-term follow-up studies, enrollment in a long-term follow-up study with a biochemical geneticist can be offered.
Preventive measures if necessary include avoidance of fasting longer than 12 hours (during childhood) and an age-appropriate heart-healthy diet. For infants and toddlers, age-appropriate shorter limits on fasting periods would be required. No dietary fat restriction or specific supplements are recommended in SCADD [
Longitudinal follow up of persons with SCADD on a research basis, including annual visits to a metabolic clinic to assess growth and development as well as nutritional status (protein and iron stores, concentration of RBC or plasma essential fatty acids, and plasma carnitine concentration), may be helpful in order to more clearly define the natural history over the life span.
See
Search
## Evaluations Following Initial Diagnosis
Once a molecular diagnosis of SCAD deficiency is made, there is no need for additional clinical evaluation or further follow up.
## Treatment of Manifestations
Since SCADD is now viewed as a biochemical phenotype rather than a disease, there is no need for treatment.
Given the paucity of research, especially long-term follow-up studies, enrollment in a long-term follow-up study with a biochemical geneticist can be offered.
## Prevention of Primary Manifestations
Preventive measures if necessary include avoidance of fasting longer than 12 hours (during childhood) and an age-appropriate heart-healthy diet. For infants and toddlers, age-appropriate shorter limits on fasting periods would be required. No dietary fat restriction or specific supplements are recommended in SCADD [
## Surveillance
Longitudinal follow up of persons with SCADD on a research basis, including annual visits to a metabolic clinic to assess growth and development as well as nutritional status (protein and iron stores, concentration of RBC or plasma essential fatty acids, and plasma carnitine concentration), may be helpful in order to more clearly define the natural history over the life span.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is inherited in an autosomal recessive manner.
The parents of a child with SCADD are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical findings related to SCADD.
At conception, each sib of an individual with SCADD has a 25% chance of inheriting biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical findings related to SCADD.
Carrier testing for at-risk family members is possible 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 have SCADD, are carriers, or are at risk of being carriers.
Once the
• The parents of a child with SCADD are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical findings related to SCADD.
• At conception, each sib of an individual with SCADD has a 25% chance of inheriting biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical findings related to SCADD.
• 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 have SCADD, are carriers, or are at risk of being carriers.
## Mode of Inheritance
Short-chain acyl-CoA dehydrogenase deficiency (SCADD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of a child with SCADD are obligate heterozygotes (i.e., carriers of one
Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical findings related to SCADD.
At conception, each sib of an individual with SCADD has a 25% chance of inheriting biallelic
Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical findings related to SCADD.
• The parents of a child with SCADD are obligate heterozygotes (i.e., carriers of one
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical findings related to SCADD.
• At conception, each sib of an individual with SCADD has a 25% chance of inheriting biallelic
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing clinical findings related to SCADD.
## Carrier Detection
Carrier testing for at-risk family members is possible if 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 have SCADD, 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 have SCADD, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the
## Resources
United Kingdom
Health Resources & Services Administration
•
•
•
•
•
• United Kingdom
•
•
• Health Resources & Services Administration
•
•
•
## Molecular Genetics
Short-Chain Acyl-CoA Dehydrogenase Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Short-Chain Acyl-CoA Dehydrogenase Deficiency (
Possible pathogenic explanations for the observation that most individuals with short-chain acyl-CoA dehydrogenase (SCAD) deficiency do not present with the classic picture of metabolic acidosis and hypoketotic hypoglycemia characteristic of many fatty acid oxidation disorders include the following:
SCAD is only needed at the end of the β-oxidation cycle; therefore, gluconeogenesis and ketogenic capacity from the preceding steps of fatty acid oxidation may be sufficient to meet cellular energy needs [
Overlapping substrate specificity by medium-chain acyl CoA dehydrogenase (MCAD) may partially compensate for deficient SCAD activity [
While developmental delay and seizures (findings uncommon in other fatty acid oxidation defects) raise the possibility of a neurotoxic effect in SCADD directly related to metabolite accumulation [
Ethylmalonic acid (EMA) inhibits creatine kinase activity, increases lipid peroxidation and protein oxidation, and reduces glutathione levels in the cerebral cortex of Wistar rats [
EMA inhibits electron transport chain activity in vitro [
Dicarboxylic acids such as EMA do not cross the blood-brain barrier, and thus sequester in the CNS, another possible explanation of EMA toxicity resulting in neurologic findings [
EMA toxicity may play a role in the neurologic dysfunction observed in ethylmalonic encephalopathy, characterized by psychomotor delays and progressive pyramidal findings resulting from basal ganglia and white matter damage caused by accumulation of large amounts of butyrylcarnitine and EMA [
Butyric acid, which accumulates in SCADD, can modulate gene expression at high levels as a result of its action as a histone deacetylase [
Most pathogenic variants identified in persons diagnosed with SCADD, including the Ashkenazi Jewish
c.511C>T in exon 5
c.625G>A in exon 6
Both variants are relatively common in the general population.
In a study of 694 newborns in the United States, approximately 6% were c.625G>A homozygous, 0.3% were c.511C>T homozygous, and 0.9% were compound heterozygous (one allele with each variation) [
In the US, 7% of the population is estimated to be either homozygous or compound heterozygous for one of these common variants [
In one European study, 14% of controls were homozygous for one of the variants as compared to 69% of 133 subjects with increased urinary EMA excretion.
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Residue in the precursor peptide
Residue in the mature enzyme, after cleavage of the 24 N-terminal amino acids of the transit peptide that directs the protein to the mitochondria
• SCAD is only needed at the end of the β-oxidation cycle; therefore, gluconeogenesis and ketogenic capacity from the preceding steps of fatty acid oxidation may be sufficient to meet cellular energy needs [
• Overlapping substrate specificity by medium-chain acyl CoA dehydrogenase (MCAD) may partially compensate for deficient SCAD activity [
• While developmental delay and seizures (findings uncommon in other fatty acid oxidation defects) raise the possibility of a neurotoxic effect in SCADD directly related to metabolite accumulation [
• Ethylmalonic acid (EMA) inhibits creatine kinase activity, increases lipid peroxidation and protein oxidation, and reduces glutathione levels in the cerebral cortex of Wistar rats [
• EMA inhibits electron transport chain activity in vitro [
• Dicarboxylic acids such as EMA do not cross the blood-brain barrier, and thus sequester in the CNS, another possible explanation of EMA toxicity resulting in neurologic findings [
• Ethylmalonic acid (EMA) inhibits creatine kinase activity, increases lipid peroxidation and protein oxidation, and reduces glutathione levels in the cerebral cortex of Wistar rats [
• EMA inhibits electron transport chain activity in vitro [
• Dicarboxylic acids such as EMA do not cross the blood-brain barrier, and thus sequester in the CNS, another possible explanation of EMA toxicity resulting in neurologic findings [
• EMA toxicity may play a role in the neurologic dysfunction observed in ethylmalonic encephalopathy, characterized by psychomotor delays and progressive pyramidal findings resulting from basal ganglia and white matter damage caused by accumulation of large amounts of butyrylcarnitine and EMA [
• Butyric acid, which accumulates in SCADD, can modulate gene expression at high levels as a result of its action as a histone deacetylase [
• Most pathogenic variants identified in persons diagnosed with SCADD, including the Ashkenazi Jewish
• Ethylmalonic acid (EMA) inhibits creatine kinase activity, increases lipid peroxidation and protein oxidation, and reduces glutathione levels in the cerebral cortex of Wistar rats [
• EMA inhibits electron transport chain activity in vitro [
• Dicarboxylic acids such as EMA do not cross the blood-brain barrier, and thus sequester in the CNS, another possible explanation of EMA toxicity resulting in neurologic findings [
• c.511C>T in exon 5
• c.625G>A in exon 6
• In a study of 694 newborns in the United States, approximately 6% were c.625G>A homozygous, 0.3% were c.511C>T homozygous, and 0.9% were compound heterozygous (one allele with each variation) [
• In the US, 7% of the population is estimated to be either homozygous or compound heterozygous for one of these common variants [
• In one European study, 14% of controls were homozygous for one of the variants as compared to 69% of 133 subjects with increased urinary EMA excretion.
## Molecular Pathogenesis
Possible pathogenic explanations for the observation that most individuals with short-chain acyl-CoA dehydrogenase (SCAD) deficiency do not present with the classic picture of metabolic acidosis and hypoketotic hypoglycemia characteristic of many fatty acid oxidation disorders include the following:
SCAD is only needed at the end of the β-oxidation cycle; therefore, gluconeogenesis and ketogenic capacity from the preceding steps of fatty acid oxidation may be sufficient to meet cellular energy needs [
Overlapping substrate specificity by medium-chain acyl CoA dehydrogenase (MCAD) may partially compensate for deficient SCAD activity [
While developmental delay and seizures (findings uncommon in other fatty acid oxidation defects) raise the possibility of a neurotoxic effect in SCADD directly related to metabolite accumulation [
Ethylmalonic acid (EMA) inhibits creatine kinase activity, increases lipid peroxidation and protein oxidation, and reduces glutathione levels in the cerebral cortex of Wistar rats [
EMA inhibits electron transport chain activity in vitro [
Dicarboxylic acids such as EMA do not cross the blood-brain barrier, and thus sequester in the CNS, another possible explanation of EMA toxicity resulting in neurologic findings [
EMA toxicity may play a role in the neurologic dysfunction observed in ethylmalonic encephalopathy, characterized by psychomotor delays and progressive pyramidal findings resulting from basal ganglia and white matter damage caused by accumulation of large amounts of butyrylcarnitine and EMA [
Butyric acid, which accumulates in SCADD, can modulate gene expression at high levels as a result of its action as a histone deacetylase [
Most pathogenic variants identified in persons diagnosed with SCADD, including the Ashkenazi Jewish
c.511C>T in exon 5
c.625G>A in exon 6
Both variants are relatively common in the general population.
In a study of 694 newborns in the United States, approximately 6% were c.625G>A homozygous, 0.3% were c.511C>T homozygous, and 0.9% were compound heterozygous (one allele with each variation) [
In the US, 7% of the population is estimated to be either homozygous or compound heterozygous for one of these common variants [
In one European study, 14% of controls were homozygous for one of the variants as compared to 69% of 133 subjects with increased urinary EMA excretion.
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Residue in the precursor peptide
Residue in the mature enzyme, after cleavage of the 24 N-terminal amino acids of the transit peptide that directs the protein to the mitochondria
• SCAD is only needed at the end of the β-oxidation cycle; therefore, gluconeogenesis and ketogenic capacity from the preceding steps of fatty acid oxidation may be sufficient to meet cellular energy needs [
• Overlapping substrate specificity by medium-chain acyl CoA dehydrogenase (MCAD) may partially compensate for deficient SCAD activity [
• While developmental delay and seizures (findings uncommon in other fatty acid oxidation defects) raise the possibility of a neurotoxic effect in SCADD directly related to metabolite accumulation [
• Ethylmalonic acid (EMA) inhibits creatine kinase activity, increases lipid peroxidation and protein oxidation, and reduces glutathione levels in the cerebral cortex of Wistar rats [
• EMA inhibits electron transport chain activity in vitro [
• Dicarboxylic acids such as EMA do not cross the blood-brain barrier, and thus sequester in the CNS, another possible explanation of EMA toxicity resulting in neurologic findings [
• Ethylmalonic acid (EMA) inhibits creatine kinase activity, increases lipid peroxidation and protein oxidation, and reduces glutathione levels in the cerebral cortex of Wistar rats [
• EMA inhibits electron transport chain activity in vitro [
• Dicarboxylic acids such as EMA do not cross the blood-brain barrier, and thus sequester in the CNS, another possible explanation of EMA toxicity resulting in neurologic findings [
• EMA toxicity may play a role in the neurologic dysfunction observed in ethylmalonic encephalopathy, characterized by psychomotor delays and progressive pyramidal findings resulting from basal ganglia and white matter damage caused by accumulation of large amounts of butyrylcarnitine and EMA [
• Butyric acid, which accumulates in SCADD, can modulate gene expression at high levels as a result of its action as a histone deacetylase [
• Most pathogenic variants identified in persons diagnosed with SCADD, including the Ashkenazi Jewish
• Ethylmalonic acid (EMA) inhibits creatine kinase activity, increases lipid peroxidation and protein oxidation, and reduces glutathione levels in the cerebral cortex of Wistar rats [
• EMA inhibits electron transport chain activity in vitro [
• Dicarboxylic acids such as EMA do not cross the blood-brain barrier, and thus sequester in the CNS, another possible explanation of EMA toxicity resulting in neurologic findings [
• c.511C>T in exon 5
• c.625G>A in exon 6
• In a study of 694 newborns in the United States, approximately 6% were c.625G>A homozygous, 0.3% were c.511C>T homozygous, and 0.9% were compound heterozygous (one allele with each variation) [
• In the US, 7% of the population is estimated to be either homozygous or compound heterozygous for one of these common variants [
• In one European study, 14% of controls were homozygous for one of the variants as compared to 69% of 133 subjects with increased urinary EMA excretion.
## Chapter Notes
The American College of Medical Genetics has published online an algorithm delineating the appropriate response to an elevated C4 on newborn screening (
9 August 2018 (ha) Comprehensive update posted live
7 August 2014 (me) Comprehensive update posted live
22 September 2011 (me) Review posted live
21 March 2011 (lw) Original submission
• 9 August 2018 (ha) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 22 September 2011 (me) Review posted live
• 21 March 2011 (lw) Original submission
## Author Notes
The American College of Medical Genetics has published online an algorithm delineating the appropriate response to an elevated C4 on newborn screening (
## Revision History
9 August 2018 (ha) Comprehensive update posted live
7 August 2014 (me) Comprehensive update posted live
22 September 2011 (me) Review posted live
21 March 2011 (lw) Original submission
• 9 August 2018 (ha) Comprehensive update posted live
• 7 August 2014 (me) Comprehensive update posted live
• 22 September 2011 (me) Review posted live
• 21 March 2011 (lw) Original submission
## References
## Literature Cited
|
[] |
22/9/2011
|
9/8/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
scan1
|
scan1
|
[
"SCAN1, TDP1-Related Spinocerebellar Ataxia with Axonal Neuropathy",
"SCAN1",
"TDP1-Related Spinocerebellar Ataxia with Axonal Neuropathy",
"Tyrosyl-DNA phosphodiesterase 1",
"TDP1",
"Spinocerebellar Ataxia with Axonal Neuropathy Type 1"
] |
Spinocerebellar Ataxia with Axonal Neuropathy Type 1
|
Mustafa AM Salih, Hiroshi Takashima, Cornelius F Boerkoel
|
Summary Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is characterized by late-childhood-onset slowly progressive cerebellar ataxia and distal sensorimotor axonal neuropathy. Gaze nystagmus and dysarthria usually develop after the onset of ataxic gait. As the disease advances, pain and touch sensation in the hands and feet become impaired; vibration sense is lost in hands and lower thighs. Individuals with advanced disease develop a steppage gait and pes cavus and eventually become wheelchair dependent. Cognitive dysfunction – present in some – manifests as mild intellectual disability and poor executive function. To date only seven affected individuals have been described from three apparently unrelated consanguineous families (one from Saudi Arabia and two from Oman); therefore, it is likely that the full phenotypic spectrum of this disorder is not yet known. The diagnosis of SCAN1 is established in a proband with suggestive findings and biallelic pathogenic (or likely pathogenic) variants in SCAN1 is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) have been published.
SCAN1 is suspected in individuals with the following clinical findings, electrophysiologic studies, laboratory findings, brain imaging, and family history [
Slowly progressive disorder beginning in late childhood to early adulthood (ages 13-27 years)
Cerebellar ataxia manifesting initially as gait ataxia and subsequently as dysarthria
Distal sensorimotor neuropathy manifesting initially as areflexia and subsequently as weakness and loss of sensation
Cognitive dysfunction in some, manifesting as mild intellectual disability and poor executive function
Absence of:
Oculomotor apraxia
Extraneurologic findings
The diagnosis of SCAN1
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 SCAN1 is indistinguishable from many other inherited disorders with ataxia, recommended molecular genetic testing approaches include use of a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spinocerebellar Ataxia with Axonal Neuropathy Type 1
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.
• Slowly progressive disorder beginning in late childhood to early adulthood (ages 13-27 years)
• Cerebellar ataxia manifesting initially as gait ataxia and subsequently as dysarthria
• Distal sensorimotor neuropathy manifesting initially as areflexia and subsequently as weakness and loss of sensation
• Cognitive dysfunction in some, manifesting as mild intellectual disability and poor executive function
• Absence of:
• Oculomotor apraxia
• Extraneurologic findings
• Oculomotor apraxia
• Extraneurologic findings
• Oculomotor apraxia
• Extraneurologic findings
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
SCAN1 is suspected in individuals with the following clinical findings, electrophysiologic studies, laboratory findings, brain imaging, and family history [
Slowly progressive disorder beginning in late childhood to early adulthood (ages 13-27 years)
Cerebellar ataxia manifesting initially as gait ataxia and subsequently as dysarthria
Distal sensorimotor neuropathy manifesting initially as areflexia and subsequently as weakness and loss of sensation
Cognitive dysfunction in some, manifesting as mild intellectual disability and poor executive function
Absence of:
Oculomotor apraxia
Extraneurologic findings
• Slowly progressive disorder beginning in late childhood to early adulthood (ages 13-27 years)
• Cerebellar ataxia manifesting initially as gait ataxia and subsequently as dysarthria
• Distal sensorimotor neuropathy manifesting initially as areflexia and subsequently as weakness and loss of sensation
• Cognitive dysfunction in some, manifesting as mild intellectual disability and poor executive function
• Absence of:
• Oculomotor apraxia
• Extraneurologic findings
• Oculomotor apraxia
• Extraneurologic findings
• Oculomotor apraxia
• Extraneurologic findings
## Establishing the Diagnosis
The diagnosis of SCAN1
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 SCAN1 is indistinguishable from many other inherited disorders with ataxia, recommended molecular genetic testing approaches include use of a
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Spinocerebellar Ataxia with Axonal Neuropathy Type 1
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
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is characterized by progressive ataxia, cerebellar atrophy, and distal sensorimotor axonal neuropathy based on findings in three persons in a consanguineous family from Saudi Arabia [
Horizontal gaze-evoked nystagmus and mild dysarthria usually develop after the onset of ataxic gait.
Deep tendon reflexes are lost in the third decade of life.
Sensory function is initially preserved. As the disease advances, pain, cold, and touch sensations become severely impaired in the hands and lower thigh. Vibration sense disappears in the hands and legs.
In the advanced stages of the disease, affected persons develop a steppage gait and pes cavus.
Dysphagia develops with progression of the cerebellar ataxia.
No genotype-phenotype correlations are known as the data available are too limited [
SCAN1 may also be referred to as "
Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is very rare.
To date, one extended family from Saudi Arabia with nine affected individuals [
## Clinical Description
Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is characterized by progressive ataxia, cerebellar atrophy, and distal sensorimotor axonal neuropathy based on findings in three persons in a consanguineous family from Saudi Arabia [
Horizontal gaze-evoked nystagmus and mild dysarthria usually develop after the onset of ataxic gait.
Deep tendon reflexes are lost in the third decade of life.
Sensory function is initially preserved. As the disease advances, pain, cold, and touch sensations become severely impaired in the hands and lower thigh. Vibration sense disappears in the hands and legs.
In the advanced stages of the disease, affected persons develop a steppage gait and pes cavus.
Dysphagia develops with progression of the cerebellar ataxia.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are known as the data available are too limited [
## Nomenclature
SCAN1 may also be referred to as "
## Prevalence
Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) is very rare.
To date, one extended family from Saudi Arabia with nine affected individuals [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Spinocerebellar Ataxia with Axonal Neuropathy Type 1
Adapted from
AR = autosomal recessive; ID = intellectual disability; MOI = mode of inheritance; RP = retinitis pigmentosa; SCAN1 = spinocerebellar ataxia with axonal neuropathy type 1
The ataxia neuropathy spectrum (ANS) includes the phenotypes previously referred to as mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO).
## Management
No clinical practice guidelines for spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) have been published.
To establish the extent of disease and needs in an individual diagnosed with SCAN1, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Complete neurologic examination including use of the Scale for the Assessment and Rating of Ataxia (SARA) and assessment of muscle strength, reflexes, and sensation
Assessment by specialists in rehabilitation medicine, occupational therapy, and physical therapy regarding gross motor skills, fine motor skills, and need for adaptive equipment such as prostheses, walking aids, and/or wheelchairs
Assessment by a speech-language pathologist for evidence of dysarthria and need for ongoing speech-language therapy
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 SCAN1 in order to facilitate medical and personal decision making
To support the family of an individual diagnosed with SCAN1, review of the following options is recommended:
Use of community or online resources (e.g.,
Social work involvement for parental support
Home nursing referral (if needed)
Ethics consultation (clinical ethics services) to assess health care decisions in the context of the best interest of the child and the values and preferences of the family
There is no cure for SCAN1.
Supportive care is provided by specialists in neurology, rehabilitation medicine, occupational therapy, physical therapy, speech-language pathology, and clinical genetics.
Physical therapy may be helpful in maintaining a more active lifestyle.
Routine follow up as determined by treating specialists is recommended to monitor the response to supportive care and to assess for changes in existing manifestations and/or emergence of new manifestations.
Likely to be extremely harmful and possibly fatal:
Exposure to genotoxic anti-cancer drugs such as camptothecins (e.g., irinotecan and topotecan) and bleomycin [
Exposure to radiation [
See
Search
• Complete neurologic examination including use of the Scale for the Assessment and Rating of Ataxia (SARA) and assessment of muscle strength, reflexes, and sensation
• Assessment by specialists in rehabilitation medicine, occupational therapy, and physical therapy regarding gross motor skills, fine motor skills, and need for adaptive equipment such as prostheses, walking aids, and/or wheelchairs
• Assessment by a speech-language pathologist for evidence of dysarthria and need for ongoing speech-language therapy
• 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 SCAN1 in order to facilitate medical and personal decision making
• Use of community or online resources (e.g.,
• Social work involvement for parental support
• Home nursing referral (if needed)
• Ethics consultation (clinical ethics services) to assess health care decisions in the context of the best interest of the child and the values and preferences of the family
• Exposure to genotoxic anti-cancer drugs such as camptothecins (e.g., irinotecan and topotecan) and bleomycin [
• Exposure to radiation [
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SCAN1, the evaluations summarized in this section (if not performed as part of the evaluation that led to the diagnosis) are recommended:
Complete neurologic examination including use of the Scale for the Assessment and Rating of Ataxia (SARA) and assessment of muscle strength, reflexes, and sensation
Assessment by specialists in rehabilitation medicine, occupational therapy, and physical therapy regarding gross motor skills, fine motor skills, and need for adaptive equipment such as prostheses, walking aids, and/or wheelchairs
Assessment by a speech-language pathologist for evidence of dysarthria and need for ongoing speech-language therapy
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 SCAN1 in order to facilitate medical and personal decision making
To support the family of an individual diagnosed with SCAN1, review of the following options is recommended:
Use of community or online resources (e.g.,
Social work involvement for parental support
Home nursing referral (if needed)
Ethics consultation (clinical ethics services) to assess health care decisions in the context of the best interest of the child and the values and preferences of the family
• Complete neurologic examination including use of the Scale for the Assessment and Rating of Ataxia (SARA) and assessment of muscle strength, reflexes, and sensation
• Assessment by specialists in rehabilitation medicine, occupational therapy, and physical therapy regarding gross motor skills, fine motor skills, and need for adaptive equipment such as prostheses, walking aids, and/or wheelchairs
• Assessment by a speech-language pathologist for evidence of dysarthria and need for ongoing speech-language therapy
• 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 SCAN1 in order to facilitate medical and personal decision making
• Use of community or online resources (e.g.,
• Social work involvement for parental support
• Home nursing referral (if needed)
• Ethics consultation (clinical ethics services) to assess health care decisions in the context of the best interest of the child and the values and preferences of the family
## Treatment of Manifestations
There is no cure for SCAN1.
Supportive care is provided by specialists in neurology, rehabilitation medicine, occupational therapy, physical therapy, speech-language pathology, and clinical genetics.
Physical therapy may be helpful in maintaining a more active lifestyle.
## Surveillance
Routine follow up as determined by treating specialists is recommended to monitor the response to supportive care and to assess for changes in existing manifestations and/or emergence of new manifestations.
## Agents/Circumstances to Avoid
Likely to be extremely harmful and possibly fatal:
Exposure to genotoxic anti-cancer drugs such as camptothecins (e.g., irinotecan and topotecan) and bleomycin [
Exposure to radiation [
• Exposure to genotoxic anti-cancer drugs such as camptothecins (e.g., irinotecan and topotecan) and bleomycin [
• Exposure to radiation [
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) 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.
Unless an affected individual's reproductive partner also has SCAN1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a
The offspring of an individual with SCAN1 and an individual who is heterozygous for a
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 affected, are carriers, or 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 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.
• Unless an affected individual's reproductive partner also has SCAN1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a
• The offspring of an individual with SCAN1 and an individual who is heterozygous for 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 young adults who are affected, are carriers, or at risk of being carriers.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if consanguinity is likely.
## Mode of Inheritance
Spinocerebellar ataxia with axonal neuropathy type 1 (SCAN1) 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.
Unless an affected individual's reproductive partner also has SCAN1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a
The offspring of an individual with SCAN1 and an individual who is heterozygous for a
• 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.
• Unless an affected individual's reproductive partner also has SCAN1 or is a carrier, offspring will be obligate heterozygotes (carriers) for a
• The offspring of an individual with SCAN1 and an individual who is heterozygous for a
## 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 affected, are carriers, or 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 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
United Kingdom
United Kingdom
Sanford Research
•
• United Kingdom
•
•
• United Kingdom
•
•
•
•
•
•
• Sanford Research
•
## Molecular Genetics
Spinocerebellar Ataxia with Axonal Neuropathy, Autosomal Recessive: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Spinocerebellar Ataxia with Axonal Neuropathy, Autosomal Recessive (
TDP1 contains two HKD motifs that comprise the active site of this enzyme and catalyze phosphoryl transfer reactions [
Protein modeling showed that the pathogenic variant
In the absence of wild type
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
TDP1 contains two HKD motifs that comprise the active site of this enzyme and catalyze phosphoryl transfer reactions [
Protein modeling showed that the pathogenic variant
In the absence of wild type
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Cornelius Boerkoel, MD, PhD (2007-present)Hok Khim Fam, BSc; University of British Columbia (2012-2022)Ryuki Hirano, MD, PhD; Kagoshima University (2007-2012)Mustafa AM Salih, MD, Dr Med Sci, FRCPCH (2007-present)Hiroshi Takashima, MD, PhD (2007-present)
30 June 2022 (bp) Comprehensive update posted live
26 April 2012 (me) Comprehensive update posted live
22 October 2007 (me) Review posted live
26 September 2007 (cfb) Original submission
• 30 June 2022 (bp) Comprehensive update posted live
• 26 April 2012 (me) Comprehensive update posted live
• 22 October 2007 (me) Review posted live
• 26 September 2007 (cfb) Original submission
## Author History
Cornelius Boerkoel, MD, PhD (2007-present)Hok Khim Fam, BSc; University of British Columbia (2012-2022)Ryuki Hirano, MD, PhD; Kagoshima University (2007-2012)Mustafa AM Salih, MD, Dr Med Sci, FRCPCH (2007-present)Hiroshi Takashima, MD, PhD (2007-present)
## Revision History
30 June 2022 (bp) Comprehensive update posted live
26 April 2012 (me) Comprehensive update posted live
22 October 2007 (me) Review posted live
26 September 2007 (cfb) Original submission
• 30 June 2022 (bp) Comprehensive update posted live
• 26 April 2012 (me) Comprehensive update posted live
• 22 October 2007 (me) Review posted live
• 26 September 2007 (cfb) Original submission
## References
## Literature Cited
|
[] |
22/10/2007
|
30/6/2022
|
20/12/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
schaaf-yang
|
schaaf-yang
|
[
"Chitayat-Hall Syndrome",
"Chitayat-Hall Syndrome",
"MAGE-like protein 2",
"MAGEL2",
"Schaaf-Yang Syndrome"
] |
Schaaf-Yang Syndrome
|
Christian P Schaaf, Felix Marbach
|
Summary Schaaf-Yang syndrome (SYS) is a rare neurodevelopmental disorder that shares multiple clinical features with the genetically related The diagnosis of Schaaf-Yang syndrome is established in a proband by identification of a heterozygous pathogenic variant in the paternally derived Schaaf-Yang syndrome is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the paternally derived
|
## Diagnosis
Formal clinical diagnostic criteria for Schaaf-Yang syndrome (SYS) have not been established.
SYS
Generalized hypotonia of infancy
Respiratory distress in infancy
Infant feeding difficulties with failure to thrive
Hyperphagia with subsequent obesity in childhood or adolescence
Mild-to-profound developmental delay or intellectual disability
Autism spectrum disorder or autistic features
Nonspecific dysmorphic facial features, including a pointed chin, frontal bossing, and low-set ears
Short stature
Joint contractures of variable severity, ranging from mild contractures of the distal phalanges of the hands to severe arthrogryposis multiplex congenita
Endocrinopathy, including:
Hypopituitarism
Growth hormone deficiency
Hypogonadism and/or undervirilization in males
Normal methylation analysis of the 15q11.2 region (Prader-Willi/Angelman syndrome locus)
Any of the following hormonal or metabolic findings [
Low IGF-1 levels despite normal weight and adequate nutrition
Elevated glucose levels on oral glucose tolerance testing (OGTT)
Elevated fasting ghrelin levels
The diagnosis of Schaaf-Yang syndrome
Note: (1) The 15q11.2 locus that includes
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 combination of findings described in
When the phenotypic and laboratory findings suggest the diagnosis of SYS, molecular genetic testing approaches can include
If no variant is detected by the sequencing method used, a gene-targeted deletion/duplication analysis to detect larger deletions/duplications or whole-gene deletions may be performed (e.g., by quantitative PCR, MLPA, or chromosome microarray testing). Parental/methylation-sensitive testing may be required to confirm the diagnosis.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by infantile hypotonia and/or intellectual disability, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schaaf-Yang 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 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:
Larger deletions of the paternally derived 15q11.2 region that include
A 22-kb inversion and 3-kb deletion, which removed the last 852 bp of
• Generalized hypotonia of infancy
• Respiratory distress in infancy
• Infant feeding difficulties with failure to thrive
• Hyperphagia with subsequent obesity in childhood or adolescence
• Mild-to-profound developmental delay or intellectual disability
• Autism spectrum disorder or autistic features
• Nonspecific dysmorphic facial features, including a pointed chin, frontal bossing, and low-set ears
• Short stature
• Joint contractures of variable severity, ranging from mild contractures of the distal phalanges of the hands to severe arthrogryposis multiplex congenita
• Endocrinopathy, including:
• Hypopituitarism
• Growth hormone deficiency
• Hypogonadism and/or undervirilization in males
• Hypopituitarism
• Growth hormone deficiency
• Hypogonadism and/or undervirilization in males
• Hypopituitarism
• Growth hormone deficiency
• Hypogonadism and/or undervirilization in males
• Normal methylation analysis of the 15q11.2 region (Prader-Willi/Angelman syndrome locus)
• Any of the following hormonal or metabolic findings [
• Low IGF-1 levels despite normal weight and adequate nutrition
• Elevated glucose levels on oral glucose tolerance testing (OGTT)
• Elevated fasting ghrelin levels
• Low IGF-1 levels despite normal weight and adequate nutrition
• Elevated glucose levels on oral glucose tolerance testing (OGTT)
• Elevated fasting ghrelin levels
• Low IGF-1 levels despite normal weight and adequate nutrition
• Elevated glucose levels on oral glucose tolerance testing (OGTT)
• Elevated fasting ghrelin levels
• If no variant is detected by the sequencing method used, a gene-targeted deletion/duplication analysis to detect larger deletions/duplications or whole-gene deletions may be performed (e.g., by quantitative PCR, MLPA, or chromosome microarray testing). Parental/methylation-sensitive testing may be required to confirm the diagnosis.
• For an introduction to multigene panels click
## Suggestive Findings
SYS
Generalized hypotonia of infancy
Respiratory distress in infancy
Infant feeding difficulties with failure to thrive
Hyperphagia with subsequent obesity in childhood or adolescence
Mild-to-profound developmental delay or intellectual disability
Autism spectrum disorder or autistic features
Nonspecific dysmorphic facial features, including a pointed chin, frontal bossing, and low-set ears
Short stature
Joint contractures of variable severity, ranging from mild contractures of the distal phalanges of the hands to severe arthrogryposis multiplex congenita
Endocrinopathy, including:
Hypopituitarism
Growth hormone deficiency
Hypogonadism and/or undervirilization in males
Normal methylation analysis of the 15q11.2 region (Prader-Willi/Angelman syndrome locus)
Any of the following hormonal or metabolic findings [
Low IGF-1 levels despite normal weight and adequate nutrition
Elevated glucose levels on oral glucose tolerance testing (OGTT)
Elevated fasting ghrelin levels
• Generalized hypotonia of infancy
• Respiratory distress in infancy
• Infant feeding difficulties with failure to thrive
• Hyperphagia with subsequent obesity in childhood or adolescence
• Mild-to-profound developmental delay or intellectual disability
• Autism spectrum disorder or autistic features
• Nonspecific dysmorphic facial features, including a pointed chin, frontal bossing, and low-set ears
• Short stature
• Joint contractures of variable severity, ranging from mild contractures of the distal phalanges of the hands to severe arthrogryposis multiplex congenita
• Endocrinopathy, including:
• Hypopituitarism
• Growth hormone deficiency
• Hypogonadism and/or undervirilization in males
• Hypopituitarism
• Growth hormone deficiency
• Hypogonadism and/or undervirilization in males
• Hypopituitarism
• Growth hormone deficiency
• Hypogonadism and/or undervirilization in males
• Normal methylation analysis of the 15q11.2 region (Prader-Willi/Angelman syndrome locus)
• Any of the following hormonal or metabolic findings [
• Low IGF-1 levels despite normal weight and adequate nutrition
• Elevated glucose levels on oral glucose tolerance testing (OGTT)
• Elevated fasting ghrelin levels
• Low IGF-1 levels despite normal weight and adequate nutrition
• Elevated glucose levels on oral glucose tolerance testing (OGTT)
• Elevated fasting ghrelin levels
• Low IGF-1 levels despite normal weight and adequate nutrition
• Elevated glucose levels on oral glucose tolerance testing (OGTT)
• Elevated fasting ghrelin levels
## Establishing the Diagnosis
The diagnosis of Schaaf-Yang syndrome
Note: (1) The 15q11.2 locus that includes
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 combination of findings described in
When the phenotypic and laboratory findings suggest the diagnosis of SYS, molecular genetic testing approaches can include
If no variant is detected by the sequencing method used, a gene-targeted deletion/duplication analysis to detect larger deletions/duplications or whole-gene deletions may be performed (e.g., by quantitative PCR, MLPA, or chromosome microarray testing). Parental/methylation-sensitive testing may be required to confirm the diagnosis.
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by infantile hypotonia and/or intellectual disability, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schaaf-Yang 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 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:
Larger deletions of the paternally derived 15q11.2 region that include
A 22-kb inversion and 3-kb deletion, which removed the last 852 bp of
• If no variant is detected by the sequencing method used, a gene-targeted deletion/duplication analysis to detect larger deletions/duplications or whole-gene deletions may be performed (e.g., by quantitative PCR, MLPA, or chromosome microarray testing). Parental/methylation-sensitive testing may be required to confirm the diagnosis.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of SYS, molecular genetic testing approaches can include
If no variant is detected by the sequencing method used, a gene-targeted deletion/duplication analysis to detect larger deletions/duplications or whole-gene deletions may be performed (e.g., by quantitative PCR, MLPA, or chromosome microarray testing). Parental/methylation-sensitive testing may be required to confirm the diagnosis.
For an introduction to multigene panels click
• If no variant is detected by the sequencing method used, a gene-targeted deletion/duplication analysis to detect larger deletions/duplications or whole-gene deletions may be performed (e.g., by quantitative PCR, MLPA, or chromosome microarray testing). Parental/methylation-sensitive testing may be required to confirm the diagnosis.
• For an introduction to multigene panels click
## Option 2
When the phenotype is indistinguishable from many other inherited disorders characterized by infantile hypotonia and/or intellectual disability, comprehensive genomic testing may be considered.
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schaaf-Yang 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 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:
Larger deletions of the paternally derived 15q11.2 region that include
A 22-kb inversion and 3-kb deletion, which removed the last 852 bp of
## Clinical Characteristics
Schaaf-Yang Syndrome (SYS) is a rare, paternally derived neurodevelopmental disorder that shares multiple clinical features with the genetically related
To date, more than 250 individuals have been identified with a paternally derived pathogenic variant in
Select Features of Schaaf-Yang Syndrome
DD = developmental delay; GERD = gastroesophageal reflux; ID = intellectual disability
Almost all affected individuals have feeding problems in infancy. Most infants are dependent on special feeding techniques (special nipple, nasogastric tube feeding) during the first months of life.
While feeding problems resolve in about half during the first year of life, insufficient oral food uptake remains a problem in the other half, and these affected individuals eventually require gastrostomy tube placement, which could be continued into childhood.
Although not a hallmark of SYS in childhood, hyperphagia and obesity can be found in a significant proportion of affected adults, and the incidence of hyperphagia appears to increase with age [
Chronic constipation is present in the majority of affected individuals.
Gastroesophageal reflux is present in more than half of affected individuals.
Growth hormone (GH) treatment has been effective in some affected individuals [
A retrospective analysis of GH treatment in children with SYS including 14 treated and 12 untreated individuals found a significant increase in body height in the treated group over a course of six months (improvement of mean height z scores from -2.6 before to -1.7 after treatment) [
Satisfaction with GH therapy was high among parents of treated individuals, who reported a subjective increase or strong increase in muscle strength in 13 of 14 individuals.
Based on seven individuals for whom sufficient data was available, a non-significant improvement of mean weight for stature z scores (decrease by 0.8 after 6 months on GH therapy) was noted. The authors hypothesized that this may indicate a positive effect of GH treatment on body composition, which would be in line with established effects of GH therapy in children with
Worsening of sleep apnea was reported in one individual with SYS who was on GH, and worsening of scoliosis/kyphosis was reported in two individuals in the treatment group, without the need to interrupt or discontinue GH therapy.
The authors proposed that the same precautions should be taken in individuals with SYS undergoing GH therapy that apply for individuals with
More than half of the individuals reported by
Central apnea and/or obstructive sleep apnea is seen in approximately 75% of all affected individuals.
Episodes of apnea or severe respiratory distress can occur, especially during the first year of life [
Distal joint contractures of the upper limbs are present in the majority of affected individuals. The severity of this symptom varies from isolated contractures of the interphalangeal joints to severe arthrogryposis multiplex congenita [
Scoliosis is present in more than half of affected individuals. Exaggerated kyphosis can be observed in some.
Low bone mineral density (>2 SD below the mean) was reported in the majority of affected individuals studied by
Motor milestones are usually delayed – on average, children with SYS sit independently at age 18 months, crawl at 31 months, and walk at 50 months.
First words are spoken at an average age of 36 months, and the first two-word sentence at an average of 40 months.
However, affected individuals vary greatly with regard to motor and language development, and some adults with SYS do not acquire speech or independent walking [
A few affected individuals have borderline intellectual function [
Neurologic deterioration following febrile illness has been reported in four individuals with SYS [
Common findings include social withdrawal, restricted interests/fascinations, or stereotypic behavior such as hand flapping when stressed.
75%-80% of affected individuals meet the formal clinical diagnostic criteria of autism spectrum disorder (ASD) [
Additionally, skin picking and self-injurious behavior, which are frequent among individuals with ASD, are present in 70%-80% of those with SYS. Whether this behavior coincides with other features of ASD or whether it occurs as an isolated symptom is as yet unknown.
Two of the four individuals with neurologic deterioration following febrile illness reported by
Hypogonadism is reported in 15%-25% of females and 55%-65% of males, although
While true hypogonadotropic hypogonadism is among the cardinal features of PWS, it may be less frequent among individuals with SYS.
Temperature instability has been reported, with a majority of affected individuals experiencing excessive cold or excessive sweating [
Hypothyroidism has been observed in some affected adults (see
Cognitive abilities vary from complete dependence on external care to mild ID or borderline cognitive function.
Most affected adults reported to date are verbal and have basic reading skills, and some are able to work in a structured environment.
Frequent behavioral issues include a lack of activity and motivation, stubbornness, and social withdrawal. Features of ASD are present in most, and heightened anxiety is reported in almost all cases.
Obsessive-compulsive disorder and attention-deficit disorder are also reported, and one affected adult has been diagnosed with schizophrenia [
Overeating and obesity characterizes the majority of adults with SYS. While variable, the onset of obesity appears to be later than in PWS, where it usually occurs in childhood.
Obesity in adulthood can lead to features of metabolic syndrome, including hyperlipidemia and insulin resistance.
The
The pathogenic
Penetrance is considered to be 100% for individuals with a pathogenic
Prior to the description of SYS as a distinct genetic condition, individuals with Schaaf-Yang syndrome may have been diagnosed with Prader-Willi-like syndrome (PWLS). PWLS is considered to be an umbrella term for a genetically heterogeneous group of disorders with phenotypic similarities to PWS [
More than 250 individuals with SYS have been reported to date. SYS affects both sexes and all ethnicities equally.
• Almost all affected individuals have feeding problems in infancy. Most infants are dependent on special feeding techniques (special nipple, nasogastric tube feeding) during the first months of life.
• While feeding problems resolve in about half during the first year of life, insufficient oral food uptake remains a problem in the other half, and these affected individuals eventually require gastrostomy tube placement, which could be continued into childhood.
• Although not a hallmark of SYS in childhood, hyperphagia and obesity can be found in a significant proportion of affected adults, and the incidence of hyperphagia appears to increase with age [
• Chronic constipation is present in the majority of affected individuals.
• Gastroesophageal reflux is present in more than half of affected individuals.
• Growth hormone (GH) treatment has been effective in some affected individuals [
• A retrospective analysis of GH treatment in children with SYS including 14 treated and 12 untreated individuals found a significant increase in body height in the treated group over a course of six months (improvement of mean height z scores from -2.6 before to -1.7 after treatment) [
• Satisfaction with GH therapy was high among parents of treated individuals, who reported a subjective increase or strong increase in muscle strength in 13 of 14 individuals.
• Based on seven individuals for whom sufficient data was available, a non-significant improvement of mean weight for stature z scores (decrease by 0.8 after 6 months on GH therapy) was noted. The authors hypothesized that this may indicate a positive effect of GH treatment on body composition, which would be in line with established effects of GH therapy in children with
• Worsening of sleep apnea was reported in one individual with SYS who was on GH, and worsening of scoliosis/kyphosis was reported in two individuals in the treatment group, without the need to interrupt or discontinue GH therapy.
• The authors proposed that the same precautions should be taken in individuals with SYS undergoing GH therapy that apply for individuals with
• More than half of the individuals reported by
• Central apnea and/or obstructive sleep apnea is seen in approximately 75% of all affected individuals.
• Episodes of apnea or severe respiratory distress can occur, especially during the first year of life [
• Distal joint contractures of the upper limbs are present in the majority of affected individuals. The severity of this symptom varies from isolated contractures of the interphalangeal joints to severe arthrogryposis multiplex congenita [
• Scoliosis is present in more than half of affected individuals. Exaggerated kyphosis can be observed in some.
• Low bone mineral density (>2 SD below the mean) was reported in the majority of affected individuals studied by
• Motor milestones are usually delayed – on average, children with SYS sit independently at age 18 months, crawl at 31 months, and walk at 50 months.
• First words are spoken at an average age of 36 months, and the first two-word sentence at an average of 40 months.
• However, affected individuals vary greatly with regard to motor and language development, and some adults with SYS do not acquire speech or independent walking [
• A few affected individuals have borderline intellectual function [
• Neurologic deterioration following febrile illness has been reported in four individuals with SYS [
• Common findings include social withdrawal, restricted interests/fascinations, or stereotypic behavior such as hand flapping when stressed.
• 75%-80% of affected individuals meet the formal clinical diagnostic criteria of autism spectrum disorder (ASD) [
• Additionally, skin picking and self-injurious behavior, which are frequent among individuals with ASD, are present in 70%-80% of those with SYS. Whether this behavior coincides with other features of ASD or whether it occurs as an isolated symptom is as yet unknown.
• Hypogonadism is reported in 15%-25% of females and 55%-65% of males, although
• While true hypogonadotropic hypogonadism is among the cardinal features of PWS, it may be less frequent among individuals with SYS.
• Temperature instability has been reported, with a majority of affected individuals experiencing excessive cold or excessive sweating [
• Hypothyroidism has been observed in some affected adults (see
• Cognitive abilities vary from complete dependence on external care to mild ID or borderline cognitive function.
• Most affected adults reported to date are verbal and have basic reading skills, and some are able to work in a structured environment.
• Frequent behavioral issues include a lack of activity and motivation, stubbornness, and social withdrawal. Features of ASD are present in most, and heightened anxiety is reported in almost all cases.
• Obsessive-compulsive disorder and attention-deficit disorder are also reported, and one affected adult has been diagnosed with schizophrenia [
• Overeating and obesity characterizes the majority of adults with SYS. While variable, the onset of obesity appears to be later than in PWS, where it usually occurs in childhood.
• Obesity in adulthood can lead to features of metabolic syndrome, including hyperlipidemia and insulin resistance.
## Clinical Description
Schaaf-Yang Syndrome (SYS) is a rare, paternally derived neurodevelopmental disorder that shares multiple clinical features with the genetically related
To date, more than 250 individuals have been identified with a paternally derived pathogenic variant in
Select Features of Schaaf-Yang Syndrome
DD = developmental delay; GERD = gastroesophageal reflux; ID = intellectual disability
Almost all affected individuals have feeding problems in infancy. Most infants are dependent on special feeding techniques (special nipple, nasogastric tube feeding) during the first months of life.
While feeding problems resolve in about half during the first year of life, insufficient oral food uptake remains a problem in the other half, and these affected individuals eventually require gastrostomy tube placement, which could be continued into childhood.
Although not a hallmark of SYS in childhood, hyperphagia and obesity can be found in a significant proportion of affected adults, and the incidence of hyperphagia appears to increase with age [
Chronic constipation is present in the majority of affected individuals.
Gastroesophageal reflux is present in more than half of affected individuals.
Growth hormone (GH) treatment has been effective in some affected individuals [
A retrospective analysis of GH treatment in children with SYS including 14 treated and 12 untreated individuals found a significant increase in body height in the treated group over a course of six months (improvement of mean height z scores from -2.6 before to -1.7 after treatment) [
Satisfaction with GH therapy was high among parents of treated individuals, who reported a subjective increase or strong increase in muscle strength in 13 of 14 individuals.
Based on seven individuals for whom sufficient data was available, a non-significant improvement of mean weight for stature z scores (decrease by 0.8 after 6 months on GH therapy) was noted. The authors hypothesized that this may indicate a positive effect of GH treatment on body composition, which would be in line with established effects of GH therapy in children with
Worsening of sleep apnea was reported in one individual with SYS who was on GH, and worsening of scoliosis/kyphosis was reported in two individuals in the treatment group, without the need to interrupt or discontinue GH therapy.
The authors proposed that the same precautions should be taken in individuals with SYS undergoing GH therapy that apply for individuals with
More than half of the individuals reported by
Central apnea and/or obstructive sleep apnea is seen in approximately 75% of all affected individuals.
Episodes of apnea or severe respiratory distress can occur, especially during the first year of life [
Distal joint contractures of the upper limbs are present in the majority of affected individuals. The severity of this symptom varies from isolated contractures of the interphalangeal joints to severe arthrogryposis multiplex congenita [
Scoliosis is present in more than half of affected individuals. Exaggerated kyphosis can be observed in some.
Low bone mineral density (>2 SD below the mean) was reported in the majority of affected individuals studied by
Motor milestones are usually delayed – on average, children with SYS sit independently at age 18 months, crawl at 31 months, and walk at 50 months.
First words are spoken at an average age of 36 months, and the first two-word sentence at an average of 40 months.
However, affected individuals vary greatly with regard to motor and language development, and some adults with SYS do not acquire speech or independent walking [
A few affected individuals have borderline intellectual function [
Neurologic deterioration following febrile illness has been reported in four individuals with SYS [
Common findings include social withdrawal, restricted interests/fascinations, or stereotypic behavior such as hand flapping when stressed.
75%-80% of affected individuals meet the formal clinical diagnostic criteria of autism spectrum disorder (ASD) [
Additionally, skin picking and self-injurious behavior, which are frequent among individuals with ASD, are present in 70%-80% of those with SYS. Whether this behavior coincides with other features of ASD or whether it occurs as an isolated symptom is as yet unknown.
Two of the four individuals with neurologic deterioration following febrile illness reported by
Hypogonadism is reported in 15%-25% of females and 55%-65% of males, although
While true hypogonadotropic hypogonadism is among the cardinal features of PWS, it may be less frequent among individuals with SYS.
Temperature instability has been reported, with a majority of affected individuals experiencing excessive cold or excessive sweating [
Hypothyroidism has been observed in some affected adults (see
Cognitive abilities vary from complete dependence on external care to mild ID or borderline cognitive function.
Most affected adults reported to date are verbal and have basic reading skills, and some are able to work in a structured environment.
Frequent behavioral issues include a lack of activity and motivation, stubbornness, and social withdrawal. Features of ASD are present in most, and heightened anxiety is reported in almost all cases.
Obsessive-compulsive disorder and attention-deficit disorder are also reported, and one affected adult has been diagnosed with schizophrenia [
Overeating and obesity characterizes the majority of adults with SYS. While variable, the onset of obesity appears to be later than in PWS, where it usually occurs in childhood.
Obesity in adulthood can lead to features of metabolic syndrome, including hyperlipidemia and insulin resistance.
• Almost all affected individuals have feeding problems in infancy. Most infants are dependent on special feeding techniques (special nipple, nasogastric tube feeding) during the first months of life.
• While feeding problems resolve in about half during the first year of life, insufficient oral food uptake remains a problem in the other half, and these affected individuals eventually require gastrostomy tube placement, which could be continued into childhood.
• Although not a hallmark of SYS in childhood, hyperphagia and obesity can be found in a significant proportion of affected adults, and the incidence of hyperphagia appears to increase with age [
• Chronic constipation is present in the majority of affected individuals.
• Gastroesophageal reflux is present in more than half of affected individuals.
• Growth hormone (GH) treatment has been effective in some affected individuals [
• A retrospective analysis of GH treatment in children with SYS including 14 treated and 12 untreated individuals found a significant increase in body height in the treated group over a course of six months (improvement of mean height z scores from -2.6 before to -1.7 after treatment) [
• Satisfaction with GH therapy was high among parents of treated individuals, who reported a subjective increase or strong increase in muscle strength in 13 of 14 individuals.
• Based on seven individuals for whom sufficient data was available, a non-significant improvement of mean weight for stature z scores (decrease by 0.8 after 6 months on GH therapy) was noted. The authors hypothesized that this may indicate a positive effect of GH treatment on body composition, which would be in line with established effects of GH therapy in children with
• Worsening of sleep apnea was reported in one individual with SYS who was on GH, and worsening of scoliosis/kyphosis was reported in two individuals in the treatment group, without the need to interrupt or discontinue GH therapy.
• The authors proposed that the same precautions should be taken in individuals with SYS undergoing GH therapy that apply for individuals with
• More than half of the individuals reported by
• Central apnea and/or obstructive sleep apnea is seen in approximately 75% of all affected individuals.
• Episodes of apnea or severe respiratory distress can occur, especially during the first year of life [
• Distal joint contractures of the upper limbs are present in the majority of affected individuals. The severity of this symptom varies from isolated contractures of the interphalangeal joints to severe arthrogryposis multiplex congenita [
• Scoliosis is present in more than half of affected individuals. Exaggerated kyphosis can be observed in some.
• Low bone mineral density (>2 SD below the mean) was reported in the majority of affected individuals studied by
• Motor milestones are usually delayed – on average, children with SYS sit independently at age 18 months, crawl at 31 months, and walk at 50 months.
• First words are spoken at an average age of 36 months, and the first two-word sentence at an average of 40 months.
• However, affected individuals vary greatly with regard to motor and language development, and some adults with SYS do not acquire speech or independent walking [
• A few affected individuals have borderline intellectual function [
• Neurologic deterioration following febrile illness has been reported in four individuals with SYS [
• Common findings include social withdrawal, restricted interests/fascinations, or stereotypic behavior such as hand flapping when stressed.
• 75%-80% of affected individuals meet the formal clinical diagnostic criteria of autism spectrum disorder (ASD) [
• Additionally, skin picking and self-injurious behavior, which are frequent among individuals with ASD, are present in 70%-80% of those with SYS. Whether this behavior coincides with other features of ASD or whether it occurs as an isolated symptom is as yet unknown.
• Hypogonadism is reported in 15%-25% of females and 55%-65% of males, although
• While true hypogonadotropic hypogonadism is among the cardinal features of PWS, it may be less frequent among individuals with SYS.
• Temperature instability has been reported, with a majority of affected individuals experiencing excessive cold or excessive sweating [
• Hypothyroidism has been observed in some affected adults (see
• Cognitive abilities vary from complete dependence on external care to mild ID or borderline cognitive function.
• Most affected adults reported to date are verbal and have basic reading skills, and some are able to work in a structured environment.
• Frequent behavioral issues include a lack of activity and motivation, stubbornness, and social withdrawal. Features of ASD are present in most, and heightened anxiety is reported in almost all cases.
• Obsessive-compulsive disorder and attention-deficit disorder are also reported, and one affected adult has been diagnosed with schizophrenia [
• Overeating and obesity characterizes the majority of adults with SYS. While variable, the onset of obesity appears to be later than in PWS, where it usually occurs in childhood.
• Obesity in adulthood can lead to features of metabolic syndrome, including hyperlipidemia and insulin resistance.
## Genotype-Phenotype Correlations
The
The pathogenic
## Penetrance
Penetrance is considered to be 100% for individuals with a pathogenic
## Nomenclature
Prior to the description of SYS as a distinct genetic condition, individuals with Schaaf-Yang syndrome may have been diagnosed with Prader-Willi-like syndrome (PWLS). PWLS is considered to be an umbrella term for a genetically heterogeneous group of disorders with phenotypic similarities to PWS [
## Prevalence
More than 250 individuals with SYS have been reported to date. SYS affects both sexes and all ethnicities equally.
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Neurodevelopmental Disorders of Interest in the Differential Diagnosis of Schaaf-Yang Syndrome (SYS)
+++ = core feature in this disorder; ++ = variable feature of this disorder; + = rare feature of this disorder; – = not typically associated with this disorder; AD = autosomal dominant; AR = autosomal recessive; ASD = autism spectrum disorder; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; PWCR = Prader-Willi critical region; UPD = uniparental disomy
See
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.
Infants may present with clenched or flexed fingers.
See also
## Management
To establish the extent of disease and needs in an individual diagnosed with Schaaf-Yang syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Schaaf-Yang Syndrome
To incl eval for aspiration risk, nutritional status, & signs & symptoms of GERD & constipation
May require use of special nipple &/or nasogastric tube in infancy
Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk.
Gross motor & fine motor skills
Contractures, clubfoot, & scoliosis
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
Urologist in males w/undescended testes;
Endocrinologist in those w/evidence of hypoplastic genitalia &/or hypogonadism.
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; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
This is particularly important for those who may be considering growth hormone (GH) therapy and should be completed, along with an adenotonsillar evaluation, prior to the initiation of GH therapy [
The following laboratory studies should be considered, depending on the age of the affected individual: fasting blood glucose and glucose tolerance after 120 mins; insulin-like growth factor 1 / insulin-like growth factor binding protein 3; random growth hormone level; follicle-stimulating hormone and luteinizing hormone; total testosterone (in males); thyroid-stimulating hormone and thyroxine; a lipid panel to include total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol; uric acid level.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment of Manifestations in Individuals with Schaaf-Yang Syndrome
Feeding therapy
A special nipple or nasogastric tube may be required.
Gastrostomy tube placement may be considered for persistent feeding issues.
Nutritional intervention incl restricted caloric intake
Standard treatment for insulin resistance / diabetes
Standard treatment for hyperlipidemia
Affected persons w/short stature should benefit from off-label GH supplementation to improve body height. GH therapy may also have positive effects on muscle strength & body composition.
Polysomnography & adenotonsillar eval should be completed prior to initiation of GH therapy.
Optimization of Ca
Bisphosphonates may be considered.
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
ASM = anti-seizure medication; CPAP = continuous positive airway pressure; DD = developmental delay; GERD = gastroesophageal reflux disease; GH = growth hormone; 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 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.
Recommended Surveillance for Individuals with Schaaf-Yang Syndrome
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor for scoliosis & for progression of contractures.
OT/PT assessment of mobility & self-help skills
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures & changes in tone.
ASD = autism spectrum disorder; DXA = dual-energy x-ray absorptiometry; GH = growth hormone; OT = occupational therapy; PT = physical therapy
See
Search
• To incl eval for aspiration risk, nutritional status, & signs & symptoms of GERD & constipation
• May require use of special nipple &/or nasogastric tube in infancy
• Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk.
• Gross motor & fine motor skills
• Contractures, clubfoot, & scoliosis
• 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
• Urologist in males w/undescended testes;
• Endocrinologist in those w/evidence of hypoplastic genitalia &/or hypogonadism.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Feeding therapy
• A special nipple or nasogastric tube may be required.
• Gastrostomy tube placement may be considered for persistent feeding issues.
• Nutritional intervention incl restricted caloric intake
• Standard treatment for insulin resistance / diabetes
• Standard treatment for hyperlipidemia
• Affected persons w/short stature should benefit from off-label GH supplementation to improve body height. GH therapy may also have positive effects on muscle strength & body composition.
• Polysomnography & adenotonsillar eval should be completed prior to initiation of GH therapy.
• Optimization of Ca
• Bisphosphonates may be considered.
• 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
• 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
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor for scoliosis & for progression of contractures.
• OT/PT assessment of mobility & self-help skills
• 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 Schaaf-Yang syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Schaaf-Yang Syndrome
To incl eval for aspiration risk, nutritional status, & signs & symptoms of GERD & constipation
May require use of special nipple &/or nasogastric tube in infancy
Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk.
Gross motor & fine motor skills
Contractures, clubfoot, & scoliosis
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
Urologist in males w/undescended testes;
Endocrinologist in those w/evidence of hypoplastic genitalia &/or hypogonadism.
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; DXA = dual-energy x-ray absorptiometry; GERD = gastroesophageal reflux disease; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy
This is particularly important for those who may be considering growth hormone (GH) therapy and should be completed, along with an adenotonsillar evaluation, prior to the initiation of GH therapy [
The following laboratory studies should be considered, depending on the age of the affected individual: fasting blood glucose and glucose tolerance after 120 mins; insulin-like growth factor 1 / insulin-like growth factor binding protein 3; random growth hormone level; follicle-stimulating hormone and luteinizing hormone; total testosterone (in males); thyroid-stimulating hormone and thyroxine; a lipid panel to include total cholesterol, triglycerides, HDL cholesterol, and LDL cholesterol; uric acid level.
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• To incl eval for aspiration risk, nutritional status, & signs & symptoms of GERD & constipation
• May require use of special nipple &/or nasogastric tube in infancy
• Consider eval for gastrostomy tube placement in affected persons w/dysphagia &/or aspiration risk.
• Gross motor & fine motor skills
• Contractures, clubfoot, & scoliosis
• 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
• Urologist in males w/undescended testes;
• Endocrinologist in those w/evidence of hypoplastic genitalia &/or hypogonadism.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Schaaf-Yang Syndrome
Feeding therapy
A special nipple or nasogastric tube may be required.
Gastrostomy tube placement may be considered for persistent feeding issues.
Nutritional intervention incl restricted caloric intake
Standard treatment for insulin resistance / diabetes
Standard treatment for hyperlipidemia
Affected persons w/short stature should benefit from off-label GH supplementation to improve body height. GH therapy may also have positive effects on muscle strength & body composition.
Polysomnography & adenotonsillar eval should be completed prior to initiation of GH therapy.
Optimization of Ca
Bisphosphonates may be considered.
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
ASM = anti-seizure medication; CPAP = continuous positive airway pressure; DD = developmental delay; GERD = gastroesophageal reflux disease; GH = growth hormone; 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 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.
• Feeding therapy
• A special nipple or nasogastric tube may be required.
• Gastrostomy tube placement may be considered for persistent feeding issues.
• Nutritional intervention incl restricted caloric intake
• Standard treatment for insulin resistance / diabetes
• Standard treatment for hyperlipidemia
• Affected persons w/short stature should benefit from off-label GH supplementation to improve body height. GH therapy may also have positive effects on muscle strength & body composition.
• Polysomnography & adenotonsillar eval should be completed prior to initiation of GH therapy.
• Optimization of Ca
• Bisphosphonates may be considered.
• 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
• 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
## 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 Schaaf-Yang Syndrome
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor for scoliosis & for progression of contractures.
OT/PT assessment of mobility & self-help skills
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures & changes in tone.
ASD = autism spectrum disorder; DXA = dual-energy x-ray absorptiometry; GH = growth hormone; OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor for scoliosis & for progression of contractures.
• OT/PT assessment of mobility & self-help skills
• 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
Schaaf-Yang syndrome (SYS) is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the paternally derived
Approximately 50% of individuals diagnosed with SYS inherited a
Approximately 50% of individuals diagnosed with SYS have the disorder as the result of a
Molecular genetic testing is recommended for the biological father of the proband to confirm his genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is situated on the paternal allele but is not identified in paternal DNA, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a father with germline (or somatic and germline) mosaicism. Paternal somatic/germline mosaicism has been reported [
Note: Testing of paternal leukocyte DNA may not detect all instances of somatic mosaicism.
The mother of a proband will not be affected with SYS nor will she be heterozygous for a
If the father of the proband is heterozygous for the
If the
The recurrence risk within the family of the proband's mother is that of the general population.
If the father of the proband is heterozygous for a
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to the parents of affected individuals and to males who are heterozygous for a maternally inherited
Genetic counseling is also recommended for members of the paternal family of the proband (such as the father's mother and sibs) if the proband's father is heterozygous for a
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.
• Approximately 50% of individuals diagnosed with SYS inherited a
• Approximately 50% of individuals diagnosed with SYS have the disorder as the result of a
• Molecular genetic testing is recommended for the biological father of the proband to confirm his genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is situated on the paternal allele but is not identified in paternal DNA, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a father with germline (or somatic and germline) mosaicism. Paternal somatic/germline mosaicism has been reported [
• Note: Testing of paternal leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a father with germline (or somatic and germline) mosaicism. Paternal somatic/germline mosaicism has been reported [
• Note: Testing of paternal leukocyte DNA may not detect all instances of somatic mosaicism.
• The mother of a proband will not be affected with SYS nor will she be heterozygous for a
• The proband has a
• The proband inherited a pathogenic variant from a father with germline (or somatic and germline) mosaicism. Paternal somatic/germline mosaicism has been reported [
• Note: Testing of paternal leukocyte DNA may not detect all instances of somatic mosaicism.
• If the father of the proband is heterozygous for the
• If the
• The recurrence risk within the family of the proband's mother is that of the general population.
• If the father of the proband is heterozygous for a
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to the parents of affected individuals and to males who are heterozygous for a maternally inherited
• Genetic counseling is also recommended for members of the paternal family of the proband (such as the father's mother and sibs) if the proband's father is heterozygous for a
## Mode of Inheritance
Schaaf-Yang syndrome (SYS) is inherited in an autosomal dominant, maternally imprinted manner (i.e., a heterozygous pathogenic variant on the paternally derived
## Risk to Family Members
Approximately 50% of individuals diagnosed with SYS inherited a
Approximately 50% of individuals diagnosed with SYS have the disorder as the result of a
Molecular genetic testing is recommended for the biological father of the proband to confirm his genetic status and to allow reliable recurrence risk counseling.
If the pathogenic variant identified in the proband is situated on the paternal allele but is not identified in paternal DNA, the following possibilities should be considered:
The proband has a
The proband inherited a pathogenic variant from a father with germline (or somatic and germline) mosaicism. Paternal somatic/germline mosaicism has been reported [
Note: Testing of paternal leukocyte DNA may not detect all instances of somatic mosaicism.
The mother of a proband will not be affected with SYS nor will she be heterozygous for a
If the father of the proband is heterozygous for the
If the
The recurrence risk within the family of the proband's mother is that of the general population.
If the father of the proband is heterozygous for a
• Approximately 50% of individuals diagnosed with SYS inherited a
• Approximately 50% of individuals diagnosed with SYS have the disorder as the result of a
• Molecular genetic testing is recommended for the biological father of the proband to confirm his genetic status and to allow reliable recurrence risk counseling.
• If the pathogenic variant identified in the proband is situated on the paternal allele but is not identified in paternal DNA, the following possibilities should be considered:
• The proband has a
• The proband inherited a pathogenic variant from a father with germline (or somatic and germline) mosaicism. Paternal somatic/germline mosaicism has been reported [
• Note: Testing of paternal leukocyte DNA may not detect all instances of somatic mosaicism.
• The proband has a
• The proband inherited a pathogenic variant from a father with germline (or somatic and germline) mosaicism. Paternal somatic/germline mosaicism has been reported [
• Note: Testing of paternal leukocyte DNA may not detect all instances of somatic mosaicism.
• The mother of a proband will not be affected with SYS nor will she be heterozygous for a
• The proband has a
• The proband inherited a pathogenic variant from a father with germline (or somatic and germline) mosaicism. Paternal somatic/germline mosaicism has been reported [
• Note: Testing of paternal leukocyte DNA may not detect all instances of somatic mosaicism.
• If the father of the proband is heterozygous for the
• If the
• The recurrence risk within the family of the proband's mother is that of the general population.
• If the father of the proband is heterozygous for a
## 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.
Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to the parents of affected individuals and to males who are heterozygous for a maternally inherited
Genetic counseling is also recommended for members of the paternal family of the proband (such as the father's mother and sibs) if the proband's father is heterozygous for a
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before pregnancy.
• Genetic counseling (including discussion of potential risks to offspring and reproductive options) should be offered to the parents of affected individuals and to males who are heterozygous for a maternally inherited
• Genetic counseling is also recommended for members of the paternal family of the proband (such as the father's mother and sibs) if the proband's father is heterozygous for a
## 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
340 Lemon Ave
Suite 3620
Walnut CA 91789
•
• 340 Lemon Ave
• Suite 3620
• Walnut CA 91789
•
•
•
•
•
## Molecular Genetics
Schaaf-Yang Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Schaaf-Yang Syndrome (
Given its position within the PWCR, it is remarkable that individuals with
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Given its position within the PWCR, it is remarkable that individuals with
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
4 November 2021 (cps) Revision: information on growth hormone (GH) therapy updated by authors
11 February 2021 (ma) Review posted live
31 August 2020 (cps) Original submission
• 4 November 2021 (cps) Revision: information on growth hormone (GH) therapy updated by authors
• 11 February 2021 (ma) Review posted live
• 31 August 2020 (cps) Original submission
## Revision History
4 November 2021 (cps) Revision: information on growth hormone (GH) therapy updated by authors
11 February 2021 (ma) Review posted live
31 August 2020 (cps) Original submission
• 4 November 2021 (cps) Revision: information on growth hormone (GH) therapy updated by authors
• 11 February 2021 (ma) Review posted live
• 31 August 2020 (cps) Original submission
## References
## Literature Cited
|
[] |
11/2/2021
|
4/11/2021
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
schinzel-giedion
|
schinzel-giedion
|
[
"Classic Schinzel-Giedion Syndrome",
"Atypical Schinzel-Giedion Syndrome",
"SET-binding protein",
"SETBP1",
"Schinzel-Giedion Syndrome"
] |
Schinzel-Giedion Syndrome
|
Jessica Duis, Bregje WM van Bon
|
Summary Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder caused by gain-of-function pathogenic variants in a To date, more than 50 individuals have been reported with molecularly confirmed classic SGS. Atypical SGS, reported in five individuals to date, is caused by pathogenic The diagnosis of classic SGS can be established in a proband based on published clinical diagnostic criteria, or the molecular diagnosis can be established in a proband with suggestive findings and a heterozygous Classic and atypical SGS are autosomal dominant disorders typically caused by a
|
Pathogenic variants in
Spectrum of Phenotypes Associated with
Broad spectrum of clinical features of variable severity that partially overlap w/classic SGS
Atypical SGS is milder than classic SGS.
"
Note: "
See
• Broad spectrum of clinical features of variable severity that partially overlap w/classic SGS
• Atypical SGS is milder than classic SGS.
• "
• Note: "
• See
## Diagnosis
This chapter focuses on classic and atypical Schinzel-Giedion syndrome (SGS). Before pathogenic variants within
Schinzel-Giedion syndrome (SGS)
Moderate-to-profound developmental delay (DD) or intellectual disability (ID)
Facial features include a prominent forehead, midface retrusion, and bitemporal narrowing with or without other characteristics features (see
AND any of the following features presenting in infancy or childhood:
Tone abnormalities (including hypotonia or spasticity)
Feeding difficulties
Swallowing difficulties (laryngomalacia, choanal stenosis)
Epilepsy (multiple types of seizures)
Microcephaly
Cerebral vision impairment (CVI), 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
Hearing impairment, mainly sensorineural hearing loss and less commonly conductive hearing loss
Congenital anomalies of the kidney and urinary tract, such as hydronephrosis, ureteral anomalies, and renal cysts
Genital anomalies (in males: hypospadias and hypoplastic scrotum; in females: hypoplastic labia)
Cardiac anomalies, the majority of which are atrial septal defects, patent ductus arteriosus, and patent foramen ovale
Skeletal features, including sclerotic base of the skull, wide supraoccipital-exoccipital synchondroses, broad ribs, increased cortical density or thickness, hypoplastic distal phalanges, and talipes equinovarus
Neoplasia (reported in classic SGS only to date) that may be benign or malignant. The majority of neoplasias are of neuroepithelial origin (mainly sacrococcygeal teratomas). Depending on their location, tumors may also cause obstructive problems.
The
Classic Schinzel-Giedion Syndrome: Clinical Diagnostic Criteria
Sclerotic skull base
Wide supraoccipital-exoccipital synchondroses
↑ cortical density or thickness
Broad ribs
Adapted from
The
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
Note: Single-gene testing is typically NOT recommended as multi-gene panel testing offers significant advantages including more efficient (and often more affordable) testing, especially when the clinician has not suspected the diagnosis of SGS. However, when resources are limited or when a clinical diagnosis of SGS (that fulfils the original criteria proposed by
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schinzel-Giedion 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 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.
To date, large intragenic deletions/duplications have not been reported and are not expected in individuals with classic or atypical SGS.
• Moderate-to-profound developmental delay (DD) or intellectual disability (ID)
• Facial features include a prominent forehead, midface retrusion, and bitemporal narrowing with or without other characteristics features (see
• Tone abnormalities (including hypotonia or spasticity)
• Feeding difficulties
• Swallowing difficulties (laryngomalacia, choanal stenosis)
• Epilepsy (multiple types of seizures)
• Microcephaly
• Cerebral vision impairment (CVI), 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
• Hearing impairment, mainly sensorineural hearing loss and less commonly conductive hearing loss
• Congenital anomalies of the kidney and urinary tract, such as hydronephrosis, ureteral anomalies, and renal cysts
• Genital anomalies (in males: hypospadias and hypoplastic scrotum; in females: hypoplastic labia)
• Cardiac anomalies, the majority of which are atrial septal defects, patent ductus arteriosus, and patent foramen ovale
• Skeletal features, including sclerotic base of the skull, wide supraoccipital-exoccipital synchondroses, broad ribs, increased cortical density or thickness, hypoplastic distal phalanges, and talipes equinovarus
• Neoplasia (reported in classic SGS only to date) that may be benign or malignant. The majority of neoplasias are of neuroepithelial origin (mainly sacrococcygeal teratomas). Depending on their location, tumors may also cause obstructive problems.
• Sclerotic skull base
• Wide supraoccipital-exoccipital synchondroses
• ↑ cortical density or thickness
• Broad ribs
## Suggestive Findings
Schinzel-Giedion syndrome (SGS)
Moderate-to-profound developmental delay (DD) or intellectual disability (ID)
Facial features include a prominent forehead, midface retrusion, and bitemporal narrowing with or without other characteristics features (see
AND any of the following features presenting in infancy or childhood:
Tone abnormalities (including hypotonia or spasticity)
Feeding difficulties
Swallowing difficulties (laryngomalacia, choanal stenosis)
Epilepsy (multiple types of seizures)
Microcephaly
Cerebral vision impairment (CVI), 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
Hearing impairment, mainly sensorineural hearing loss and less commonly conductive hearing loss
Congenital anomalies of the kidney and urinary tract, such as hydronephrosis, ureteral anomalies, and renal cysts
Genital anomalies (in males: hypospadias and hypoplastic scrotum; in females: hypoplastic labia)
Cardiac anomalies, the majority of which are atrial septal defects, patent ductus arteriosus, and patent foramen ovale
Skeletal features, including sclerotic base of the skull, wide supraoccipital-exoccipital synchondroses, broad ribs, increased cortical density or thickness, hypoplastic distal phalanges, and talipes equinovarus
Neoplasia (reported in classic SGS only to date) that may be benign or malignant. The majority of neoplasias are of neuroepithelial origin (mainly sacrococcygeal teratomas). Depending on their location, tumors may also cause obstructive problems.
• Moderate-to-profound developmental delay (DD) or intellectual disability (ID)
• Facial features include a prominent forehead, midface retrusion, and bitemporal narrowing with or without other characteristics features (see
• Tone abnormalities (including hypotonia or spasticity)
• Feeding difficulties
• Swallowing difficulties (laryngomalacia, choanal stenosis)
• Epilepsy (multiple types of seizures)
• Microcephaly
• Cerebral vision impairment (CVI), 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
• Hearing impairment, mainly sensorineural hearing loss and less commonly conductive hearing loss
• Congenital anomalies of the kidney and urinary tract, such as hydronephrosis, ureteral anomalies, and renal cysts
• Genital anomalies (in males: hypospadias and hypoplastic scrotum; in females: hypoplastic labia)
• Cardiac anomalies, the majority of which are atrial septal defects, patent ductus arteriosus, and patent foramen ovale
• Skeletal features, including sclerotic base of the skull, wide supraoccipital-exoccipital synchondroses, broad ribs, increased cortical density or thickness, hypoplastic distal phalanges, and talipes equinovarus
• Neoplasia (reported in classic SGS only to date) that may be benign or malignant. The majority of neoplasias are of neuroepithelial origin (mainly sacrococcygeal teratomas). Depending on their location, tumors may also cause obstructive problems.
## Establishing the Diagnosis
The
Classic Schinzel-Giedion Syndrome: Clinical Diagnostic Criteria
Sclerotic skull base
Wide supraoccipital-exoccipital synchondroses
↑ cortical density or thickness
Broad ribs
Adapted from
The
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
Note: Single-gene testing is typically NOT recommended as multi-gene panel testing offers significant advantages including more efficient (and often more affordable) testing, especially when the clinician has not suspected the diagnosis of SGS. However, when resources are limited or when a clinical diagnosis of SGS (that fulfils the original criteria proposed by
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schinzel-Giedion 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 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.
To date, large intragenic deletions/duplications have not been reported and are not expected in individuals with classic or atypical SGS.
• Sclerotic skull base
• Wide supraoccipital-exoccipital synchondroses
• ↑ cortical density or thickness
• Broad ribs
## Classic SGS
The
Classic Schinzel-Giedion Syndrome: Clinical Diagnostic Criteria
Sclerotic skull base
Wide supraoccipital-exoccipital synchondroses
↑ cortical density or thickness
Broad ribs
Adapted from
• Sclerotic skull base
• Wide supraoccipital-exoccipital synchondroses
• ↑ cortical density or thickness
• Broad ribs
## Atypical SGS
The
## Molecular Genetic Testing
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
Note: Single-gene testing is typically NOT recommended as multi-gene panel testing offers significant advantages including more efficient (and often more affordable) testing, especially when the clinician has not suspected the diagnosis of SGS. However, when resources are limited or when a clinical diagnosis of SGS (that fulfils the original criteria proposed by
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schinzel-Giedion 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 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.
To date, large intragenic deletions/duplications have not been reported and are not expected in individuals with classic or atypical SGS.
##
For an introduction to multigene panels click
Note: Single-gene testing is typically NOT recommended as multi-gene panel testing offers significant advantages including more efficient (and often more affordable) testing, especially when the clinician has not suspected the diagnosis of SGS. However, when resources are limited or when a clinical diagnosis of SGS (that fulfils the original criteria proposed by
##
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schinzel-Giedion 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 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.
To date, large intragenic deletions/duplications have not been reported and are not expected in individuals with classic or atypical SGS.
## Clinical Characteristics
Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder, is characterized by a range of physical and developmental abnormalities. The main features include global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), tone abnormalities, dysautonomia, and cerebral visual and hearing impairment. Poor weight gain is common and often associated with gastroesophageal reflux disease, chronic vomiting, constipation, gastroparesis, and/or feeding intolerance. Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain. Rarely there may be anomalies of the liver, spleen, and/or pancreas. Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
To date, more than 50 individuals have been reported with molecularly confirmed classic SGS [
In addition, more than 40 individuals with the clinical diagnosis of SGS were reported in the medical literature before pathogenic variants in
Atypical SGS, caused by
The following clinical description is mainly based on reports of individuals with molecularly confirmed classic SGS (see
Classic Schinzel-Giedion Syndrome: Frequency of Select Features
100%
Based on
CAKUT = congenital anomalies of the kidney and urinary tract
Most seizures are refractory to treatment with anti-seizure medications (ASMs), adrenocorticotropic hormone, steroids, and the ketogenic diet.
Other reported types of hearing loss include mixed or conductive hearing loss. For example, mixed moderate hearing loss was reported in two individuals due to bilateral deformations of the stapes (that had a tuning fork shape) and in one individual with a flattened last cochlear spire (identified by temporal bone CT scan) [
Postaxial polydactyly (predominantly of the hands) was noted in about 5%-10% of individuals with classic SGS.
Stenosis of the ureteropelvic junction or vesicoureteral reflux are common. Bladder atony may be the cause of frequent and persistent urinary tract infections.
Other anomalies can include abnormal ureters and renal cysts.
One individual had bilateral large coralliform (i.e., resembling the calyx cavities) renal stones that were predominantly calcium oxalate and calcium phosphate without pyelic dilatation [
Sacrococcygeal teratoma is the most common tumor. Other reported tumors include hepatoblastoma, lumbosacral teratoma, lumbosacral primitive neuroectodermal tumor, Wilms tumor, and extradural ependymomas. To date, juvenile myelomonocytic leukemia has been reported in one individual [
Although most children with SGS die from other causes, a 24-month-old child died of organ failure due to a sacrococcygeal teratoma and a five-year-old child died due to relapse of an extradural ependymal tumor [
In one individual, an abnormal posterior fossa with stretching of the pituitary stalk resulted in central diabetes insipidus and central hypothyroidism [
Postmortem microscopic evaluation of the pancreas in a four-day-old infant showed dilated interlobular ducts, filled with eosinic mucus and surrounded by abundant connective tissue. Additionally, dilated glands and mucus depositions were found in larynx and bronchial glands; although these findings were like those observed in cystic fibrosis,
One infant developed gingival hyperplasia at age seven months (two weeks prior to the initiation of ASMs) that became severe after age two years. His gingivae were so large that they protruded from his mouth, pressed his tongue to the pharynx, and covered his teeth. Because of difficulty with eating and breathing, he underwent full mouth gingivectomy twice, once at age four years and again at age six years. Histologic findings were gingival fibrous hyperplasia with mucoid depositions [
Pathogenic variants in
Classic SGS is associated with pathogenic gain-of-function
Atypical SGS is associated with pathogenic missense
To date, more than 50 individuals have been reported in the medical literature with molecularly confirmed classic SGS; more than 40 additional individuals were reported with the clinical diagnosis of classic SGS before
To date, five individuals with atypical SGS have been reported. For a summary of case reports and reported pathogenic missense variants in
• In one individual, an abnormal posterior fossa with stretching of the pituitary stalk resulted in central diabetes insipidus and central hypothyroidism [
• Postmortem microscopic evaluation of the pancreas in a four-day-old infant showed dilated interlobular ducts, filled with eosinic mucus and surrounded by abundant connective tissue. Additionally, dilated glands and mucus depositions were found in larynx and bronchial glands; although these findings were like those observed in cystic fibrosis,
• One infant developed gingival hyperplasia at age seven months (two weeks prior to the initiation of ASMs) that became severe after age two years. His gingivae were so large that they protruded from his mouth, pressed his tongue to the pharynx, and covered his teeth. Because of difficulty with eating and breathing, he underwent full mouth gingivectomy twice, once at age four years and again at age six years. Histologic findings were gingival fibrous hyperplasia with mucoid depositions [
• Classic SGS is associated with pathogenic gain-of-function
• Atypical SGS is associated with pathogenic missense
## Clinical Description
Classic Schinzel-Giedion syndrome (SGS), an ultra-rare multisystem disorder, is characterized by a range of physical and developmental abnormalities. The main features include global neurodevelopmental impairment leading to moderate-to-profound intellectual disability, epilepsy (often refractory to treatment), tone abnormalities, dysautonomia, and cerebral visual and hearing impairment. Poor weight gain is common and often associated with gastroesophageal reflux disease, chronic vomiting, constipation, gastroparesis, and/or feeding intolerance. Structural malformations can involve the heart, skeleton, kidney and urinary tract, genitalia, and brain. Rarely there may be anomalies of the liver, spleen, and/or pancreas. Other features may include neuroepithelial neoplasia, severely disrupted sleep, choanal stenosis, inguinal hernia, sensitive skin, and increased risk of infection.
To date, more than 50 individuals have been reported with molecularly confirmed classic SGS [
In addition, more than 40 individuals with the clinical diagnosis of SGS were reported in the medical literature before pathogenic variants in
Atypical SGS, caused by
The following clinical description is mainly based on reports of individuals with molecularly confirmed classic SGS (see
Classic Schinzel-Giedion Syndrome: Frequency of Select Features
100%
Based on
CAKUT = congenital anomalies of the kidney and urinary tract
Most seizures are refractory to treatment with anti-seizure medications (ASMs), adrenocorticotropic hormone, steroids, and the ketogenic diet.
Other reported types of hearing loss include mixed or conductive hearing loss. For example, mixed moderate hearing loss was reported in two individuals due to bilateral deformations of the stapes (that had a tuning fork shape) and in one individual with a flattened last cochlear spire (identified by temporal bone CT scan) [
Postaxial polydactyly (predominantly of the hands) was noted in about 5%-10% of individuals with classic SGS.
Stenosis of the ureteropelvic junction or vesicoureteral reflux are common. Bladder atony may be the cause of frequent and persistent urinary tract infections.
Other anomalies can include abnormal ureters and renal cysts.
One individual had bilateral large coralliform (i.e., resembling the calyx cavities) renal stones that were predominantly calcium oxalate and calcium phosphate without pyelic dilatation [
Sacrococcygeal teratoma is the most common tumor. Other reported tumors include hepatoblastoma, lumbosacral teratoma, lumbosacral primitive neuroectodermal tumor, Wilms tumor, and extradural ependymomas. To date, juvenile myelomonocytic leukemia has been reported in one individual [
Although most children with SGS die from other causes, a 24-month-old child died of organ failure due to a sacrococcygeal teratoma and a five-year-old child died due to relapse of an extradural ependymal tumor [
In one individual, an abnormal posterior fossa with stretching of the pituitary stalk resulted in central diabetes insipidus and central hypothyroidism [
Postmortem microscopic evaluation of the pancreas in a four-day-old infant showed dilated interlobular ducts, filled with eosinic mucus and surrounded by abundant connective tissue. Additionally, dilated glands and mucus depositions were found in larynx and bronchial glands; although these findings were like those observed in cystic fibrosis,
One infant developed gingival hyperplasia at age seven months (two weeks prior to the initiation of ASMs) that became severe after age two years. His gingivae were so large that they protruded from his mouth, pressed his tongue to the pharynx, and covered his teeth. Because of difficulty with eating and breathing, he underwent full mouth gingivectomy twice, once at age four years and again at age six years. Histologic findings were gingival fibrous hyperplasia with mucoid depositions [
• In one individual, an abnormal posterior fossa with stretching of the pituitary stalk resulted in central diabetes insipidus and central hypothyroidism [
• Postmortem microscopic evaluation of the pancreas in a four-day-old infant showed dilated interlobular ducts, filled with eosinic mucus and surrounded by abundant connective tissue. Additionally, dilated glands and mucus depositions were found in larynx and bronchial glands; although these findings were like those observed in cystic fibrosis,
• One infant developed gingival hyperplasia at age seven months (two weeks prior to the initiation of ASMs) that became severe after age two years. His gingivae were so large that they protruded from his mouth, pressed his tongue to the pharynx, and covered his teeth. Because of difficulty with eating and breathing, he underwent full mouth gingivectomy twice, once at age four years and again at age six years. Histologic findings were gingival fibrous hyperplasia with mucoid depositions [
## Genotype-Phenotype Correlations
Pathogenic variants in
Classic SGS is associated with pathogenic gain-of-function
Atypical SGS is associated with pathogenic missense
• Classic SGS is associated with pathogenic gain-of-function
• Atypical SGS is associated with pathogenic missense
## Prevalence
To date, more than 50 individuals have been reported in the medical literature with molecularly confirmed classic SGS; more than 40 additional individuals were reported with the clinical diagnosis of classic SGS before
To date, five individuals with atypical SGS have been reported. For a summary of case reports and reported pathogenic missense variants in
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
The phenotypic features associated with classic Schinzel-Giedion syndrome (SGS) are often sufficient to diagnose this condition clinically. However, in individuals with findings in the moderate end of the spectrum of classic SGS (e.g., less apparent dysmorphisms, no hydronephrosis or other congenital anomalies and/or epilepsy) or atypical SGS, the following monogenic disorders (see
Selected Monogenic Disorders in the Differential Diagnosis of Classic and Atypical Schinzel-Giedion Syndrome
AR = autosomal recessive; MOI = mode of inheritance; MPS = mucopolysaccharidosis; XL = X-linked
Mucopolysaccharidosis is inherited in an autosomal recessive manner except for MPS II; MPS II is caused by pathogenic variants in
Zellweger spectrum disorder (ZSD) is typically inherited in an autosomal recessive manner. One
## Management
No clinical practice guidelines for classic or atypical Schinzel-Giedion syndrome (SGS) have been published. The recommendations in this section reflect the authors' experience in the management of individuals with SGS.
To establish the extent of disease and needs in an individual diagnosed with classic or atypical SGS, the evaluations summarized in
Schinzel-Giedion Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl brain MRI
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Evaluate for early intervention / special education
Gross motor & fine motor skills
Contractures, clubfoot, & (kypho)scoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of swallowing, aspiration risk, & nutritional status
Consider eval for gastrostomy tube or gastrostomy-jejunostomy tube placement in persons w/dysphagia &/or aspiration risk.
Perform pelvic ultrasound in children age ≤6 mos
Perform pelvic MRI in children age >6 mos
Attempt to insert flexible nasal endoscope to detect choanal stenosis/atresia.
Assess for tracheo- & laryngomalacia; additional imaging may be needed.
Mgmt of drooling due to risk of aspiration
Assess for congenital cardiac defects (mainly atrial septal defects).
Other defects incl patent foramen ovale, patent ductus arteriosus, & cardiac hypertrophy.
Note that excessive mucus production may lead to breathing problems.
Assess for tracheo- & laryngomalacia; additional imaging may be needed.
Lung ultrasound or MRI
Assess for UPJ obstruction or VUR & hydronephrosis.
Exclude other renal/bladder anomalies such as abnormal ureters, cysts & stones, & bladder atony.
Males: assess for hypospadias, cryptorchidism, micropenis, hypoplastic scrotum.
Females: assess for abnormal labia, hypoplastic uterus.
Assess for an anteriorly displaced anus.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Community or online
Social work involvement for parental support;
Palliative care involvement &/or home nursing referral.
ADL = activities of daily living; AFP = alpha-fetoprotein; CAKUT = congenital anomalies of the kidney and urinary tract; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UPJ = ureteropelvic junction; VUR = vesicoureteral reflux
For children with atypical SGS, the treating physician may weigh the disadvantages of anesthesia to perform an MRI against the possible advantages of a low-risk screen; however, more data are needed to inform these recommendations.
An option is to consider a full-body MRI at the time of diagnosis to evaluate for anomalies of the brain, lung, spinal cord, pancreas (e.g., splenopancreatic fusion / pancreatic hypoplasia), liver and spleen (hepatosplenomegaly), kidney, and urinary tract. Abnormal findings can then be evaluated in more detail.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for classic or atypical Schinzel-Giedion syndrome. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, ENT, surgery, pulmonology, oncology, urology, nephrology, audiology, gastroenterology, orthopedics, cardiology, and medical genetics (see
Schinzel-Giedion Syndrome: Treatment of Manifestations
Seizures may be extremely refractory to ASMs, ACTH, steroids, & ketogenic diet.
Different (combined) ASMs may be effective but none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Gastrostomy tube placement may be required for persistent feeding issues.
Standard mgmt for gastroparesis
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision service / OT / mobility services
Straight catheterization on daily schedule
Surgical interventions, such as vesicostomy, as needed
Therapy depending on type of cancer
Standard guidelines for respective cancer may be followed
Ensure appropriate social work involvement to connect families w/local resources, palliative care, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Based on needs of affected person
Hospice services if applicable
ACTH = adrenocorticotropic hormone; ASM = anti-seizure medication; CPAP = continuous positive airway pressure; 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 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, standers, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities refer to rehabilitation and physical medicine to consider management of muscle tone that may be an unrecognized source of pain and irritability.
Consultation with a developmental pediatrician may be helpful in guiding parents in appropriate behavior management strategies and therapies that may benefit the child and/or prescribing medications as needed. Severe irritability requires evaluation to determine an underlying medical cause such as urinary tract infection, hydrocephalus, or – in children with classic SGS – sacrococcygeal teratoma.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Schinzel-Giedion syndrome: Recommended Surveillance
Measurement of growth parameters (weight, height, & head circumference)
Eval of nutritional status & safety of oral intake incl swallowing problems / dysphagia
Monitor for constipation.
Monitor gastroesophageal reflux disease & perform additional GI assessments if needed.
In case of chronic vomiting, consider gastroparesis.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Consider brain &/or spine MRI depending on clinical changes (incl changes in mood, irritability, alertness).
Frequency based on clinical findings
Consider bladder atony when urinary tract infections are frequent & persistent.
Standard follow up of hydronephrosis & renal function
Frequency based on type of features
At each visit
Perform complete blood count when clinically indicated.
AFP = alpha-fetoprotein; CAKUT = congenital anomalies of the kidney and urinary tract; OT = occupational therapy; PT = physical therapy
Monitor renal function closely due to high frequency of renal scarring from recurrent pyelonephritis and structural urinary tract anomalies.
Based on screening guidelines for other disorders associated with increased risk of childhood cancers in the absence of established guidelines for SGS.
For children with atypical SGS, the treating physician may weigh the disadvantages of anesthesia needed to perform an MRI against the possible advantages of a low-risk screen; however, more data are needed to inform these recommendations.
Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal scarring from recurrent pyelonephritis and structural renal anomalies.
See
Search
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Evaluate for early intervention / special education
• Gross motor & fine motor skills
• Contractures, clubfoot, & (kypho)scoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of swallowing, aspiration risk, & nutritional status
• Consider eval for gastrostomy tube or gastrostomy-jejunostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Perform pelvic ultrasound in children age ≤6 mos
• Perform pelvic MRI in children age >6 mos
• Attempt to insert flexible nasal endoscope to detect choanal stenosis/atresia.
• Assess for tracheo- & laryngomalacia; additional imaging may be needed.
• Mgmt of drooling due to risk of aspiration
• Assess for congenital cardiac defects (mainly atrial septal defects).
• Other defects incl patent foramen ovale, patent ductus arteriosus, & cardiac hypertrophy.
• Note that excessive mucus production may lead to breathing problems.
• Assess for tracheo- & laryngomalacia; additional imaging may be needed.
• Lung ultrasound or MRI
• Assess for UPJ obstruction or VUR & hydronephrosis.
• Exclude other renal/bladder anomalies such as abnormal ureters, cysts & stones, & bladder atony.
• Males: assess for hypospadias, cryptorchidism, micropenis, hypoplastic scrotum.
• Females: assess for abnormal labia, hypoplastic uterus.
• Assess for an anteriorly displaced anus.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Community or online
• Social work involvement for parental support;
• Palliative care involvement &/or home nursing referral.
• Seizures may be extremely refractory to ASMs, ACTH, steroids, & ketogenic diet.
• Different (combined) ASMs may be effective but none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Gastrostomy tube placement may be required for persistent feeding issues.
• Standard mgmt for gastroparesis
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision service / OT / mobility services
• Straight catheterization on daily schedule
• Surgical interventions, such as vesicostomy, as needed
• Therapy depending on type of cancer
• Standard guidelines for respective cancer may be followed
• Ensure appropriate social work involvement to connect families w/local resources, palliative care, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Based on needs of affected person
• Hospice services if applicable
• 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, standers, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities refer to rehabilitation and physical medicine to consider management of muscle tone that may be an unrecognized source of pain and irritability.
• Measurement of growth parameters (weight, height, & head circumference)
• Eval of nutritional status & safety of oral intake incl swallowing problems / dysphagia
• Monitor for constipation.
• Monitor gastroesophageal reflux disease & perform additional GI assessments if needed.
• In case of chronic vomiting, consider gastroparesis.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Consider brain &/or spine MRI depending on clinical changes (incl changes in mood, irritability, alertness).
• Frequency based on clinical findings
• Consider bladder atony when urinary tract infections are frequent & persistent.
• Standard follow up of hydronephrosis & renal function
• Frequency based on type of features
• At each visit
• Perform complete blood count when clinically indicated.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with classic or atypical SGS, the evaluations summarized in
Schinzel-Giedion Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl brain MRI
Consider EEG if seizures are a concern.
To incl motor, adaptive, cognitive, & speech-language eval
Evaluate for early intervention / special education
Gross motor & fine motor skills
Contractures, clubfoot, & (kypho)scoliosis
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
To incl eval of swallowing, aspiration risk, & nutritional status
Consider eval for gastrostomy tube or gastrostomy-jejunostomy tube placement in persons w/dysphagia &/or aspiration risk.
Perform pelvic ultrasound in children age ≤6 mos
Perform pelvic MRI in children age >6 mos
Attempt to insert flexible nasal endoscope to detect choanal stenosis/atresia.
Assess for tracheo- & laryngomalacia; additional imaging may be needed.
Mgmt of drooling due to risk of aspiration
Assess for congenital cardiac defects (mainly atrial septal defects).
Other defects incl patent foramen ovale, patent ductus arteriosus, & cardiac hypertrophy.
Note that excessive mucus production may lead to breathing problems.
Assess for tracheo- & laryngomalacia; additional imaging may be needed.
Lung ultrasound or MRI
Assess for UPJ obstruction or VUR & hydronephrosis.
Exclude other renal/bladder anomalies such as abnormal ureters, cysts & stones, & bladder atony.
Males: assess for hypospadias, cryptorchidism, micropenis, hypoplastic scrotum.
Females: assess for abnormal labia, hypoplastic uterus.
Assess for an anteriorly displaced anus.
Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Community or online
Social work involvement for parental support;
Palliative care involvement &/or home nursing referral.
ADL = activities of daily living; AFP = alpha-fetoprotein; CAKUT = congenital anomalies of the kidney and urinary tract; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; UPJ = ureteropelvic junction; VUR = vesicoureteral reflux
For children with atypical SGS, the treating physician may weigh the disadvantages of anesthesia to perform an MRI against the possible advantages of a low-risk screen; however, more data are needed to inform these recommendations.
An option is to consider a full-body MRI at the time of diagnosis to evaluate for anomalies of the brain, lung, spinal cord, pancreas (e.g., splenopancreatic fusion / pancreatic hypoplasia), liver and spleen (hepatosplenomegaly), kidney, and urinary tract. Abnormal findings can then be evaluated in more detail.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl brain MRI
• Consider EEG if seizures are a concern.
• To incl motor, adaptive, cognitive, & speech-language eval
• Evaluate for early intervention / special education
• Gross motor & fine motor skills
• Contractures, clubfoot, & (kypho)scoliosis
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• To incl eval of swallowing, aspiration risk, & nutritional status
• Consider eval for gastrostomy tube or gastrostomy-jejunostomy tube placement in persons w/dysphagia &/or aspiration risk.
• Perform pelvic ultrasound in children age ≤6 mos
• Perform pelvic MRI in children age >6 mos
• Attempt to insert flexible nasal endoscope to detect choanal stenosis/atresia.
• Assess for tracheo- & laryngomalacia; additional imaging may be needed.
• Mgmt of drooling due to risk of aspiration
• Assess for congenital cardiac defects (mainly atrial septal defects).
• Other defects incl patent foramen ovale, patent ductus arteriosus, & cardiac hypertrophy.
• Note that excessive mucus production may lead to breathing problems.
• Assess for tracheo- & laryngomalacia; additional imaging may be needed.
• Lung ultrasound or MRI
• Assess for UPJ obstruction or VUR & hydronephrosis.
• Exclude other renal/bladder anomalies such as abnormal ureters, cysts & stones, & bladder atony.
• Males: assess for hypospadias, cryptorchidism, micropenis, hypoplastic scrotum.
• Females: assess for abnormal labia, hypoplastic uterus.
• Assess for an anteriorly displaced anus.
• Ensure appropriate social work involvement to connect families w/local resources, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Community or online
• Social work involvement for parental support;
• Palliative care involvement &/or home nursing referral.
## Treatment of Manifestations
There is no cure for classic or atypical Schinzel-Giedion syndrome. Supportive treatment to improve quality of life, maximize function, and reduce complications is recommended. This can include multidisciplinary care by specialists in pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, ENT, surgery, pulmonology, oncology, urology, nephrology, audiology, gastroenterology, orthopedics, cardiology, and medical genetics (see
Schinzel-Giedion Syndrome: Treatment of Manifestations
Seizures may be extremely refractory to ASMs, ACTH, steroids, & ketogenic diet.
Different (combined) ASMs may be effective but none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Gastrostomy tube placement may be required for persistent feeding issues.
Standard mgmt for gastroparesis
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision service / OT / mobility services
Straight catheterization on daily schedule
Surgical interventions, such as vesicostomy, as needed
Therapy depending on type of cancer
Standard guidelines for respective cancer may be followed
Ensure appropriate social work involvement to connect families w/local resources, palliative care, respite, & support.
Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
Based on needs of affected person
Hospice services if applicable
ACTH = adrenocorticotropic hormone; ASM = anti-seizure medication; CPAP = continuous positive airway pressure; 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 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, standers, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities refer to rehabilitation and physical medicine to consider management of muscle tone that may be an unrecognized source of pain and irritability.
Consultation with a developmental pediatrician may be helpful in guiding parents in appropriate behavior management strategies and therapies that may benefit the child and/or prescribing medications as needed. Severe irritability requires evaluation to determine an underlying medical cause such as urinary tract infection, hydrocephalus, or – in children with classic SGS – sacrococcygeal teratoma.
• Seizures may be extremely refractory to ASMs, ACTH, steroids, & ketogenic diet.
• Different (combined) ASMs may be effective but none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Gastrostomy tube placement may be required for persistent feeding issues.
• Standard mgmt for gastroparesis
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision service / OT / mobility services
• Straight catheterization on daily schedule
• Surgical interventions, such as vesicostomy, as needed
• Therapy depending on type of cancer
• Standard guidelines for respective cancer may be followed
• Ensure appropriate social work involvement to connect families w/local resources, palliative care, respite, & support.
• Coordinate care to manage multiple subspecialty appointments, equipment, medications, & supplies.
• Based on needs of affected person
• Hospice services if applicable
• 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, standers, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities refer to rehabilitation and physical medicine to consider management of muscle tone that may be an unrecognized source of pain and irritability.
## 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, standers, walkers, bath chairs, orthotics, adaptive strollers).
For muscle tone abnormalities refer to rehabilitation and physical medicine to consider management of muscle tone that may be an unrecognized source of pain and irritability.
• 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, standers, walkers, bath chairs, orthotics, adaptive strollers).
• For muscle tone abnormalities refer to rehabilitation and physical medicine to consider management of muscle tone that may be an unrecognized source of pain and irritability.
## Neurobehavioral Concerns
Consultation with a developmental pediatrician may be helpful in guiding parents in appropriate behavior management strategies and therapies that may benefit the child and/or prescribing medications as needed. Severe irritability requires evaluation to determine an underlying medical cause such as urinary tract infection, hydrocephalus, or – in children with classic SGS – sacrococcygeal teratoma.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Schinzel-Giedion syndrome: Recommended Surveillance
Measurement of growth parameters (weight, height, & head circumference)
Eval of nutritional status & safety of oral intake incl swallowing problems / dysphagia
Monitor for constipation.
Monitor gastroesophageal reflux disease & perform additional GI assessments if needed.
In case of chronic vomiting, consider gastroparesis.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Consider brain &/or spine MRI depending on clinical changes (incl changes in mood, irritability, alertness).
Frequency based on clinical findings
Consider bladder atony when urinary tract infections are frequent & persistent.
Standard follow up of hydronephrosis & renal function
Frequency based on type of features
At each visit
Perform complete blood count when clinically indicated.
AFP = alpha-fetoprotein; CAKUT = congenital anomalies of the kidney and urinary tract; OT = occupational therapy; PT = physical therapy
Monitor renal function closely due to high frequency of renal scarring from recurrent pyelonephritis and structural urinary tract anomalies.
Based on screening guidelines for other disorders associated with increased risk of childhood cancers in the absence of established guidelines for SGS.
For children with atypical SGS, the treating physician may weigh the disadvantages of anesthesia needed to perform an MRI against the possible advantages of a low-risk screen; however, more data are needed to inform these recommendations.
• Measurement of growth parameters (weight, height, & head circumference)
• Eval of nutritional status & safety of oral intake incl swallowing problems / dysphagia
• Monitor for constipation.
• Monitor gastroesophageal reflux disease & perform additional GI assessments if needed.
• In case of chronic vomiting, consider gastroparesis.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Consider brain &/or spine MRI depending on clinical changes (incl changes in mood, irritability, alertness).
• Frequency based on clinical findings
• Consider bladder atony when urinary tract infections are frequent & persistent.
• Standard follow up of hydronephrosis & renal function
• Frequency based on type of features
• At each visit
• Perform complete blood count when clinically indicated.
## Agents/Circumstances to Avoid
Nephrotoxic drugs such as nonsteroidal anti-inflammatory drugs and vancomycin should be used with caution due to high frequency of chronic renal scarring from recurrent pyelonephritis and structural renal anomalies.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Classic and atypical Schinzel-Giedion syndrome (SGS) are autosomal dominant disorders typically caused by a
Most probands reported to date with classic or atypical SGS have the disorder as the result of a
Rarely, individuals diagnosed with SGS have the disorder as the result of a pathogenic variant inherited from a parent. Sib recurrence of clinically defined classic SGS, presumed to be due to parental germline mosaicism, has been reported in two families [
If a molecular diagnosis has been established in the proband, 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 molecular diagnosis has been established in proband and 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 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 classic or atypical SGS have the disorder as the result of a
• Rarely, individuals diagnosed with SGS have the disorder as the result of a pathogenic variant inherited from a parent. Sib recurrence of clinically defined classic SGS, presumed to be due to parental germline mosaicism, has been reported in two families [
• If a molecular diagnosis has been established in the proband, 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 molecular diagnosis has been established in proband and 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 parents of affected individuals.
## Mode of Inheritance
Classic and atypical Schinzel-Giedion syndrome (SGS) are autosomal dominant disorders typically caused by a
## Risk to Family Members
Most probands reported to date with classic or atypical SGS have the disorder as the result of a
Rarely, individuals diagnosed with SGS have the disorder as the result of a pathogenic variant inherited from a parent. Sib recurrence of clinically defined classic SGS, presumed to be due to parental germline mosaicism, has been reported in two families [
If a molecular diagnosis has been established in the proband, 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 molecular diagnosis has been established in proband and the
If the parents have not been tested for the
• Most probands reported to date with classic or atypical SGS have the disorder as the result of a
• Rarely, individuals diagnosed with SGS have the disorder as the result of a pathogenic variant inherited from a parent. Sib recurrence of clinically defined classic SGS, presumed to be due to parental germline mosaicism, has been reported in two families [
• If a molecular diagnosis has been established in the proband, 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 molecular diagnosis has been established in proband and 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 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
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
Schinzel-Giedion Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Schinzel-Giedion Syndrome (
Classic Schinzel-Giedion syndrome (SGS) is caused by pathogenic heterozygous gain-of-function variants within a
Atypical SGS is caused by other pathogenic
Notably, other
Variants listed in the table have been provided by the authors.
It is expected that there will be a spectrum of severity even within classic SGS syndrome-associated pathogenic variants as knowledge regarding the clinical and molecular spectrum continues to evolve. Further, pathogenic
## Molecular Pathogenesis
Classic Schinzel-Giedion syndrome (SGS) is caused by pathogenic heterozygous gain-of-function variants within a
Atypical SGS is caused by other pathogenic
Notably, other
Variants listed in the table have been provided by the authors.
It is expected that there will be a spectrum of severity even within classic SGS syndrome-associated pathogenic variants as knowledge regarding the clinical and molecular spectrum continues to evolve. Further, pathogenic
## Chapter Notes
Dr Bregje van Bon is involved in clinical follow up of individuals with
The authors would like to thank all individuals with SGS, their families, and the Schinzel-Giedion Syndrome Foundation for sharing their medical and personal stories at the clinic and during live and online international meetings. They are the true experts, and we have been able write this
7 March 2024 (bp) Review posted live
9 August 2023 (bvb) Original submission
• 7 March 2024 (bp) Review posted live
• 9 August 2023 (bvb) Original submission
## Author Notes
Dr Bregje van Bon is involved in clinical follow up of individuals with
## Acknowledgments
The authors would like to thank all individuals with SGS, their families, and the Schinzel-Giedion Syndrome Foundation for sharing their medical and personal stories at the clinic and during live and online international meetings. They are the true experts, and we have been able write this
## Revision History
7 March 2024 (bp) Review posted live
9 August 2023 (bvb) Original submission
• 7 March 2024 (bp) Review posted live
• 9 August 2023 (bvb) Original submission
## References
## Literature Cited
Characteristic hand posture with clenched hand in an individual with Schinzel-Giedion syndrome
Adapted with permission from
Characteristic facial features in individuals with Schinzel-Giedion syndrome (SGS), including prominent forehead, bitemporal narrowing, midface retrusion, hypertelorism, infraorbital crease, short nose with upturned nasal tip, and low-set, abnormally formed ears
Most individuals with SGS have a characteristic facial gestalt that is easily recognizable. There are large fontanelles, a prominent forehead, bitemporal narrowing, shallow orbits or prominent eyes, hypertelorism, midface retrusion, shortened midface, and full cheeks, leading to a facial frontal silhouette in the shape of the number eight. Additionally, most individuals have an infraorbital crease, upslanted palpebral fissures, and short nose with a bulbous nasal tip. During the first weeks of life some infants may have less recognizable facial features.
Additional diagnostic clues include abnormal ear shape, which are low-set and posteriorly rotated with anteriorly angulated lobules leading to a question mark shape. Often, individuals have a large mouth with an everted vermilion of the lower lip, protruding tongue, and macroglossia. Some may also have micrognathia, a short neck, and/or facial hemangioma.
Reprinted with permission from
|
[] |
7/3/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
schmid-mcd
|
schmid-mcd
|
[
"Metaphyseal Chondrodysplasia Type Schmid (MCDS)",
"Metaphyseal Dysplasia Schmid (MCS), COL10A1-Related",
"Metaphyseal Chondrodysplasia Type Schmid (MCDS)",
"Metaphyseal Dysplasia Schmid (MCS), COL10A1-Related",
"Collagen alpha-1(X) chain",
"COL10A1",
"Schmid Metaphyseal Chondrodysplasia"
] |
Schmid Metaphyseal Chondrodysplasia
|
Christopher Mark Richmond, Ravi Savarirayan
|
Summary Schmid metaphyseal chondrodysplasia (SMCD) is characterized by progressive short stature that develops by age two years. The clinical and radiographic features are usually not present at birth, but manifest in early childhood with short limbs, genu varum, and waddling gait. Facial features and head size are normal. Radiographs show metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping); shortening of the tubular bones; widened growth plates; coxa vara; and anterior cupping, sclerosis, and splaying of the ribs. Mild hand involvement often includes shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges. Platyspondyly and vertebral end plate irregularities are less common. Hand and vertebral involvement can resolve with age. Early motor milestones may be delayed due to orthopedic complications. Intelligence is normal. Joint pain in the knees and hips is common and may limit physical activity. Adult height is typically more than 3.5 standard deviations below the mean, although a wide spectrum that overlaps normal height has been reported. There are no extraskeletal manifestations. The diagnosis of SMCD is established in a proband with characteristic clinical and radiographic features and/or identification of a heterozygous pathogenic variant in SMCD is inherited in an autosomal dominant manner. Approximately half of individuals diagnosed with SMCD have an affected parent (the heterozygous parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed). Approximately half of individuals diagnosed with SMCD have the disorder as the result of a
|
## Diagnosis
No formal diagnostic criteria for Schmid metaphyseal chondrodysplasia (SMCD) have been established.
SMCD
Short-limbed short stature by age two years (in >60%)
Genu varum (bowed legs) (>60%)
Waddling gait (>80%)
Lumbar lordosis by age three to five years
Normal craniofacies and absence of extraskeletal manifestations
Shortening of the tubular bones (>60%)
Metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping), especially the proximal and distal femora (~100%)
Widening of the growth plates
Coxa vara (>80%)
Anterior cupping, sclerosis, and splaying of the ribs (>90%)
Mild hand involvement including shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges (~50%). Radiographic phalangeal and metacarpal findings may resolve with age.
Vertebral involvement including platyspondyly and end plate irregularities (~10%)
The diagnosis of SMCD is established in a proband with characteristic clinical and radiographic features (see
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 radiographic findings suggest a diagnosis of SMCD, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype overlaps other inherited disorders characterized by metaphyseal dysplasia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schmid Metaphyseal Chondrodysplasia
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.
Review of all published reports, ClinVar [
• Short-limbed short stature by age two years (in >60%)
• Genu varum (bowed legs) (>60%)
• Waddling gait (>80%)
• Lumbar lordosis by age three to five years
• Normal craniofacies and absence of extraskeletal manifestations
• Shortening of the tubular bones (>60%)
• Metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping), especially the proximal and distal femora (~100%)
• Widening of the growth plates
• Coxa vara (>80%)
• Anterior cupping, sclerosis, and splaying of the ribs (>90%)
• Mild hand involvement including shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges (~50%). Radiographic phalangeal and metacarpal findings may resolve with age.
• Vertebral involvement including platyspondyly and end plate irregularities (~10%)
• For an introduction to multigene panels click
## Suggestive Findings
SMCD
Short-limbed short stature by age two years (in >60%)
Genu varum (bowed legs) (>60%)
Waddling gait (>80%)
Lumbar lordosis by age three to five years
Normal craniofacies and absence of extraskeletal manifestations
Shortening of the tubular bones (>60%)
Metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping), especially the proximal and distal femora (~100%)
Widening of the growth plates
Coxa vara (>80%)
Anterior cupping, sclerosis, and splaying of the ribs (>90%)
Mild hand involvement including shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges (~50%). Radiographic phalangeal and metacarpal findings may resolve with age.
Vertebral involvement including platyspondyly and end plate irregularities (~10%)
• Short-limbed short stature by age two years (in >60%)
• Genu varum (bowed legs) (>60%)
• Waddling gait (>80%)
• Lumbar lordosis by age three to five years
• Normal craniofacies and absence of extraskeletal manifestations
• Shortening of the tubular bones (>60%)
• Metaphyseal irregularities of the long bones (e.g., splaying, flaring, cupping), especially the proximal and distal femora (~100%)
• Widening of the growth plates
• Coxa vara (>80%)
• Anterior cupping, sclerosis, and splaying of the ribs (>90%)
• Mild hand involvement including shortening of the tubular bones and metaphyseal cupping of the metacarpals and proximal phalanges (~50%). Radiographic phalangeal and metacarpal findings may resolve with age.
• Vertebral involvement including platyspondyly and end plate irregularities (~10%)
## Establishing the Diagnosis
The diagnosis of SMCD is established in a proband with characteristic clinical and radiographic features (see
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 radiographic findings suggest a diagnosis of SMCD, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype overlaps other inherited disorders characterized by metaphyseal dysplasia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schmid Metaphyseal Chondrodysplasia
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.
Review of all published reports, ClinVar [
• For an introduction to multigene panels click
## Option 1
When the phenotypic and radiographic findings suggest a diagnosis of SMCD, 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 overlaps other inherited disorders characterized by metaphyseal dysplasia,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schmid Metaphyseal Chondrodysplasia
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.
Review of all published reports, ClinVar [
## Clinical Characteristics
Schmid metaphyseal chondrodysplasia (SMCD) is typically diagnosed in early childhood and is the most common and least severe metaphyseal chondrodysplasia [
A comprehensive review of the published reports and clinical databases identified at least 150 published unrelated individuals with SMCD and a confirmed pathogenic variant in
Schmid Metaphyseal Chondrodysplasia: Frequency of Select Clinical and Radiographic Features
Hand involvement is present in fewer than half of individuals and is usually mild. Metaphyseal cupping of the distal metacarpals and proximal phalanges and shortening of the phalanges may be seen and are more pronounced in the fifth ray. Hand features may become less apparent with age [
Vertebral involvement is less common and, when present, is usually mild. Reported findings include platyspondyly and vertebral end plate anomalies (e.g., rounding of the anterior aspects of the vertebral bodies, superior and inferior indentations of the vertebral bodies, posterior wedging of the vertebrae) [
A more severe phenotype has been observed in individuals with missense pathogenic variants in the signal peptide domain at the N-terminal end of the protein and in the NC1 domain compared to truncating pathogenic variants [
Penetrance approaches 100%; however, there is wide inter- and intrafamilial phenotypic variation [
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The exact prevalence of SMCD is unknown. Incidence has historically been estimated at between three and six individuals per million [
## Clinical Description
Schmid metaphyseal chondrodysplasia (SMCD) is typically diagnosed in early childhood and is the most common and least severe metaphyseal chondrodysplasia [
A comprehensive review of the published reports and clinical databases identified at least 150 published unrelated individuals with SMCD and a confirmed pathogenic variant in
Schmid Metaphyseal Chondrodysplasia: Frequency of Select Clinical and Radiographic Features
Hand involvement is present in fewer than half of individuals and is usually mild. Metaphyseal cupping of the distal metacarpals and proximal phalanges and shortening of the phalanges may be seen and are more pronounced in the fifth ray. Hand features may become less apparent with age [
Vertebral involvement is less common and, when present, is usually mild. Reported findings include platyspondyly and vertebral end plate anomalies (e.g., rounding of the anterior aspects of the vertebral bodies, superior and inferior indentations of the vertebral bodies, posterior wedging of the vertebrae) [
## Genotype-Phenotype Correlations
A more severe phenotype has been observed in individuals with missense pathogenic variants in the signal peptide domain at the N-terminal end of the protein and in the NC1 domain compared to truncating pathogenic variants [
## Penetrance
Penetrance approaches 100%; however, there is wide inter- and intrafamilial phenotypic variation [
## Nomenclature
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
The exact prevalence of SMCD is unknown. Incidence has historically been estimated at between three and six individuals per million [
## Genetically Related (Allelic) Disorders
No phenotypes other than SMCD are known to be associated with germline pathogenic variants in
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Schmid Metaphyseal Chondrodysplasia
Short stature
Metaphyseal widening & irregularities
Skeletal changes usually milder
Metaphyseal changes usually greatest in ribs
Extraskeletal features: exocrine pancreatic insufficiency, neutropenia, ↑ infections, anemia
Genu varum
Metaphyseal dysplasia
Short limbs, limb disproportion
Apparent in 1st few mos of life but resolves spontaneously w/age
Epiphyseal dysplasia
Generalized osteopenia
Normal stature by adolescence
Genu varum
Short limbs, limb disproportion
Severe metaphyseal changes in long bones (irregularities, widening, marginal blurring)
Apparent in 1st few mos of life but resolves spontaneously w/age
Epiphyseal dysplasia
Generalized osteopenia
Normal stature by adolescence
Genu varum
Metaphyseal dysplasia
Moderate short stature
Abnormal ribs
Carpal bone hypoplasia
Iliac crest irregularity in childhood
Genu varum
Short stature
Metaphyseal dysplasia
Waddling gait
± dysmorphic features: prominent superciliary arches, exophthalmos
Hypercalcemia, hypercalciuria
Metaphyseal changes more severe
Sclerosis of skull in late adulthood
Genu varum
Short-limbed short stature
Variable metaphyseal dysplasia
Coxa vara rarely seen
Extraskeletal features: fine/sparse hair, immune dysfunction, transient macrocytic anemia, Hirschsprung disease
Ligament laxity
Metaphyseal flaring of long bones
Short stature
Broad clavicles
Maxillary hypoplasia
Variable brachydactyly
AD = autosomal dominant; AR = autosomal recessive; SMCD = Schmid metaphyseal chondrodysplasia; MOI = mode of inheritance
Shwachman-Diamond syndrome (SDS) caused by pathogenic variants in
Terminology per 2023 revision of the Nosology of Genetic Skeletal Disorders [
Biochemical Findings in Schmid Metaphyseal Chondrodysplasia Compared with Vitamin D-Deficient Rickets and Metabolic Bone Diseases
SMCD = Schmid metaphyseal chondrodysplasia; PTH = parathyroid stimulating hormone
Urinary phosphates may be increased.
Caused by deficient 25-OHD-1-α-hydroxylase activity
• Short stature
• Metaphyseal widening & irregularities
• Skeletal changes usually milder
• Metaphyseal changes usually greatest in ribs
• Extraskeletal features: exocrine pancreatic insufficiency, neutropenia, ↑ infections, anemia
• Genu varum
• Metaphyseal dysplasia
• Short limbs, limb disproportion
• Apparent in 1st few mos of life but resolves spontaneously w/age
• Epiphyseal dysplasia
• Generalized osteopenia
• Normal stature by adolescence
• Genu varum
• Short limbs, limb disproportion
• Severe metaphyseal changes in long bones (irregularities, widening, marginal blurring)
• Apparent in 1st few mos of life but resolves spontaneously w/age
• Epiphyseal dysplasia
• Generalized osteopenia
• Normal stature by adolescence
• Genu varum
• Metaphyseal dysplasia
• Moderate short stature
• Abnormal ribs
• Carpal bone hypoplasia
• Iliac crest irregularity in childhood
• Genu varum
• Short stature
• Metaphyseal dysplasia
• Waddling gait
• ± dysmorphic features: prominent superciliary arches, exophthalmos
• Hypercalcemia, hypercalciuria
• Metaphyseal changes more severe
• Sclerosis of skull in late adulthood
• Genu varum
• Short-limbed short stature
• Variable metaphyseal dysplasia
• Coxa vara rarely seen
• Extraskeletal features: fine/sparse hair, immune dysfunction, transient macrocytic anemia, Hirschsprung disease
• Ligament laxity
• Metaphyseal flaring of long bones
• Short stature
• Broad clavicles
• Maxillary hypoplasia
• Variable brachydactyly
## Management
No clinical practice management guidelines for Schmid metaphyseal chondrodysplasia (SMCD) have been published. In the absence of published guidelines, the following recommendations are based on the authors' personal experience managing individuals with this disorder. Management should emphasize multidisciplinary care and a considered approach to surgical intervention when appropriate.
To establish the extent of disease and needs in an individual diagnosed with SMCD, the evaluations summarized in
Schmid Metaphyseal Chondrodysplasia: Recommended Evaluations Following Initial Diagnosis
Qualification of functional limitations / activities of daily living;
Referral to PT &/or OT.
Assessment for adaptive needs due to short stature
Referral to support resources
In school: step stools, lowered light switches, appropriate-height toilets or other means to make them accessible, lower desks, & foot support in front of chairs. All children need to be able to independently escape the building in an emergency.
In adults: pedal extenders for driving, workplace modification (e.g., lower desks, smaller keyboards, step stools, & toilet access)
MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist; SMCD = Schmid metaphyseal chondrodysplasia
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
Schmid Metaphyseal Chondrodysplasia: Treatment of Manifestations
Referral to orthopedic surgeon for eval
Referral to PT
Referral to OT if indicated
Analgesics, pain specialist referral if appropriate
Advice on joint-friendly activities (e.g., swimming, cycling)
Counseling re weight optimization where appropriate
Consider need for a mobility device.
Avoidance of physical activities that strain joints, when possible
Referral to orthopedic surgeon
Guided growth surgery
Valgus osteotomy
Progressive or symptomatic varus deformity (e.g., varus angulation >120 degrees) or significant coxa vara;
Triangular fragment in the inferior femoral neck;
Poor or deteriorating function.
Guided growth using 8-plates, hemiepiphysiodesis, stapling;
Valgus-producing & derotational osteotomies.
Anticipatory guidance for maintenance of healthy weight
Advice re regular low-impact exercise
Referral to support resources
Referral to psychologist
Environmental or occupational modifications may be needed (e.g., step stools, lower desks).
Consultation w/OT may be beneficial.
OT = occupational therapist; PT = physical therapist; SMCD = Schmid metaphyseal chondrodysplasia
Adapted from
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Schmid Metaphyseal Chondrodysplasia: Recommended Surveillance
Clinical exam
Referral for orthopedic assessment if indicated
Referral to PT if indicated
Monitoring for surgical complications if indicated
PT = physical therapist
Individuals with SMCD should maintain an appropriate weight for height, as obesity increases stress on the joints and may exacerbate joint pain and worsen the impact of genu varum and waddling gait on mobility. Education should include advice regarding weight loss (when appropriate), maintenance of a healthy diet, and regular low-impact exercise.
High-impact exercise or exercise that causes repetitive strain on affected joints should be avoided in favor of joint-friendly low-impact activities, including swimming and biking.
See
Carbamazepine is an FDA-approved medication for use in epilepsy and bipolar affective disorder. Its additional action as a stimulator of autophagy and proteasomal degradation pathways have led to its repurposing as a candidate therapy for conditions caused by retention of misfolded mutated structural proteins, such as SMCD [
Search
• Qualification of functional limitations / activities of daily living;
• Referral to PT &/or OT.
• Assessment for adaptive needs due to short stature
• Referral to support resources
• In school: step stools, lowered light switches, appropriate-height toilets or other means to make them accessible, lower desks, & foot support in front of chairs. All children need to be able to independently escape the building in an emergency.
• In adults: pedal extenders for driving, workplace modification (e.g., lower desks, smaller keyboards, step stools, & toilet access)
• Referral to orthopedic surgeon for eval
• Referral to PT
• Referral to OT if indicated
• Analgesics, pain specialist referral if appropriate
• Advice on joint-friendly activities (e.g., swimming, cycling)
• Counseling re weight optimization where appropriate
• Consider need for a mobility device.
• Avoidance of physical activities that strain joints, when possible
• Referral to orthopedic surgeon
• Guided growth surgery
• Valgus osteotomy
• Progressive or symptomatic varus deformity (e.g., varus angulation >120 degrees) or significant coxa vara;
• Triangular fragment in the inferior femoral neck;
• Poor or deteriorating function.
• Guided growth using 8-plates, hemiepiphysiodesis, stapling;
• Valgus-producing & derotational osteotomies.
• Anticipatory guidance for maintenance of healthy weight
• Advice re regular low-impact exercise
• Referral to support resources
• Referral to psychologist
• Environmental or occupational modifications may be needed (e.g., step stools, lower desks).
• Consultation w/OT may be beneficial.
• Clinical exam
• Referral for orthopedic assessment if indicated
• Referral to PT if indicated
• Monitoring for surgical complications if indicated
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SMCD, the evaluations summarized in
Schmid Metaphyseal Chondrodysplasia: Recommended Evaluations Following Initial Diagnosis
Qualification of functional limitations / activities of daily living;
Referral to PT &/or OT.
Assessment for adaptive needs due to short stature
Referral to support resources
In school: step stools, lowered light switches, appropriate-height toilets or other means to make them accessible, lower desks, & foot support in front of chairs. All children need to be able to independently escape the building in an emergency.
In adults: pedal extenders for driving, workplace modification (e.g., lower desks, smaller keyboards, step stools, & toilet access)
MOI = mode of inheritance; OT = occupational therapist; PT = physical therapist; SMCD = Schmid metaphyseal chondrodysplasia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Qualification of functional limitations / activities of daily living;
• Referral to PT &/or OT.
• Assessment for adaptive needs due to short stature
• Referral to support resources
• In school: step stools, lowered light switches, appropriate-height toilets or other means to make them accessible, lower desks, & foot support in front of chairs. All children need to be able to independently escape the building in an emergency.
• In adults: pedal extenders for driving, workplace modification (e.g., lower desks, smaller keyboards, step stools, & toilet access)
## 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
Schmid Metaphyseal Chondrodysplasia: Treatment of Manifestations
Referral to orthopedic surgeon for eval
Referral to PT
Referral to OT if indicated
Analgesics, pain specialist referral if appropriate
Advice on joint-friendly activities (e.g., swimming, cycling)
Counseling re weight optimization where appropriate
Consider need for a mobility device.
Avoidance of physical activities that strain joints, when possible
Referral to orthopedic surgeon
Guided growth surgery
Valgus osteotomy
Progressive or symptomatic varus deformity (e.g., varus angulation >120 degrees) or significant coxa vara;
Triangular fragment in the inferior femoral neck;
Poor or deteriorating function.
Guided growth using 8-plates, hemiepiphysiodesis, stapling;
Valgus-producing & derotational osteotomies.
Anticipatory guidance for maintenance of healthy weight
Advice re regular low-impact exercise
Referral to support resources
Referral to psychologist
Environmental or occupational modifications may be needed (e.g., step stools, lower desks).
Consultation w/OT may be beneficial.
OT = occupational therapist; PT = physical therapist; SMCD = Schmid metaphyseal chondrodysplasia
Adapted from
• Referral to orthopedic surgeon for eval
• Referral to PT
• Referral to OT if indicated
• Analgesics, pain specialist referral if appropriate
• Advice on joint-friendly activities (e.g., swimming, cycling)
• Counseling re weight optimization where appropriate
• Consider need for a mobility device.
• Avoidance of physical activities that strain joints, when possible
• Referral to orthopedic surgeon
• Guided growth surgery
• Valgus osteotomy
• Progressive or symptomatic varus deformity (e.g., varus angulation >120 degrees) or significant coxa vara;
• Triangular fragment in the inferior femoral neck;
• Poor or deteriorating function.
• Guided growth using 8-plates, hemiepiphysiodesis, stapling;
• Valgus-producing & derotational osteotomies.
• Anticipatory guidance for maintenance of healthy weight
• Advice re regular low-impact exercise
• Referral to support resources
• Referral to psychologist
• Environmental or occupational modifications may be needed (e.g., step stools, lower desks).
• Consultation w/OT may be beneficial.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Schmid Metaphyseal Chondrodysplasia: Recommended Surveillance
Clinical exam
Referral for orthopedic assessment if indicated
Referral to PT if indicated
Monitoring for surgical complications if indicated
PT = physical therapist
• Clinical exam
• Referral for orthopedic assessment if indicated
• Referral to PT if indicated
• Monitoring for surgical complications if indicated
## Agents/Circumstances to Avoid
Individuals with SMCD should maintain an appropriate weight for height, as obesity increases stress on the joints and may exacerbate joint pain and worsen the impact of genu varum and waddling gait on mobility. Education should include advice regarding weight loss (when appropriate), maintenance of a healthy diet, and regular low-impact exercise.
High-impact exercise or exercise that causes repetitive strain on affected joints should be avoided in favor of joint-friendly low-impact activities, including swimming and biking.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Carbamazepine is an FDA-approved medication for use in epilepsy and bipolar affective disorder. Its additional action as a stimulator of autophagy and proteasomal degradation pathways have led to its repurposing as a candidate therapy for conditions caused by retention of misfolded mutated structural proteins, such as SMCD [
Search
## Genetic Counseling
Schmid metaphyseal chondrodysplasia (SMCD) is inherited in an autosomal dominant manner.
Approximately half (45%-57%) of individuals diagnosed with SMCD inherited the condition from a parent. The heterozygous parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed in SMCD, and the heterozygous parent may only have mild features [
Approximately half (43%-55%) of individuals diagnosed with SMCD represent simplex cases (i.e., a single occurrence in a family) and have the disorder as the result of a
If the proband appears to be the only affected family member, recommendations for the parents of the proband include physical examination and measurement of proportions. Recommendations may also include radiographs (as isolated asymptomatic individuals have been reported with radiographic changes only) and, if a molecular diagnosis has been established in the proband, molecular genetic testing.
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 family history of some individuals diagnosed with SMCD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (reported in rare, isolated cases), or mild radiographic features in an affected parent that have not previously come to medical attention. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the
If the proband has a known SMCD-causing 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 germline mosaicism [
If the parents are clinically unaffected (based on physical examination, measurement of proportions, and radiographs) 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 SMCD because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
Each child of an individual with SMCD has a 50% chance of inheriting the
Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMCD may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals have serious sequelae and poor outcomes [
If the proband and the proband's reproductive partner are both affected with SMCD, each child has a 25% likelihood of average stature (unaffected), a 50% likelihood of having SMCD due to a heterozygous pathogenic variant, and a 25% likelihood of having a more severe SMCD phenotype due to inheritance of biallelic pathogenic variants.
Two individuals with biallelic SMCD-causing pathogenic variants and more severe presentations have been reported [
Multiple miscarriages have been reported in a large consanguineous family segregating SMCD, suggesting that some homozygous
If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has at conception a 25% likelihood of average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a more severe blended skeletal phenotype, including fetal demise.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 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 half (45%-57%) of individuals diagnosed with SMCD inherited the condition from a parent. The heterozygous parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed in SMCD, and the heterozygous parent may only have mild features [
• Approximately half (43%-55%) of individuals diagnosed with SMCD represent simplex cases (i.e., a single occurrence in a family) and have the disorder as the result of a
• If the proband appears to be the only affected family member, recommendations for the parents of the proband include physical examination and measurement of proportions. Recommendations may also include radiographs (as isolated asymptomatic individuals have been reported with radiographic changes only) and, if a molecular diagnosis has been established in the proband, molecular genetic testing.
• 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 family history of some individuals diagnosed with SMCD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (reported in rare, isolated cases), or mild radiographic features in an affected parent that have not previously come to medical attention. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
• 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 is known to have the
• If the proband has a known SMCD-causing 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 germline mosaicism [
• If the parents are clinically unaffected (based on physical examination, measurement of proportions, and radiographs) 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 SMCD because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
• Each child of an individual with SMCD has a 50% chance of inheriting the
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMCD may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals have serious sequelae and poor outcomes [
• If the proband and the proband's reproductive partner are both affected with SMCD, each child has a 25% likelihood of average stature (unaffected), a 50% likelihood of having SMCD due to a heterozygous pathogenic variant, and a 25% likelihood of having a more severe SMCD phenotype due to inheritance of biallelic pathogenic variants.
• Two individuals with biallelic SMCD-causing pathogenic variants and more severe presentations have been reported [
• Multiple miscarriages have been reported in a large consanguineous family segregating SMCD, suggesting that some homozygous
• Two individuals with biallelic SMCD-causing pathogenic variants and more severe presentations have been reported [
• Multiple miscarriages have been reported in a large consanguineous family segregating SMCD, suggesting that some homozygous
• If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has at conception a 25% likelihood of average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a more severe blended skeletal phenotype, including fetal demise.
• Two individuals with biallelic SMCD-causing pathogenic variants and more severe presentations have been reported [
• Multiple miscarriages have been reported in a large consanguineous family segregating SMCD, suggesting that some homozygous
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Schmid metaphyseal chondrodysplasia (SMCD) is inherited in an autosomal dominant manner.
## Risk to Family Members
Approximately half (45%-57%) of individuals diagnosed with SMCD inherited the condition from a parent. The heterozygous parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed in SMCD, and the heterozygous parent may only have mild features [
Approximately half (43%-55%) of individuals diagnosed with SMCD represent simplex cases (i.e., a single occurrence in a family) and have the disorder as the result of a
If the proband appears to be the only affected family member, recommendations for the parents of the proband include physical examination and measurement of proportions. Recommendations may also include radiographs (as isolated asymptomatic individuals have been reported with radiographic changes only) and, if a molecular diagnosis has been established in the proband, molecular genetic testing.
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 family history of some individuals diagnosed with SMCD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (reported in rare, isolated cases), or mild radiographic features in an affected parent that have not previously come to medical attention. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
If a parent of the proband is affected and/or is known to have the
If the proband has a known SMCD-causing 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 germline mosaicism [
If the parents are clinically unaffected (based on physical examination, measurement of proportions, and radiographs) 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 SMCD because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
Each child of an individual with SMCD has a 50% chance of inheriting the
Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMCD may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals have serious sequelae and poor outcomes [
If the proband and the proband's reproductive partner are both affected with SMCD, each child has a 25% likelihood of average stature (unaffected), a 50% likelihood of having SMCD due to a heterozygous pathogenic variant, and a 25% likelihood of having a more severe SMCD phenotype due to inheritance of biallelic pathogenic variants.
Two individuals with biallelic SMCD-causing pathogenic variants and more severe presentations have been reported [
Multiple miscarriages have been reported in a large consanguineous family segregating SMCD, suggesting that some homozygous
If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has at conception a 25% likelihood of average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a more severe blended skeletal phenotype, including fetal demise.
• Approximately half (45%-57%) of individuals diagnosed with SMCD inherited the condition from a parent. The heterozygous parent almost always exhibits features of the condition; however, considerable intrafamilial phenotypic variability is observed in SMCD, and the heterozygous parent may only have mild features [
• Approximately half (43%-55%) of individuals diagnosed with SMCD represent simplex cases (i.e., a single occurrence in a family) and have the disorder as the result of a
• If the proband appears to be the only affected family member, recommendations for the parents of the proband include physical examination and measurement of proportions. Recommendations may also include radiographs (as isolated asymptomatic individuals have been reported with radiographic changes only) and, if a molecular diagnosis has been established in the proband, molecular genetic testing.
• 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 family history of some individuals diagnosed with SMCD may appear to be negative because of failure to recognize the disorder in family members, reduced penetrance (reported in rare, isolated cases), or mild radiographic features in an affected parent that have not previously come to medical attention. Therefore, an apparently negative family history cannot be confirmed unless molecular genetic testing has established that neither parent is heterozygous for the pathogenic variant identified in the proband.
• 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 is known to have the
• If the proband has a known SMCD-causing 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 germline mosaicism [
• If the parents are clinically unaffected (based on physical examination, measurement of proportions, and radiographs) 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 SMCD because of the possibility of reduced penetrance in a heterozygous parent or the possibility of parental germline mosaicism.
• Each child of an individual with SMCD has a 50% chance of inheriting the
• Because many individuals with short stature have reproductive partners with short stature, offspring of individuals with SMCD may be at risk of having double heterozygosity for two dominantly inherited bone growth disorders. The phenotypes of these individuals are distinct from those of the parents, and the affected individuals have serious sequelae and poor outcomes [
• If the proband and the proband's reproductive partner are both affected with SMCD, each child has a 25% likelihood of average stature (unaffected), a 50% likelihood of having SMCD due to a heterozygous pathogenic variant, and a 25% likelihood of having a more severe SMCD phenotype due to inheritance of biallelic pathogenic variants.
• Two individuals with biallelic SMCD-causing pathogenic variants and more severe presentations have been reported [
• Multiple miscarriages have been reported in a large consanguineous family segregating SMCD, suggesting that some homozygous
• Two individuals with biallelic SMCD-causing pathogenic variants and more severe presentations have been reported [
• Multiple miscarriages have been reported in a large consanguineous family segregating SMCD, suggesting that some homozygous
• If the proband and the proband's reproductive partner are affected with different dominantly inherited skeletal dysplasias, each child has at conception a 25% likelihood of average stature, a 25% likelihood of having the same skeletal dysplasia as the father, a 25% likelihood of having the same skeletal dysplasia as the mother, and a 25% likelihood of inheriting a pathogenic variant from both parents and being at risk for a more severe blended skeletal phenotype, including fetal demise.
• Two individuals with biallelic SMCD-causing pathogenic variants and more severe presentations have been reported [
• Multiple miscarriages have been reported in a large consanguineous family segregating SMCD, suggesting that some homozygous
## 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
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
Schmid Metaphyseal Chondrodysplasia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Schmid Metaphyseal Chondrodysplasia (
Type X collagen, encoded by
Pathogenic variants in
## Molecular Pathogenesis
Type X collagen, encoded by
Pathogenic variants in
## Chapter Notes
Dr Richmond and Prof Savarirayan are actively involved in clinical research regarding individuals with SMCD. They would be happy to communicate with persons who have any questions regarding diagnosis of SMCD or other considerations.
The authors wish to acknowledge the patients, their families, and the clinicians of the multidisciplinary bone dysplasia clinics at the Victorian Clinical Genetics Services, Royal Children's Hospital, Genetic Health Queensland, and Queensland Children's Hospital.
9 May 2024 (sw) Comprehensive updated posted live
21 October 2019 (sw) Review posted live
5 July 2019 (rs) Original submission
• 9 May 2024 (sw) Comprehensive updated posted live
• 21 October 2019 (sw) Review posted live
• 5 July 2019 (rs) Original submission
## Author Notes
Dr Richmond and Prof Savarirayan are actively involved in clinical research regarding individuals with SMCD. They would be happy to communicate with persons who have any questions regarding diagnosis of SMCD or other considerations.
## Acknowledgments
The authors wish to acknowledge the patients, their families, and the clinicians of the multidisciplinary bone dysplasia clinics at the Victorian Clinical Genetics Services, Royal Children's Hospital, Genetic Health Queensland, and Queensland Children's Hospital.
## Revision History
9 May 2024 (sw) Comprehensive updated posted live
21 October 2019 (sw) Review posted live
5 July 2019 (rs) Original submission
• 9 May 2024 (sw) Comprehensive updated posted live
• 21 October 2019 (sw) Review posted live
• 5 July 2019 (rs) Original submission
## References
## Literature Cited
Standing lower-limb radiograph of a girl age four years with Schmid metaphyseal chondrodysplasia. Note severe bilateral coxa vara with marked metaphyseal widening at proximal femurs, and metaphyseal widening and irregularity of the distal femurs with femoral bowing.
|
[] |
21/10/2019
|
9/5/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
schwann
|
schwann
|
[
"Congenital Cutaneous Neurilemmomatosis",
"Leucine-zipper-like transcriptional regulator 1",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1",
"LZTR1",
"SMARCB1",
"Schwannomatosis"
] |
Radhika Dhamija, Scott Plotkin, Alicia Gomes, Dusica Babovic-Vuksanovic
|
Summary The diagnosis of
|
## Diagnosis
Consensus diagnostic criteria for
Two or more non-intradermal tumors suggestive of schwannomas
Absence of bilateral vestibular schwannomas
A family history of schwannomatosis 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.
A diagnosis of
Note: In some instances, it may be difficult to distinguish between
See
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
Molecular Genetic Testing Used in
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.
One individual with schwannomatosis had a ~7.7-kb germline
• Two or more non-intradermal tumors suggestive of schwannomas
• Absence of bilateral vestibular schwannomas
• A family history of schwannomatosis 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.
• For an introduction to multigene panels click
## Suggestive Findings
Two or more non-intradermal tumors suggestive of schwannomas
Absence of bilateral vestibular schwannomas
A family history of schwannomatosis 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.
• Two or more non-intradermal tumors suggestive of schwannomas
• Absence of bilateral vestibular schwannomas
• A family history of schwannomatosis 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
A diagnosis of
Note: In some instances, it may be difficult to distinguish between
See
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
Molecular Genetic Testing Used in
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.
One individual with schwannomatosis had a ~7.7-kb germline
• For an introduction to multigene panels click
## Clinical Characteristics
In a study of 51 individuals with
Germline truncating
The data on penetrance are limited, though it is less than 100% for both
Schwannomatosis is now used as an umbrella term for individuals with predisposition to multiple schwannomas.
In the revised nomenclature [Plotkin et all 2022], schwannomatosis is termed:
22q-related schwannomatosis (individuals with multiple schwannomas with shared loss of heterozygosity along chromosome 22q on the same allele for each tumor along with biallelic inactivation of
Schwannomatosis-not otherwise specified (NOS) (individuals who have clinical features of
Schwannomatosis-not elsewhere classified (NEC) (individuals in whom molecular analysis of blood and tumors has failed to detect a pathogenic variant).
Previous terminology for this condition has included multiple neurilemomas, multiple schwannomas, and congenital neurilemomatosis.
• 22q-related schwannomatosis (individuals with multiple schwannomas with shared loss of heterozygosity along chromosome 22q on the same allele for each tumor along with biallelic inactivation of
• Schwannomatosis-not otherwise specified (NOS) (individuals who have clinical features of
• Schwannomatosis-not elsewhere classified (NEC) (individuals in whom molecular analysis of blood and tumors has failed to detect a pathogenic variant).
## Clinical Description
In a study of 51 individuals with
## Phenotype Correlations by Gene
## Genotype-Phenotype Correlations
Germline truncating
## Penetrance
The data on penetrance are limited, though it is less than 100% for both
## Nomenclature
Schwannomatosis is now used as an umbrella term for individuals with predisposition to multiple schwannomas.
In the revised nomenclature [Plotkin et all 2022], schwannomatosis is termed:
22q-related schwannomatosis (individuals with multiple schwannomas with shared loss of heterozygosity along chromosome 22q on the same allele for each tumor along with biallelic inactivation of
Schwannomatosis-not otherwise specified (NOS) (individuals who have clinical features of
Schwannomatosis-not elsewhere classified (NEC) (individuals in whom molecular analysis of blood and tumors has failed to detect a pathogenic variant).
Previous terminology for this condition has included multiple neurilemomas, multiple schwannomas, and congenital neurilemomatosis.
• 22q-related schwannomatosis (individuals with multiple schwannomas with shared loss of heterozygosity along chromosome 22q on the same allele for each tumor along with biallelic inactivation of
• Schwannomatosis-not otherwise specified (NOS) (individuals who have clinical features of
• Schwannomatosis-not elsewhere classified (NEC) (individuals in whom molecular analysis of blood and tumors has failed to detect a pathogenic variant).
## Prevalence
## Genetically Related (Allelic) Disorders
Allelic Disorders
AD = autosomal dominant; AR = autosomal recessive; GoF = gain-of-function; LoF = loss-of-function
An individual with a germline missense
A family with a germline missense variant in
## Cancer and Benign Tumors
## Differential Diagnosis
An individual with suspected schwannomatosis should have comprehensive molecular genetic testing (i.e., analysis of
Genetic Disorders of Interest in the Differential Diagnosis of
Peripheral nerve sheath tumors (neurofibromas)
Malignant peripheral nerve sheath tumors
Peripheral nerve sheath tumors (schwannomas)
Unilateral vestibular schwannoma
Meningioma
Bilateral vestibular schwannomas
Ependymomas
Cataracts
Retinal hamartomas
Epiretinal membrane
Intradermal schwannomas
Cutaneous schwannomas
Endocrine features
Cardiac & skin myxomas
Pigmented skin lesions
AD = autosomal dominant; chr 22q LOH = chromosome 22q loss of heterozygosity; MOI = mode of inheritance
Shared loss of heterozygosity along chromosome 22q on the same allele for each tumor along with biallelic inactivation of
• Peripheral nerve sheath tumors (neurofibromas)
• Malignant peripheral nerve sheath tumors
• Peripheral nerve sheath tumors (schwannomas)
• Unilateral vestibular schwannoma
• Meningioma
• Bilateral vestibular schwannomas
• Ependymomas
• Cataracts
• Retinal hamartomas
• Epiretinal membrane
• Intradermal schwannomas
• Cutaneous schwannomas
• Endocrine features
• Cardiac & skin myxomas
• Pigmented skin lesions
## Management
A multispecialty guideline group has developed the first comprehensive recommendations for treatment and surveillance for schwannomatosis [
To establish the extent of disease and needs in an individual diagnosed with
Detailed family & personal clinical history
Consultation w/neurologist & neurosurgeon as symptoms indicate
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance
Fine cuts through the internal auditory canal are recommended for those with
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
A comprehensive, multimodal approach to pain mgmt by pain mgmt specialist or neurologist provides opportunity for long-term mgmt w/o surgical intervention.
Various pain medications may be helpful individually or as adjuncts: calcium channel alpha 2 delta ligands (e.g., gabapentin), tricyclic antidepressants (e.g., amitriptyline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine).
Pain mgmt may be helpful for anxiety &/or depression.
Referral to mental health professionals may also be warranted.
Benefits must be weighed against risks.
Given technical challenges, referral to expert center w/peripheral nerve surgeon is recommended.
Surgery should be in conjunction w/pharmacologic pain mgmt; pain relief following tumor resection is not ensured.
Intraspinal schwannomas >5 mm warrant longitudinal imaging & clinical surveillance.
Surgical removal of symptomatic growing intraspinal schwannomas to ↓ impact to adjacent neural structures is recommended.
When considering surgical intervention consider medical history cues, physical exam findings, & imaging observations to delineate a facial nerve etiology.
Hearing & facial nerve preservation are significant considerations when considering treatment of schwannomas of internal auditory canal.
Hearing preservation dramatically ↓ for vestibular schwannomas >1 cm; facial nerve function significantly ↓ for schwannomas >2.5-3 cm.
Radiotherapy may ↑ risk of malignant transformation. It should only be considered when surgery is not an option.
CNS = central nervous system
Authors, personal communication
There is a paucity of outcome data from surgical, radiosurgical, and radiation therapy for meningiomas in individuals with schwannomatosis.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Neurologic exam
Pain assessment
Brain & spine MRI or whole-body MRI
Note: Fine cuts through internal auditory canal are recommended for those w/
High cost and poor insurance reimbursement limit the wider use of whole-body MRI.
Radiation can increase the risk for malignant transformation and should be avoided when possible [
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 surveillance and clinical management.
See
A Phase II study of tanezumab (an investigational humanized monoclonal antibody that inhibits nerve growth factor) in individuals with moderate to severe pain due to schwannomatosis is active. It is the first therapeutic clinical trial for schwannomatosis, targeting biological drivers of schwannomatosis-related pain [
Search
• Detailed family & personal clinical history
• Consultation w/neurologist & neurosurgeon as symptoms indicate
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• A comprehensive, multimodal approach to pain mgmt by pain mgmt specialist or neurologist provides opportunity for long-term mgmt w/o surgical intervention.
• Various pain medications may be helpful individually or as adjuncts: calcium channel alpha 2 delta ligands (e.g., gabapentin), tricyclic antidepressants (e.g., amitriptyline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine).
• Pain mgmt may be helpful for anxiety &/or depression.
• Referral to mental health professionals may also be warranted.
• Benefits must be weighed against risks.
• Given technical challenges, referral to expert center w/peripheral nerve surgeon is recommended.
• Surgery should be in conjunction w/pharmacologic pain mgmt; pain relief following tumor resection is not ensured.
• Intraspinal schwannomas >5 mm warrant longitudinal imaging & clinical surveillance.
• Surgical removal of symptomatic growing intraspinal schwannomas to ↓ impact to adjacent neural structures is recommended.
• When considering surgical intervention consider medical history cues, physical exam findings, & imaging observations to delineate a facial nerve etiology.
• Hearing & facial nerve preservation are significant considerations when considering treatment of schwannomas of internal auditory canal.
• Hearing preservation dramatically ↓ for vestibular schwannomas >1 cm; facial nerve function significantly ↓ for schwannomas >2.5-3 cm.
• Radiotherapy may ↑ risk of malignant transformation. It should only be considered when surgery is not an option.
• Neurologic exam
• Pain assessment
• Brain & spine MRI or whole-body MRI
• Note: Fine cuts through internal auditory canal are recommended for those w/
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Detailed family & personal clinical history
Consultation w/neurologist & neurosurgeon as symptoms indicate
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance
Fine cuts through the internal auditory canal are recommended for those with
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Detailed family & personal clinical history
• Consultation w/neurologist & neurosurgeon as symptoms indicate
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
A comprehensive, multimodal approach to pain mgmt by pain mgmt specialist or neurologist provides opportunity for long-term mgmt w/o surgical intervention.
Various pain medications may be helpful individually or as adjuncts: calcium channel alpha 2 delta ligands (e.g., gabapentin), tricyclic antidepressants (e.g., amitriptyline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine).
Pain mgmt may be helpful for anxiety &/or depression.
Referral to mental health professionals may also be warranted.
Benefits must be weighed against risks.
Given technical challenges, referral to expert center w/peripheral nerve surgeon is recommended.
Surgery should be in conjunction w/pharmacologic pain mgmt; pain relief following tumor resection is not ensured.
Intraspinal schwannomas >5 mm warrant longitudinal imaging & clinical surveillance.
Surgical removal of symptomatic growing intraspinal schwannomas to ↓ impact to adjacent neural structures is recommended.
When considering surgical intervention consider medical history cues, physical exam findings, & imaging observations to delineate a facial nerve etiology.
Hearing & facial nerve preservation are significant considerations when considering treatment of schwannomas of internal auditory canal.
Hearing preservation dramatically ↓ for vestibular schwannomas >1 cm; facial nerve function significantly ↓ for schwannomas >2.5-3 cm.
Radiotherapy may ↑ risk of malignant transformation. It should only be considered when surgery is not an option.
CNS = central nervous system
Authors, personal communication
There is a paucity of outcome data from surgical, radiosurgical, and radiation therapy for meningiomas in individuals with schwannomatosis.
• A comprehensive, multimodal approach to pain mgmt by pain mgmt specialist or neurologist provides opportunity for long-term mgmt w/o surgical intervention.
• Various pain medications may be helpful individually or as adjuncts: calcium channel alpha 2 delta ligands (e.g., gabapentin), tricyclic antidepressants (e.g., amitriptyline), serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine).
• Pain mgmt may be helpful for anxiety &/or depression.
• Referral to mental health professionals may also be warranted.
• Benefits must be weighed against risks.
• Given technical challenges, referral to expert center w/peripheral nerve surgeon is recommended.
• Surgery should be in conjunction w/pharmacologic pain mgmt; pain relief following tumor resection is not ensured.
• Intraspinal schwannomas >5 mm warrant longitudinal imaging & clinical surveillance.
• Surgical removal of symptomatic growing intraspinal schwannomas to ↓ impact to adjacent neural structures is recommended.
• When considering surgical intervention consider medical history cues, physical exam findings, & imaging observations to delineate a facial nerve etiology.
• Hearing & facial nerve preservation are significant considerations when considering treatment of schwannomas of internal auditory canal.
• Hearing preservation dramatically ↓ for vestibular schwannomas >1 cm; facial nerve function significantly ↓ for schwannomas >2.5-3 cm.
• Radiotherapy may ↑ risk of malignant transformation. It should only be considered when surgery is not an option.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Neurologic exam
Pain assessment
Brain & spine MRI or whole-body MRI
Note: Fine cuts through internal auditory canal are recommended for those w/
High cost and poor insurance reimbursement limit the wider use of whole-body MRI.
• Neurologic exam
• Pain assessment
• Brain & spine MRI or whole-body MRI
• Note: Fine cuts through internal auditory canal are recommended for those w/
## Agents/Circumstances to Avoid
Radiation can increase the risk for malignant transformation and should be avoided when possible [
## 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 surveillance and clinical management.
See
## Therapies Under Investigation
A Phase II study of tanezumab (an investigational humanized monoclonal antibody that inhibits nerve growth factor) in individuals with moderate to severe pain due to schwannomatosis is active. It is the first therapeutic clinical trial for schwannomatosis, targeting biological drivers of schwannomatosis-related pain [
Search
## Genetic Counseling
Fewer than 20% of individuals diagnosed with
Some individuals diagnosed with
If the proband is the only family member known to have schwannomatosis and molecular genetic testing does not suggest that the
If the
The proband has
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 be heterozygous for the
If the
The absence of clinical symptoms 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 germline mosaicism.
If the proband has other affected family members, each child of the proband has a 50% chance of inheriting an
If the proband is the only affected individual in the family:
And the proband has a
And the proband has somatic mosaicism for the pathogenic variant, offspring may have a less than 50% risk of inheriting the pathogenic variant.
See Management,
Predictive testing for at-risk asymptomatic family members requires prior identification of the germline
Potential consequences of such testing as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Because early detection of at-risk individuals affects surveillance, testing of at-risk asymptomatic individuals younger than age 18 years may be beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 germline
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.
• Fewer than 20% of individuals diagnosed with
• Some individuals diagnosed with
• If the proband is the only family member known to have schwannomatosis and molecular genetic testing does not suggest that the
• If the
• The proband has
• 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
• 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
• 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 be heterozygous for the
• If the
• The absence of clinical symptoms 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 germline mosaicism.
• If the proband has other affected family members, each child of the proband has a 50% chance of inheriting an
• If the proband is the only affected individual in the family:
• And the proband has a
• And the proband has somatic mosaicism for the pathogenic variant, offspring may have a less than 50% risk of inheriting the pathogenic variant.
• And the proband has a
• And the proband has somatic mosaicism for the pathogenic variant, offspring may have a less than 50% risk of inheriting the pathogenic variant.
• And the proband has a
• And the proband has somatic mosaicism for the pathogenic variant, offspring may have a less than 50% risk of inheriting the pathogenic variant.
• Predictive testing for at-risk asymptomatic family members requires prior identification of the germline
• Potential consequences of such testing as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Because early detection of at-risk individuals affects surveillance, testing of at-risk asymptomatic individuals younger than age 18 years may be beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Fewer than 20% of individuals diagnosed with
Some individuals diagnosed with
If the proband is the only family member known to have schwannomatosis and molecular genetic testing does not suggest that the
If the
The proband has
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 be heterozygous for the
If the
The absence of clinical symptoms 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 germline mosaicism.
If the proband has other affected family members, each child of the proband has a 50% chance of inheriting an
If the proband is the only affected individual in the family:
And the proband has a
And the proband has somatic mosaicism for the pathogenic variant, offspring may have a less than 50% risk of inheriting the pathogenic variant.
• Fewer than 20% of individuals diagnosed with
• Some individuals diagnosed with
• If the proband is the only family member known to have schwannomatosis and molecular genetic testing does not suggest that the
• If the
• The proband has
• 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
• 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
• 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 be heterozygous for the
• If the
• The absence of clinical symptoms 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 germline mosaicism.
• If the proband has other affected family members, each child of the proband has a 50% chance of inheriting an
• If the proband is the only affected individual in the family:
• And the proband has a
• And the proband has somatic mosaicism for the pathogenic variant, offspring may have a less than 50% risk of inheriting the pathogenic variant.
• And the proband has a
• And the proband has somatic mosaicism for the pathogenic variant, offspring may have a less than 50% risk of inheriting the pathogenic variant.
• And the proband has a
• And the proband has somatic mosaicism for the pathogenic variant, offspring may have a less than 50% risk of inheriting the pathogenic variant.
## Related Genetic Counseling Issues
See Management,
Predictive testing for at-risk asymptomatic family members requires prior identification of the germline
Potential consequences of such testing as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
Because early detection of at-risk individuals affects surveillance, testing of at-risk asymptomatic individuals younger than age 18 years may be beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children.
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 asymptomatic family members requires prior identification of the germline
• Potential consequences of such testing as well as the capabilities and limitations of predictive testing should be discussed in the context of formal genetic counseling prior to testing.
• Because early detection of at-risk individuals affects surveillance, testing of at-risk asymptomatic individuals younger than age 18 years may be beneficial. Parents often want to know the genetic status of their children prior to initiating screening in order to avoid unnecessary procedures for a child who has not inherited the pathogenic variant. Special consideration should be given to education of the children and their parents prior to genetic testing. A plan should be established for the manner in which results are to be given to the parents and children.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 germline
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
Children’s Tumor Foundation
•
•
•
•
•
•
•
•
•
•
•
• Children’s Tumor Foundation
•
## Molecular Genetics
LZTR1- and SMARCB1-Related Schwannomatosis: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for LZTR1- and SMARCB1-Related Schwannomatosis (
The classic Knudson two-hit model of tumorigenesis does not suffice for tumor initiation or growth in
A hypothesis has been proposed for both
UTR = untranslated region
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
The classic Knudson two-hit model of tumorigenesis does not suffice for tumor initiation or growth in
A hypothesis has been proposed for both
UTR = untranslated region
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
## Chapter Notes
The authors are actively involved in clinical research regarding individuals with schwannomatosis. They would be happy to communicate with persons who have any questions regarding diagnosis of schwannomatosis or other considerations.
Contact Alicia Gomes (
The authors would like to thank Children's Tumor Foundation for their continued work on neurofibromatosis and schwannomatosis.
Ashok Asthagiri, MD; University of Virginia (2018-2023)Dusica Babovic-Vuksanovic, MD (2018-present)Radhika Dhamija, MD (2018-present)Alicia Gomes, MS, LCGC (2023-present)Ludwine Messiaen, PhD; University of Alabama (2018-2023)Scott Plotkin, MD, PhD (2018-present)
25 April 2024 (sw) Revision: clarification of when first brain MRI is recommended (
27 July 2023 (sw) Comprehensive update posted live
8 March 2018 (sw) Review posted live
14 July 2017 (rd) Original submission
• 25 April 2024 (sw) Revision: clarification of when first brain MRI is recommended (
• 27 July 2023 (sw) Comprehensive update posted live
• 8 March 2018 (sw) Review posted live
• 14 July 2017 (rd) Original submission
## Author Notes
The authors are actively involved in clinical research regarding individuals with schwannomatosis. They would be happy to communicate with persons who have any questions regarding diagnosis of schwannomatosis or other considerations.
Contact Alicia Gomes (
## Acknowledgments
The authors would like to thank Children's Tumor Foundation for their continued work on neurofibromatosis and schwannomatosis.
## Author History
Ashok Asthagiri, MD; University of Virginia (2018-2023)Dusica Babovic-Vuksanovic, MD (2018-present)Radhika Dhamija, MD (2018-present)Alicia Gomes, MS, LCGC (2023-present)Ludwine Messiaen, PhD; University of Alabama (2018-2023)Scott Plotkin, MD, PhD (2018-present)
## Revision History
25 April 2024 (sw) Revision: clarification of when first brain MRI is recommended (
27 July 2023 (sw) Comprehensive update posted live
8 March 2018 (sw) Review posted live
14 July 2017 (rd) Original submission
• 25 April 2024 (sw) Revision: clarification of when first brain MRI is recommended (
• 27 July 2023 (sw) Comprehensive update posted live
• 8 March 2018 (sw) Review posted live
• 14 July 2017 (rd) Original submission
## References
Evans DG, Mostaccioli S, Pang D, Fadzil O Connor M, Pittara M, Champollion N, Wolkenstein P, Thomas N, Ferner RE, Kalamarides M, Peyre M, Papi L, Legius E, Becerra JL, King A, Duff C, Stivaros S, Blanco I. ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis. Eur J Hum Genet. 2022;30:812-7. [
Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Huson SM, Wolkenstein P, Evans DG. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: an international consensus recommendation. Genet Med. 2022;24:1967-77. [
• Evans DG, Mostaccioli S, Pang D, Fadzil O Connor M, Pittara M, Champollion N, Wolkenstein P, Thomas N, Ferner RE, Kalamarides M, Peyre M, Papi L, Legius E, Becerra JL, King A, Duff C, Stivaros S, Blanco I. ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis. Eur J Hum Genet. 2022;30:812-7. [
• Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Huson SM, Wolkenstein P, Evans DG. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: an international consensus recommendation. Genet Med. 2022;24:1967-77. [
## Published Guidelines / Consensus Statements
Evans DG, Mostaccioli S, Pang D, Fadzil O Connor M, Pittara M, Champollion N, Wolkenstein P, Thomas N, Ferner RE, Kalamarides M, Peyre M, Papi L, Legius E, Becerra JL, King A, Duff C, Stivaros S, Blanco I. ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis. Eur J Hum Genet. 2022;30:812-7. [
Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Huson SM, Wolkenstein P, Evans DG. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: an international consensus recommendation. Genet Med. 2022;24:1967-77. [
• Evans DG, Mostaccioli S, Pang D, Fadzil O Connor M, Pittara M, Champollion N, Wolkenstein P, Thomas N, Ferner RE, Kalamarides M, Peyre M, Papi L, Legius E, Becerra JL, King A, Duff C, Stivaros S, Blanco I. ERN GENTURIS clinical practice guidelines for the diagnosis, treatment, management and surveillance of people with schwannomatosis. Eur J Hum Genet. 2022;30:812-7. [
• Plotkin SR, Messiaen L, Legius E, Pancza P, Avery RA, Blakeley JO, Babovic-Vuksanovic D, Ferner R, Fisher MJ, Friedman JM, Giovannini M, Gutmann DH, Hanemann CO, Kalamarides M, Kehrer-Sawatzki H, Korf BR, Mautner VF, MacCollin M, Papi L, Rauen KA, Riccardi V, Schorry E, Smith MJ, Stemmer-Rachamimov A, Stevenson DA, Ullrich NJ, Viskochil D, Wimmer K, Yohay K; International Consensus Group on Neurofibromatosis Diagnostic Criteria (I-NF-DC); Huson SM, Wolkenstein P, Evans DG. Updated diagnostic criteria and nomenclature for neurofibromatosis type 2 and schwannomatosis: an international consensus recommendation. Genet Med. 2022;24:1967-77. [
## Literature Cited
|
[] |
8/3/2018
|
27/7/2023
|
25/4/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
scn3a-ndd
|
scn3a-ndd
|
[
"Sodium channel protein type 3 subunit alpha",
"SCN3A",
"SCN3A-Related Neurodevelopmental Disorder"
] |
Katherine L Helbig, Ethan M Goldberg
|
Summary The diagnosis of
|
## Diagnosis
Clinical diagnostic criteria for
Intractable seizures beginning in the first year of life, particularly in the first month of life (median age 2 weeks)
Developmental delay or intellectual disability, often in the severe-to-profound range in those with early-onset developmental and epileptic encephalopathy (DEE)
Progressive microcephaly
Ictal or non-ictal autonomic disturbances, including facial flushing, sweating, apnea and desaturation, anisocoria, and bradycardia
Significant axial hypotonia, often progressing to spastic quadriplegia
Oromotor dyspraxia and dysarthria in individuals with malformations of cortical development with or without mild focal epilepsy.
Generalized and focal tonic seizures (the most common presenting seizure type)
Focal autonomic seizures
Focal motor seizures
Epileptic spasms
Bilateral dysgyria, pachygyria, or polymicrogyria that can be focal, multifocal, or diffuse (affecting all lobes of the neocortex)
Less commonly, other malformations of cortical development with features of lissencephaly
Hypoplasia of the corpus callosum with or without malformation of cortical development
Cerebral atrophy
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 [
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 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.
All pathogenic variants identified in individuals with
• Intractable seizures beginning in the first year of life, particularly in the first month of life (median age 2 weeks)
• Developmental delay or intellectual disability, often in the severe-to-profound range in those with early-onset developmental and epileptic encephalopathy (DEE)
• Progressive microcephaly
• Ictal or non-ictal autonomic disturbances, including facial flushing, sweating, apnea and desaturation, anisocoria, and bradycardia
• Significant axial hypotonia, often progressing to spastic quadriplegia
• Oromotor dyspraxia and dysarthria in individuals with malformations of cortical development with or without mild focal epilepsy.
• Generalized and focal tonic seizures (the most common presenting seizure type)
• Focal autonomic seizures
• Focal motor seizures
• Epileptic spasms
• Bilateral dysgyria, pachygyria, or polymicrogyria that can be focal, multifocal, or diffuse (affecting all lobes of the neocortex)
• Less commonly, other malformations of cortical development with features of lissencephaly
• Hypoplasia of the corpus callosum with or without malformation of cortical development
• Cerebral atrophy
## Suggestive Findings
Intractable seizures beginning in the first year of life, particularly in the first month of life (median age 2 weeks)
Developmental delay or intellectual disability, often in the severe-to-profound range in those with early-onset developmental and epileptic encephalopathy (DEE)
Progressive microcephaly
Ictal or non-ictal autonomic disturbances, including facial flushing, sweating, apnea and desaturation, anisocoria, and bradycardia
Significant axial hypotonia, often progressing to spastic quadriplegia
Oromotor dyspraxia and dysarthria in individuals with malformations of cortical development with or without mild focal epilepsy.
Generalized and focal tonic seizures (the most common presenting seizure type)
Focal autonomic seizures
Focal motor seizures
Epileptic spasms
Bilateral dysgyria, pachygyria, or polymicrogyria that can be focal, multifocal, or diffuse (affecting all lobes of the neocortex)
Less commonly, other malformations of cortical development with features of lissencephaly
Hypoplasia of the corpus callosum with or without malformation of cortical development
Cerebral atrophy
• Intractable seizures beginning in the first year of life, particularly in the first month of life (median age 2 weeks)
• Developmental delay or intellectual disability, often in the severe-to-profound range in those with early-onset developmental and epileptic encephalopathy (DEE)
• Progressive microcephaly
• Ictal or non-ictal autonomic disturbances, including facial flushing, sweating, apnea and desaturation, anisocoria, and bradycardia
• Significant axial hypotonia, often progressing to spastic quadriplegia
• Oromotor dyspraxia and dysarthria in individuals with malformations of cortical development with or without mild focal epilepsy.
• Generalized and focal tonic seizures (the most common presenting seizure type)
• Focal autonomic seizures
• Focal motor seizures
• Epileptic spasms
• Bilateral dysgyria, pachygyria, or polymicrogyria that can be focal, multifocal, or diffuse (affecting all lobes of the neocortex)
• Less commonly, other malformations of cortical development with features of lissencephaly
• Hypoplasia of the corpus callosum with or without malformation of cortical development
• Cerebral atrophy
## 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 [
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 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.
All pathogenic variants identified in individuals with
## Clinical Characteristics
To date, 38 individuals from 31 families have been identified with a pathogenic variant in
Select Features of
DEE = developmental and epileptic encephalopathy
Developmental and epileptic encephalopathy without malformation of cortical development: 6/38 (16%) of affected individuals [
Developmental and epileptic encephalopathy with malformation of cortical development: 16/38 (42%) of affected individuals [
Malformation of cortical development with or without mild focal epilepsy: 13/38 (34%) of affected individuals [
Note: One known affected individual was a fetus whose clinical features could not be further categorized. Two additional individuals with pathogenic
Because the small number of recognized affected individuals with each phenotype and the fact that the clinical overlap between these phenotypes is broad, the following discussion applies to all three phenotypes.
In those with intractable seizures with ongoing epileptiform EEG activity:
All affected individuals have severe-to-profound developmental delays and are nonverbal and nonambulatory.
Ongoing ID is present in older individuals, ranging from severe to profound.
In those who have mild focal epilepsy or no epilepsy, long-term cognitive outcomes include:
Normal cognition in 2/11 (18%)
Borderline/mild ID in 7/11 (64%)
Moderate/severe ID in 2/11 (18%)
In individuals with DEE, neurologic examination typically reveals significant truncal or generalized hypotonia with prominent head lag in younger children.
In those with malformation of cortical development:
Hypotonia often progresses to spastic quadriplegia in later childhood in those who also have DEE;
In those without DEE, older individuals may have pyramidal signs, mild spasticity, or mild hemiparesis.
In those with DEE:
Seizure onset is typically in the first six to 12 months of life, most often in the first week of life (median age 1-2 weeks), although seizure onset can range from day of birth to age five years.
The most common presenting seizure types in those without MCD are generalized tonic seizures or epileptic spasms. In those with MCD, the most common presenting seizure types are generalized tonic and focal autonomic seizures.
Tonic seizures may have a prominent autonomic or apneic component, consistent with apparent life-threatening events (ALTEs) in infants.
Affected individuals typically develop additional seizure types, which can include the following:
Epileptic spasms
Generalized tonic-clonic seizures
Myoclonic seizures
Focal tonic seizures
Focal impaired awareness seizures
Focal autonomic seizures
Focal motor seizures
Seizures remain intractable to multiple anti-seizure medications in approximately 50% of individuals without MCD and in 90% of individuals with MCD.
In those with MCD without DEE:
A majority (11/13; 85%) do not have a history of seizures or epilepsy;
A minority (2/13; 15%) have a single unprovoked focal or generalized tonic-clonic seizure in late childhood or adolescence not requiring anti-seizure medication.
Multifocal epileptiform discharges or hypsarrhythmia in those with DEE but without MCD;
Burst-suppression early in the disease course, then multifocal epileptiform discharges, and hypsarrhythmia in those with MCD;
Focal epileptiform abnormalities on EEG even in the absence of clinical seizures in 70% (10/13) of reported individuals with
Asymmetric or unilateral flushing / color change of the face, which may be confused with Harlequin syndrome
Brady- or tachycardia
Apnea and cyanosis with oxygen desaturation
Excessive sweating
Anisocoria with sluggish pupillary response to light
These episodes may occur several times per day and may or may not be associated with ictal abnormalities on EEG.
Oromotor dysfunction is seen in a majority of individuals [
Abnormal tongue movements
Speech-language difficulties, including dysarthria
Difficulties whistling, blowing
Abnormal brisk jaw jerk
Some affected individuals with the severe
Progressive microcephaly
Dyskinesia, including choreoathetosis in those without MCD and dystonia and/or hyperkinetic movements in those with MCD [
Cortical visual impairment
Features of autism spectrum disorder
Early-childhood death in two individuals, one due to sudden unexpected death in epilepsy and the other of an undetermined cause [
The most common recurrent
Profound developmental delay / intellectual disability (in 10/10 individuals; 100%)
Neonatal onset intractable seizures (median onset 2 weeks) (8/9; 89%)
Multiple seizure types, often generalized tonic seizures
Diffuse, bilateral polymicrogyria (10/10; 100%)
Microcephaly (7/9;78%)
Paroxysmal ictal and non-ictal autonomic dysregulation (4/9; 44%)
A clear genotype-phenotype correlation between other variants or classes of variants has not yet been established.
Outdated terms previously used to describe
Cryptogenic pediatric partial epilepsy
Epilepsy, familial focal, with variable foci 4
Epileptic encephalopathy, early infantile, 62
The prevalence of
• Developmental and epileptic encephalopathy without malformation of cortical development: 6/38 (16%) of affected individuals [
• Developmental and epileptic encephalopathy with malformation of cortical development: 16/38 (42%) of affected individuals [
• Malformation of cortical development with or without mild focal epilepsy: 13/38 (34%) of affected individuals [
• All affected individuals have severe-to-profound developmental delays and are nonverbal and nonambulatory.
• Ongoing ID is present in older individuals, ranging from severe to profound.
• Normal cognition in 2/11 (18%)
• Borderline/mild ID in 7/11 (64%)
• Moderate/severe ID in 2/11 (18%)
• In individuals with DEE, neurologic examination typically reveals significant truncal or generalized hypotonia with prominent head lag in younger children.
• In those with malformation of cortical development:
• Hypotonia often progresses to spastic quadriplegia in later childhood in those who also have DEE;
• In those without DEE, older individuals may have pyramidal signs, mild spasticity, or mild hemiparesis.
• Hypotonia often progresses to spastic quadriplegia in later childhood in those who also have DEE;
• In those without DEE, older individuals may have pyramidal signs, mild spasticity, or mild hemiparesis.
• Hypotonia often progresses to spastic quadriplegia in later childhood in those who also have DEE;
• In those without DEE, older individuals may have pyramidal signs, mild spasticity, or mild hemiparesis.
• Seizure onset is typically in the first six to 12 months of life, most often in the first week of life (median age 1-2 weeks), although seizure onset can range from day of birth to age five years.
• The most common presenting seizure types in those without MCD are generalized tonic seizures or epileptic spasms. In those with MCD, the most common presenting seizure types are generalized tonic and focal autonomic seizures.
• Tonic seizures may have a prominent autonomic or apneic component, consistent with apparent life-threatening events (ALTEs) in infants.
• Affected individuals typically develop additional seizure types, which can include the following:
• Epileptic spasms
• Generalized tonic-clonic seizures
• Myoclonic seizures
• Focal tonic seizures
• Focal impaired awareness seizures
• Focal autonomic seizures
• Focal motor seizures
• Epileptic spasms
• Generalized tonic-clonic seizures
• Myoclonic seizures
• Focal tonic seizures
• Focal impaired awareness seizures
• Focal autonomic seizures
• Focal motor seizures
• Seizures remain intractable to multiple anti-seizure medications in approximately 50% of individuals without MCD and in 90% of individuals with MCD.
• Epileptic spasms
• Generalized tonic-clonic seizures
• Myoclonic seizures
• Focal tonic seizures
• Focal impaired awareness seizures
• Focal autonomic seizures
• Focal motor seizures
• A majority (11/13; 85%) do not have a history of seizures or epilepsy;
• A minority (2/13; 15%) have a single unprovoked focal or generalized tonic-clonic seizure in late childhood or adolescence not requiring anti-seizure medication.
• Multifocal epileptiform discharges or hypsarrhythmia in those with DEE but without MCD;
• Burst-suppression early in the disease course, then multifocal epileptiform discharges, and hypsarrhythmia in those with MCD;
• Focal epileptiform abnormalities on EEG even in the absence of clinical seizures in 70% (10/13) of reported individuals with
• Asymmetric or unilateral flushing / color change of the face, which may be confused with Harlequin syndrome
• Brady- or tachycardia
• Apnea and cyanosis with oxygen desaturation
• Excessive sweating
• Anisocoria with sluggish pupillary response to light
• Oromotor dysfunction is seen in a majority of individuals [
• Abnormal tongue movements
• Speech-language difficulties, including dysarthria
• Difficulties whistling, blowing
• Abnormal brisk jaw jerk
• Abnormal tongue movements
• Speech-language difficulties, including dysarthria
• Difficulties whistling, blowing
• Abnormal brisk jaw jerk
• Some affected individuals with the severe
• Abnormal tongue movements
• Speech-language difficulties, including dysarthria
• Difficulties whistling, blowing
• Abnormal brisk jaw jerk
• Progressive microcephaly
• Dyskinesia, including choreoathetosis in those without MCD and dystonia and/or hyperkinetic movements in those with MCD [
• Cortical visual impairment
• Features of autism spectrum disorder
• Early-childhood death in two individuals, one due to sudden unexpected death in epilepsy and the other of an undetermined cause [
• Profound developmental delay / intellectual disability (in 10/10 individuals; 100%)
• Neonatal onset intractable seizures (median onset 2 weeks) (8/9; 89%)
• Multiple seizure types, often generalized tonic seizures
• Diffuse, bilateral polymicrogyria (10/10; 100%)
• Microcephaly (7/9;78%)
• Paroxysmal ictal and non-ictal autonomic dysregulation (4/9; 44%)
• Cryptogenic pediatric partial epilepsy
• Epilepsy, familial focal, with variable foci 4
• Epileptic encephalopathy, early infantile, 62
## Clinical Description
To date, 38 individuals from 31 families have been identified with a pathogenic variant in
Select Features of
DEE = developmental and epileptic encephalopathy
Developmental and epileptic encephalopathy without malformation of cortical development: 6/38 (16%) of affected individuals [
Developmental and epileptic encephalopathy with malformation of cortical development: 16/38 (42%) of affected individuals [
Malformation of cortical development with or without mild focal epilepsy: 13/38 (34%) of affected individuals [
Note: One known affected individual was a fetus whose clinical features could not be further categorized. Two additional individuals with pathogenic
Because the small number of recognized affected individuals with each phenotype and the fact that the clinical overlap between these phenotypes is broad, the following discussion applies to all three phenotypes.
In those with intractable seizures with ongoing epileptiform EEG activity:
All affected individuals have severe-to-profound developmental delays and are nonverbal and nonambulatory.
Ongoing ID is present in older individuals, ranging from severe to profound.
In those who have mild focal epilepsy or no epilepsy, long-term cognitive outcomes include:
Normal cognition in 2/11 (18%)
Borderline/mild ID in 7/11 (64%)
Moderate/severe ID in 2/11 (18%)
In individuals with DEE, neurologic examination typically reveals significant truncal or generalized hypotonia with prominent head lag in younger children.
In those with malformation of cortical development:
Hypotonia often progresses to spastic quadriplegia in later childhood in those who also have DEE;
In those without DEE, older individuals may have pyramidal signs, mild spasticity, or mild hemiparesis.
In those with DEE:
Seizure onset is typically in the first six to 12 months of life, most often in the first week of life (median age 1-2 weeks), although seizure onset can range from day of birth to age five years.
The most common presenting seizure types in those without MCD are generalized tonic seizures or epileptic spasms. In those with MCD, the most common presenting seizure types are generalized tonic and focal autonomic seizures.
Tonic seizures may have a prominent autonomic or apneic component, consistent with apparent life-threatening events (ALTEs) in infants.
Affected individuals typically develop additional seizure types, which can include the following:
Epileptic spasms
Generalized tonic-clonic seizures
Myoclonic seizures
Focal tonic seizures
Focal impaired awareness seizures
Focal autonomic seizures
Focal motor seizures
Seizures remain intractable to multiple anti-seizure medications in approximately 50% of individuals without MCD and in 90% of individuals with MCD.
In those with MCD without DEE:
A majority (11/13; 85%) do not have a history of seizures or epilepsy;
A minority (2/13; 15%) have a single unprovoked focal or generalized tonic-clonic seizure in late childhood or adolescence not requiring anti-seizure medication.
Multifocal epileptiform discharges or hypsarrhythmia in those with DEE but without MCD;
Burst-suppression early in the disease course, then multifocal epileptiform discharges, and hypsarrhythmia in those with MCD;
Focal epileptiform abnormalities on EEG even in the absence of clinical seizures in 70% (10/13) of reported individuals with
Asymmetric or unilateral flushing / color change of the face, which may be confused with Harlequin syndrome
Brady- or tachycardia
Apnea and cyanosis with oxygen desaturation
Excessive sweating
Anisocoria with sluggish pupillary response to light
These episodes may occur several times per day and may or may not be associated with ictal abnormalities on EEG.
Oromotor dysfunction is seen in a majority of individuals [
Abnormal tongue movements
Speech-language difficulties, including dysarthria
Difficulties whistling, blowing
Abnormal brisk jaw jerk
Some affected individuals with the severe
Progressive microcephaly
Dyskinesia, including choreoathetosis in those without MCD and dystonia and/or hyperkinetic movements in those with MCD [
Cortical visual impairment
Features of autism spectrum disorder
Early-childhood death in two individuals, one due to sudden unexpected death in epilepsy and the other of an undetermined cause [
• Developmental and epileptic encephalopathy without malformation of cortical development: 6/38 (16%) of affected individuals [
• Developmental and epileptic encephalopathy with malformation of cortical development: 16/38 (42%) of affected individuals [
• Malformation of cortical development with or without mild focal epilepsy: 13/38 (34%) of affected individuals [
• All affected individuals have severe-to-profound developmental delays and are nonverbal and nonambulatory.
• Ongoing ID is present in older individuals, ranging from severe to profound.
• Normal cognition in 2/11 (18%)
• Borderline/mild ID in 7/11 (64%)
• Moderate/severe ID in 2/11 (18%)
• In individuals with DEE, neurologic examination typically reveals significant truncal or generalized hypotonia with prominent head lag in younger children.
• In those with malformation of cortical development:
• Hypotonia often progresses to spastic quadriplegia in later childhood in those who also have DEE;
• In those without DEE, older individuals may have pyramidal signs, mild spasticity, or mild hemiparesis.
• Hypotonia often progresses to spastic quadriplegia in later childhood in those who also have DEE;
• In those without DEE, older individuals may have pyramidal signs, mild spasticity, or mild hemiparesis.
• Hypotonia often progresses to spastic quadriplegia in later childhood in those who also have DEE;
• In those without DEE, older individuals may have pyramidal signs, mild spasticity, or mild hemiparesis.
• Seizure onset is typically in the first six to 12 months of life, most often in the first week of life (median age 1-2 weeks), although seizure onset can range from day of birth to age five years.
• The most common presenting seizure types in those without MCD are generalized tonic seizures or epileptic spasms. In those with MCD, the most common presenting seizure types are generalized tonic and focal autonomic seizures.
• Tonic seizures may have a prominent autonomic or apneic component, consistent with apparent life-threatening events (ALTEs) in infants.
• Affected individuals typically develop additional seizure types, which can include the following:
• Epileptic spasms
• Generalized tonic-clonic seizures
• Myoclonic seizures
• Focal tonic seizures
• Focal impaired awareness seizures
• Focal autonomic seizures
• Focal motor seizures
• Epileptic spasms
• Generalized tonic-clonic seizures
• Myoclonic seizures
• Focal tonic seizures
• Focal impaired awareness seizures
• Focal autonomic seizures
• Focal motor seizures
• Seizures remain intractable to multiple anti-seizure medications in approximately 50% of individuals without MCD and in 90% of individuals with MCD.
• Epileptic spasms
• Generalized tonic-clonic seizures
• Myoclonic seizures
• Focal tonic seizures
• Focal impaired awareness seizures
• Focal autonomic seizures
• Focal motor seizures
• A majority (11/13; 85%) do not have a history of seizures or epilepsy;
• A minority (2/13; 15%) have a single unprovoked focal or generalized tonic-clonic seizure in late childhood or adolescence not requiring anti-seizure medication.
• Multifocal epileptiform discharges or hypsarrhythmia in those with DEE but without MCD;
• Burst-suppression early in the disease course, then multifocal epileptiform discharges, and hypsarrhythmia in those with MCD;
• Focal epileptiform abnormalities on EEG even in the absence of clinical seizures in 70% (10/13) of reported individuals with
• Asymmetric or unilateral flushing / color change of the face, which may be confused with Harlequin syndrome
• Brady- or tachycardia
• Apnea and cyanosis with oxygen desaturation
• Excessive sweating
• Anisocoria with sluggish pupillary response to light
• Oromotor dysfunction is seen in a majority of individuals [
• Abnormal tongue movements
• Speech-language difficulties, including dysarthria
• Difficulties whistling, blowing
• Abnormal brisk jaw jerk
• Abnormal tongue movements
• Speech-language difficulties, including dysarthria
• Difficulties whistling, blowing
• Abnormal brisk jaw jerk
• Some affected individuals with the severe
• Abnormal tongue movements
• Speech-language difficulties, including dysarthria
• Difficulties whistling, blowing
• Abnormal brisk jaw jerk
• Progressive microcephaly
• Dyskinesia, including choreoathetosis in those without MCD and dystonia and/or hyperkinetic movements in those with MCD [
• Cortical visual impairment
• Features of autism spectrum disorder
• Early-childhood death in two individuals, one due to sudden unexpected death in epilepsy and the other of an undetermined cause [
## Genotype-Phenotype Correlations
The most common recurrent
Profound developmental delay / intellectual disability (in 10/10 individuals; 100%)
Neonatal onset intractable seizures (median onset 2 weeks) (8/9; 89%)
Multiple seizure types, often generalized tonic seizures
Diffuse, bilateral polymicrogyria (10/10; 100%)
Microcephaly (7/9;78%)
Paroxysmal ictal and non-ictal autonomic dysregulation (4/9; 44%)
A clear genotype-phenotype correlation between other variants or classes of variants has not yet been established.
• Profound developmental delay / intellectual disability (in 10/10 individuals; 100%)
• Neonatal onset intractable seizures (median onset 2 weeks) (8/9; 89%)
• Multiple seizure types, often generalized tonic seizures
• Diffuse, bilateral polymicrogyria (10/10; 100%)
• Microcephaly (7/9;78%)
• Paroxysmal ictal and non-ictal autonomic dysregulation (4/9; 44%)
## Nomenclature
Outdated terms previously used to describe
Cryptogenic pediatric partial epilepsy
Epilepsy, familial focal, with variable foci 4
Epileptic encephalopathy, early infantile, 62
• Cryptogenic pediatric partial epilepsy
• Epilepsy, familial focal, with variable foci 4
• Epileptic encephalopathy, early infantile, 62
## Prevalence
The prevalence of
## Genetically Related (Allelic) Disorders
Other phenotypes associated with pathogenic variants in
## Differential Diagnosis
The phenotype(s) observed in
Syndromes associated with recurrent copy number variants (e.g.,
Selected metabolic disorders such as classic
More than 40 single-gene disorders that are associated with polymicrogyria (see
Non-genetic causes of polymicrogyria (e.g., infection and prenatal hypoxia-ischemia).
• Syndromes associated with recurrent copy number variants (e.g.,
• Selected metabolic disorders such as classic
• More than 40 single-gene disorders that are associated with polymicrogyria (see
• Non-genetic causes of polymicrogyria (e.g., infection and prenatal hypoxia-ischemia).
## Management
Treatment of
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 brain MRI & EEG
Consider video EEG to assess seizure frequency, define seizure type(s), & assess for autonomic dysfunction.
To incl assessment for hyperkinetic movements
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures & kyphoscoliosis
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 eval of oromotor dysfunction & 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.
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy;
Continuous video EEG may be used to help clarify events of unclear nature, such as autonomic manifestations [
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment of Manifestations in Individuals with
Incl lacosamide, phenytoin, & carbamazepine
No one ASM has been shown to be more efficacious than another.
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 home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; FTT = failure to thrive; OT = occupational therapy; PT = physical therapy
Based on the finding that many/most variants (>90%) associated with epileptic encephalopathy in cases of
Of the 15 affected individuals in the
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
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 (ADHD), 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.
Monitor for signs & symptoms of a movement disorder & of autonomic dysfunction.
OT = occupational therapy; PT = physical therapy
Serial neurologic examination and neurodevelopmental assessment is appropriate.
EEG monitoring is appropriate when new or different seizure type(s) are suspected.
There is NO evidence that:
Specific anti-seizure medications can worsen seizures associated with
Sleep deprivation or fever exacerbates seizures associated with
It is appropriate to clarify the genetic status of apparently asymptomatic younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early treatment.
See
In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication during pregnancy reduces this risk. However, exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [
See
Therapeutic trials of anti-seizure medications that target sodium channels may be indicated in cases of severe, treatment-resistant epilepsy or epileptic encephalopathy associated with
Search
• To incl brain MRI & EEG
• Consider video EEG to assess seizure frequency, define seizure type(s), & assess for autonomic dysfunction.
• To incl assessment for hyperkinetic movements
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures & kyphoscoliosis
• 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 eval of oromotor dysfunction & 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.
• Incl lacosamide, phenytoin, & carbamazepine
• No one ASM has been shown to be more efficacious than another.
• 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 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.
• Monitor for signs & symptoms of a movement disorder & of autonomic dysfunction.
• Specific anti-seizure medications can worsen seizures associated with
• Sleep deprivation or fever exacerbates seizures associated with
## 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 brain MRI & EEG
Consider video EEG to assess seizure frequency, define seizure type(s), & assess for autonomic dysfunction.
To incl assessment for hyperkinetic movements
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Gross motor & fine motor skills
Contractures & kyphoscoliosis
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 eval of oromotor dysfunction & 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.
MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy;
Continuous video EEG may be used to help clarify events of unclear nature, such as autonomic manifestations [
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• To incl brain MRI & EEG
• Consider video EEG to assess seizure frequency, define seizure type(s), & assess for autonomic dysfunction.
• To incl assessment for hyperkinetic movements
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Gross motor & fine motor skills
• Contractures & kyphoscoliosis
• 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 eval of oromotor dysfunction & 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
Treatment of Manifestations in Individuals with
Incl lacosamide, phenytoin, & carbamazepine
No one ASM has been shown to be more efficacious than another.
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 home nursing
Consider involvement in adaptive sports or
ASM = anti-seizure medication; DD/ID = developmental delay / intellectual disability; FTT = failure to thrive; OT = occupational therapy; PT = physical therapy
Based on the finding that many/most variants (>90%) associated with epileptic encephalopathy in cases of
Of the 15 affected individuals in the
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
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 (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a pediatric psychiatrist.
• Incl lacosamide, phenytoin, & carbamazepine
• No one ASM has been shown to be more efficacious than another.
• 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 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
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 (ADHD), 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.
Monitor for signs & symptoms of a movement disorder & of autonomic dysfunction.
OT = occupational therapy; PT = physical therapy
Serial neurologic examination and neurodevelopmental assessment is appropriate.
EEG monitoring is appropriate when new or different seizure type(s) are suspected.
• Monitor those w/seizures as clinically indicated.
• Monitor for signs & symptoms of a movement disorder & of autonomic dysfunction.
## Agents/Circumstances to Avoid
There is NO evidence that:
Specific anti-seizure medications can worsen seizures associated with
Sleep deprivation or fever exacerbates seizures associated with
• Specific anti-seizure medications can worsen seizures associated with
• Sleep deprivation or fever exacerbates seizures associated with
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from early treatment.
See
## Pregnancy Management
In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication during pregnancy reduces this risk. However, exposure to anti-seizure medication may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from anti-seizure medication exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of anti-seizure medication to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given anti-seizure drug during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [
See
## Therapies Under Investigation
Therapeutic trials of anti-seizure medications that target sodium channels may be indicated in cases of severe, treatment-resistant epilepsy or epileptic encephalopathy associated with
Search
## Genetic Counseling
The majority of probands diagnosed with
All probands with
Vertical transmission of an
Transmission of an
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, 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.
Parental mosaicism not been reported in
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the
The likelihood that a sib who inherits an
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 parents of affected individuals and 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.
• The majority of probands diagnosed with
• All probands with
• Vertical transmission of an
• Transmission of an
• 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, 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.
• Parental mosaicism not been reported in
• 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.
• Parental mosaicism not been reported in
• 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.
• Parental mosaicism not been reported in
• If a parent of the proband is affected and/or is known to have the
• The likelihood that a sib who inherits an
• 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 parents of affected individuals and young adults who are affected.
## Mode of Inheritance
## Risk to Family Members
The majority of probands diagnosed with
All probands with
Vertical transmission of an
Transmission of an
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, 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.
Parental mosaicism not been reported in
The family history of some individuals diagnosed with
If a parent of the proband is affected and/or is known to have the
The likelihood that a sib who inherits an
If the proband has a known
If the parents have not been tested for the
• The majority of probands diagnosed with
• All probands with
• Vertical transmission of an
• Transmission of an
• 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, 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.
• Parental mosaicism not been reported in
• 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.
• Parental mosaicism not been reported in
• 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.
• Parental mosaicism not been reported in
• If a parent of the proband is affected and/or is known to have the
• The likelihood that a sib who inherits an
• 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 parents of affected individuals and 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 parents of affected individuals and 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
Canada
Canada
•
•
•
• Canada
•
•
• Canada
•
•
•
•
•
## Molecular Genetics
SCN3A-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SCN3A-Related Neurodevelopmental Disorder (
Pathogenic missense variants that cause
Pathogenic variants in
Notable
DD/ID = developmental delay / intellectual disability
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Pathogenic missense variants that cause
Pathogenic variants in
Notable
DD/ID = developmental delay / intellectual disability
Variants listed in the table have been provided by the authors.
## Chapter Notes
Ethan M Goldberg is Assistant Professor in the Division of Neurology at the Children's Hospital of Philadelphia and Department of Neurology & Neuroscience at the University of Pennsylvania Perelman School of Medicine and Attending Physician in the Neurogenetics Clinic at the Children's Hospital of Philadelphia. His laboratory studies mechanisms of epilepsy in experimental models of genetic epilepsies including of
The Epilepsy Neurogenetics Initiative at Children's Hospital of Philadelphia integrates genetic testing into the comprehensive care plan of children with difficult-to-treat or unexplained epilepsies and provides access to expert care for children with genetic epilepsy syndromes. Our team of child neurologists and genetic counselors has particular expertise in the clinical care of children with
1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
4 November 2021 (ma) Revision: frequency of
3 June 2021 (ma) Review posted live
9 November 2020 (klh) Original submission
• 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 4 November 2021 (ma) Revision: frequency of
• 3 June 2021 (ma) Review posted live
• 9 November 2020 (klh) Original submission
## Author Notes
Ethan M Goldberg is Assistant Professor in the Division of Neurology at the Children's Hospital of Philadelphia and Department of Neurology & Neuroscience at the University of Pennsylvania Perelman School of Medicine and Attending Physician in the Neurogenetics Clinic at the Children's Hospital of Philadelphia. His laboratory studies mechanisms of epilepsy in experimental models of genetic epilepsies including of
The Epilepsy Neurogenetics Initiative at Children's Hospital of Philadelphia integrates genetic testing into the comprehensive care plan of children with difficult-to-treat or unexplained epilepsies and provides access to expert care for children with genetic epilepsy syndromes. Our team of child neurologists and genetic counselors has particular expertise in the clinical care of children with
## Revision History
1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
4 November 2021 (ma) Revision: frequency of
3 June 2021 (ma) Review posted live
9 November 2020 (klh) Original submission
• 1 May 2025 (aa) Revision: ClinGen variant interpretation guidelines
• 4 November 2021 (ma) Revision: frequency of
• 3 June 2021 (ma) Review posted live
• 9 November 2020 (klh) Original submission
## References
## Literature Cited
Magnetic resonance imaging scans of individuals with
A. MRI of the brain of a person with profound global developmental delay and treatment-resistant epilepsy at age two years who had a
B. MRI of the brain of a person with developmental delay and treatment-resistant epilepsy at age eight months who has a
C. MRI of the brain of another person with developmental delay and treatment-resistant epilepsy at age five months who has a
Schematic of the Nav1.3 protein showing pathogenic variants associated with
Shown are locations of all missense variants corresponding to disease-associated pathogenic or likely pathogenic variants in
DEE = developmental and epileptic encephalopathy; MCD = malformation of cortical development;
|
[] |
3/6/2021
|
1/5/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
scn8a-ee
|
scn8a-ee
|
[
"SCN8A-Related Developmental and Epileptic Encephalopathy (DEE)",
"SCN8A-Related Mild-to-Moderate Developmental and Epileptic Encephalopathy (mild/modDEE)",
"SCN8A-Related Self-Limited Familial Infantile Epilepsy (SeLFIE)",
"SCN8A-Related Neurodevelopmental Disorder with Generalized Epilepsy (NDDwGE)",
"SCN8A-Related Neurodevelopmental Disorder without Epilepsy (NDDwoE)",
"Sodium channel protein type 8 subunit alpha",
"SCN8A",
"SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders"
] |
Michael F Hammer, Maya Xia, John M Schreiber
|
Summary The diagnosis of
|
For other genetic causes of these phenotypes, see
## Diagnosis
No consensus clinical diagnostic criteria for
Childhood-onset seizures: seizure onset variable, ranges from the first few months to the first few years of life
Development of multiple seizure types, including focal, multifocal, or generalized seizures
May be intractable in some individuals or treatable (especially using sodium channel blockers)
Developmental and epileptic encephalopathy (DEE). Severe intellectual disability, usually pharmacoresistant to anti-seizure medications
Mild-to-moderate DEE (mild/modDEE, also referred to as intermediate epilepsy or IE). Mild-to-moderate intellectual disability, partially treatable epilepsy
Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE). Normal cognition and medically treatable seizures (not necessarily self-limited)
Neurodevelopmental disorder with generalized epilepsy (NDDwGE). Mild-to-moderate intellectual disability, frequently with absence and other generalized seizures
Neurodevelopmental disorder without epilepsy (NDDwoE). Mild-to-moderate intellectual disability (can be severe in ~10% of affected individuals)
Motor abnormalities including hypotonia in some individuals
Movement disorders including dystonia, ataxia, choreoathetosis, or paroxysmal kinesigenic dyskinesia in some individuals
Cognitive development varies depending on the clinical phenotype and can range from normal to severe cognitive delays. In some individuals, intellectual disability occurs without epilepsy.
Non-epileptic paroxysmal episodes, including startle-like myoclonus, generalized tremor, or hyperekplexia-like startles
Language delay, autism spectrum disorder, and behavioral issues may occur with certain epilepsy phenotypes or in the absence of epilepsy.
Some individuals have severe tone abnormalities, significant gastrointestinal issues, impaired swallow function, and cortical visual impairment with early mortality.
The proband may represent a simplex case (i.e., a single occurrence in a family) or the family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations). Probands with more severe
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
To date, most
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. Small deletions and/or duplications in
To date, no large chromosomal deletions/duplications have been reported in individuals with
• Childhood-onset seizures: seizure onset variable, ranges from the first few months to the first few years of life
• Development of multiple seizure types, including focal, multifocal, or generalized seizures
• May be intractable in some individuals or treatable (especially using sodium channel blockers)
• Developmental and epileptic encephalopathy (DEE). Severe intellectual disability, usually pharmacoresistant to anti-seizure medications
• Mild-to-moderate DEE (mild/modDEE, also referred to as intermediate epilepsy or IE). Mild-to-moderate intellectual disability, partially treatable epilepsy
• Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE). Normal cognition and medically treatable seizures (not necessarily self-limited)
• Neurodevelopmental disorder with generalized epilepsy (NDDwGE). Mild-to-moderate intellectual disability, frequently with absence and other generalized seizures
• Neurodevelopmental disorder without epilepsy (NDDwoE). Mild-to-moderate intellectual disability (can be severe in ~10% of affected individuals)
• Motor abnormalities including hypotonia in some individuals
• Movement disorders including dystonia, ataxia, choreoathetosis, or paroxysmal kinesigenic dyskinesia in some individuals
• Cognitive development varies depending on the clinical phenotype and can range from normal to severe cognitive delays. In some individuals, intellectual disability occurs without epilepsy.
• Non-epileptic paroxysmal episodes, including startle-like myoclonus, generalized tremor, or hyperekplexia-like startles
• Language delay, autism spectrum disorder, and behavioral issues may occur with certain epilepsy phenotypes or in the absence of epilepsy.
• Some individuals have severe tone abnormalities, significant gastrointestinal issues, impaired swallow function, and cortical visual impairment with early mortality.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Childhood-onset seizures: seizure onset variable, ranges from the first few months to the first few years of life
Development of multiple seizure types, including focal, multifocal, or generalized seizures
May be intractable in some individuals or treatable (especially using sodium channel blockers)
Developmental and epileptic encephalopathy (DEE). Severe intellectual disability, usually pharmacoresistant to anti-seizure medications
Mild-to-moderate DEE (mild/modDEE, also referred to as intermediate epilepsy or IE). Mild-to-moderate intellectual disability, partially treatable epilepsy
Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE). Normal cognition and medically treatable seizures (not necessarily self-limited)
Neurodevelopmental disorder with generalized epilepsy (NDDwGE). Mild-to-moderate intellectual disability, frequently with absence and other generalized seizures
Neurodevelopmental disorder without epilepsy (NDDwoE). Mild-to-moderate intellectual disability (can be severe in ~10% of affected individuals)
Motor abnormalities including hypotonia in some individuals
Movement disorders including dystonia, ataxia, choreoathetosis, or paroxysmal kinesigenic dyskinesia in some individuals
Cognitive development varies depending on the clinical phenotype and can range from normal to severe cognitive delays. In some individuals, intellectual disability occurs without epilepsy.
Non-epileptic paroxysmal episodes, including startle-like myoclonus, generalized tremor, or hyperekplexia-like startles
Language delay, autism spectrum disorder, and behavioral issues may occur with certain epilepsy phenotypes or in the absence of epilepsy.
Some individuals have severe tone abnormalities, significant gastrointestinal issues, impaired swallow function, and cortical visual impairment with early mortality.
The proband may represent a simplex case (i.e., a single occurrence in a family) or the family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations). Probands with more severe
• Childhood-onset seizures: seizure onset variable, ranges from the first few months to the first few years of life
• Development of multiple seizure types, including focal, multifocal, or generalized seizures
• May be intractable in some individuals or treatable (especially using sodium channel blockers)
• Developmental and epileptic encephalopathy (DEE). Severe intellectual disability, usually pharmacoresistant to anti-seizure medications
• Mild-to-moderate DEE (mild/modDEE, also referred to as intermediate epilepsy or IE). Mild-to-moderate intellectual disability, partially treatable epilepsy
• Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE). Normal cognition and medically treatable seizures (not necessarily self-limited)
• Neurodevelopmental disorder with generalized epilepsy (NDDwGE). Mild-to-moderate intellectual disability, frequently with absence and other generalized seizures
• Neurodevelopmental disorder without epilepsy (NDDwoE). Mild-to-moderate intellectual disability (can be severe in ~10% of affected individuals)
• Motor abnormalities including hypotonia in some individuals
• Movement disorders including dystonia, ataxia, choreoathetosis, or paroxysmal kinesigenic dyskinesia in some individuals
• Cognitive development varies depending on the clinical phenotype and can range from normal to severe cognitive delays. In some individuals, intellectual disability occurs without epilepsy.
• Non-epileptic paroxysmal episodes, including startle-like myoclonus, generalized tremor, or hyperekplexia-like startles
• Language delay, autism spectrum disorder, and behavioral issues may occur with certain epilepsy phenotypes or in the absence of epilepsy.
• Some individuals have severe tone abnormalities, significant gastrointestinal issues, impaired swallow function, and cortical visual impairment with early mortality.
## Clinical Findings
Childhood-onset seizures: seizure onset variable, ranges from the first few months to the first few years of life
Development of multiple seizure types, including focal, multifocal, or generalized seizures
May be intractable in some individuals or treatable (especially using sodium channel blockers)
Developmental and epileptic encephalopathy (DEE). Severe intellectual disability, usually pharmacoresistant to anti-seizure medications
Mild-to-moderate DEE (mild/modDEE, also referred to as intermediate epilepsy or IE). Mild-to-moderate intellectual disability, partially treatable epilepsy
Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE). Normal cognition and medically treatable seizures (not necessarily self-limited)
Neurodevelopmental disorder with generalized epilepsy (NDDwGE). Mild-to-moderate intellectual disability, frequently with absence and other generalized seizures
Neurodevelopmental disorder without epilepsy (NDDwoE). Mild-to-moderate intellectual disability (can be severe in ~10% of affected individuals)
Motor abnormalities including hypotonia in some individuals
Movement disorders including dystonia, ataxia, choreoathetosis, or paroxysmal kinesigenic dyskinesia in some individuals
Cognitive development varies depending on the clinical phenotype and can range from normal to severe cognitive delays. In some individuals, intellectual disability occurs without epilepsy.
Non-epileptic paroxysmal episodes, including startle-like myoclonus, generalized tremor, or hyperekplexia-like startles
Language delay, autism spectrum disorder, and behavioral issues may occur with certain epilepsy phenotypes or in the absence of epilepsy.
Some individuals have severe tone abnormalities, significant gastrointestinal issues, impaired swallow function, and cortical visual impairment with early mortality.
• Childhood-onset seizures: seizure onset variable, ranges from the first few months to the first few years of life
• Development of multiple seizure types, including focal, multifocal, or generalized seizures
• May be intractable in some individuals or treatable (especially using sodium channel blockers)
• Developmental and epileptic encephalopathy (DEE). Severe intellectual disability, usually pharmacoresistant to anti-seizure medications
• Mild-to-moderate DEE (mild/modDEE, also referred to as intermediate epilepsy or IE). Mild-to-moderate intellectual disability, partially treatable epilepsy
• Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE). Normal cognition and medically treatable seizures (not necessarily self-limited)
• Neurodevelopmental disorder with generalized epilepsy (NDDwGE). Mild-to-moderate intellectual disability, frequently with absence and other generalized seizures
• Neurodevelopmental disorder without epilepsy (NDDwoE). Mild-to-moderate intellectual disability (can be severe in ~10% of affected individuals)
• Motor abnormalities including hypotonia in some individuals
• Movement disorders including dystonia, ataxia, choreoathetosis, or paroxysmal kinesigenic dyskinesia in some individuals
• Cognitive development varies depending on the clinical phenotype and can range from normal to severe cognitive delays. In some individuals, intellectual disability occurs without epilepsy.
• Non-epileptic paroxysmal episodes, including startle-like myoclonus, generalized tremor, or hyperekplexia-like startles
• Language delay, autism spectrum disorder, and behavioral issues may occur with certain epilepsy phenotypes or in the absence of epilepsy.
• Some individuals have severe tone abnormalities, significant gastrointestinal issues, impaired swallow function, and cortical visual impairment with early mortality.
## Family History
The proband may represent a simplex case (i.e., a single occurrence in a family) or the family history may suggest autosomal dominant inheritance (e.g., affected males and females in multiple generations). Probands with more severe
## 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
To date, most
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. Small deletions and/or duplications in
To date, no large chromosomal deletions/duplications have been reported in individuals with
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Five different clinical phenotypes have been identified in association with pathogenic
Developmental and epileptic encephalopathy (DEE)
Mild-to-moderate developmental and epileptic encephalopathy (mild/modDEE, also referred to as intermediate epilepsy or IE)
Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE)
Neurodevelopmental disorder with generalized epilepsy (NDDwGE)
Neurodevelopmental disorder without epilepsy (NDDwoE)
To date, more than 500 individuals have been identified with a pathogenic variant in
The following description of the phenotypic features associated with this condition is based on these reports.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CVI = cortical visual impairment; DEE = developmental and epileptic encephalopathy; GI = gastrointestinal; GoF = gain of function; ID = intellectual disability; LoF = loss of function; NA = not applicable; NDDwGE = neurodevelopmental disorder with generalized epilepsy; NDDwoE = neurodevelopmental disorder without epilepsy; SeLFIE = self-limited familial infantile epilepsy
Initial seizure type varies, and most affected individuals develop additional seizure types over time, including the following:
Focal clonic seizures evolving to bilateral convulsive seizures
Generalized tonic-clonic seizures
Tonic seizures
Infantile spasms
Myoclonic seizures
Focal seizures in
Although both convulsive and nonconvulsive status epilepticus appear to be common [
Seizure frequencies range from hundreds per day to fewer than one per month. Most affected individuals have refractory seizures and require polytherapy (see
Approximately half of affected children learn to sit and walk unassisted; the remainder are nonambulatory. Ataxia and sudden loss of mobility are common in those who are ambulatory.
Most individuals diagnosed with this disorder are younger than age 20 years. For the several individuals who are in their teens, cognitive and motor disabilities persist. The oldest affected individual whom the authors are aware of is age 47 years [Authors, personal communication].
Autonomic nervous system dysfunction, including difficulty with temperature regulation and tachypnea
Hearing issues
Bone fractures, often associated with prolonged seizures
Laryngomalacia
Scoliosis
Microcephaly
Cortical visual impairment
Gum hyperplasia secondary to anti-seizure medication
Focal seizures
Bilateral tonic-clonic seizures
Tonic seizures
Seizures are usually partially treatable using sodium channel blockers (see
EEG and MRI brain findings are similar to
Focal seizures
Focal seizures evolving to bilateral tonic-clonic seizures
Bilateral tonic-clonic seizures
Seizures are usually treatable using sodium channel blockers (see
Absence seizures
Generalized tonic-clonic seizures
Generalized myoclonic seizures
Febrile seizures
Seizures are usually not treatable using sodium channel blockers, which may aggravate symptoms of individuals with
Some individuals have language delays and behavioral issues.
Individuals with this phenotype typically do not have epilepsy. However, it is important to note that developmental delay may precede seizure onset in
Attention-deficit/hyperactivity disorder
Autism spectrum disorder
Microcephaly
It is unknown whether life span in the entire spectrum of
Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
Affected individuals with LoF variants mostly have
Several recurrent variants are associated with specific phenotypes (see
The variants c.2549G>A (p.Arg850Gln) and c.5614C>T (p.Arg1872Trp) are associated with
The variants c.4423G>A (p.Gly1475Arg), c.4850G>A (p.Arg1617Gln), c.5615G>A (p.Arg1872Gln), and c.5630G>T (p.Asn1877Ser) are associated with
The variant c.4447G>A (p.Glu1483Lys) is associated with
All individuals with GoF variants have epilepsy, whereas 50%-70% of individuals with LoF variants have epilepsy [
Penetrance for
Alternate naming conventions for
The prevalence of
The frequency of
A study evaluating the incidence of
• Developmental and epileptic encephalopathy (DEE)
• Mild-to-moderate developmental and epileptic encephalopathy (mild/modDEE, also referred to as intermediate epilepsy or IE)
• Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE)
• Neurodevelopmental disorder with generalized epilepsy (NDDwGE)
• Neurodevelopmental disorder without epilepsy (NDDwoE)
• Focal clonic seizures evolving to bilateral convulsive seizures
• Generalized tonic-clonic seizures
• Tonic seizures
• Infantile spasms
• Myoclonic seizures
• Autonomic nervous system dysfunction, including difficulty with temperature regulation and tachypnea
• Hearing issues
• Bone fractures, often associated with prolonged seizures
• Laryngomalacia
• Scoliosis
• Microcephaly
• Cortical visual impairment
• Gum hyperplasia secondary to anti-seizure medication
• Focal seizures
• Bilateral tonic-clonic seizures
• Tonic seizures
• Focal seizures
• Focal seizures evolving to bilateral tonic-clonic seizures
• Bilateral tonic-clonic seizures
• Absence seizures
• Generalized tonic-clonic seizures
• Generalized myoclonic seizures
• Febrile seizures
• Attention-deficit/hyperactivity disorder
• Autism spectrum disorder
• Microcephaly
• Affected individuals with LoF variants mostly have
• Several recurrent variants are associated with specific phenotypes (see
• The variants c.2549G>A (p.Arg850Gln) and c.5614C>T (p.Arg1872Trp) are associated with
• The variants c.4423G>A (p.Gly1475Arg), c.4850G>A (p.Arg1617Gln), c.5615G>A (p.Arg1872Gln), and c.5630G>T (p.Asn1877Ser) are associated with
• The variant c.4447G>A (p.Glu1483Lys) is associated with
• The variants c.2549G>A (p.Arg850Gln) and c.5614C>T (p.Arg1872Trp) are associated with
• The variants c.4423G>A (p.Gly1475Arg), c.4850G>A (p.Arg1617Gln), c.5615G>A (p.Arg1872Gln), and c.5630G>T (p.Asn1877Ser) are associated with
• The variant c.4447G>A (p.Glu1483Lys) is associated with
• All individuals with GoF variants have epilepsy, whereas 50%-70% of individuals with LoF variants have epilepsy [
• The variants c.2549G>A (p.Arg850Gln) and c.5614C>T (p.Arg1872Trp) are associated with
• The variants c.4423G>A (p.Gly1475Arg), c.4850G>A (p.Arg1617Gln), c.5615G>A (p.Arg1872Gln), and c.5630G>T (p.Asn1877Ser) are associated with
• The variant c.4447G>A (p.Glu1483Lys) is associated with
## Clinical Description
Five different clinical phenotypes have been identified in association with pathogenic
Developmental and epileptic encephalopathy (DEE)
Mild-to-moderate developmental and epileptic encephalopathy (mild/modDEE, also referred to as intermediate epilepsy or IE)
Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE)
Neurodevelopmental disorder with generalized epilepsy (NDDwGE)
Neurodevelopmental disorder without epilepsy (NDDwoE)
To date, more than 500 individuals have been identified with a pathogenic variant in
The following description of the phenotypic features associated with this condition is based on these reports.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; CVI = cortical visual impairment; DEE = developmental and epileptic encephalopathy; GI = gastrointestinal; GoF = gain of function; ID = intellectual disability; LoF = loss of function; NA = not applicable; NDDwGE = neurodevelopmental disorder with generalized epilepsy; NDDwoE = neurodevelopmental disorder without epilepsy; SeLFIE = self-limited familial infantile epilepsy
Initial seizure type varies, and most affected individuals develop additional seizure types over time, including the following:
Focal clonic seizures evolving to bilateral convulsive seizures
Generalized tonic-clonic seizures
Tonic seizures
Infantile spasms
Myoclonic seizures
Focal seizures in
Although both convulsive and nonconvulsive status epilepticus appear to be common [
Seizure frequencies range from hundreds per day to fewer than one per month. Most affected individuals have refractory seizures and require polytherapy (see
Approximately half of affected children learn to sit and walk unassisted; the remainder are nonambulatory. Ataxia and sudden loss of mobility are common in those who are ambulatory.
Most individuals diagnosed with this disorder are younger than age 20 years. For the several individuals who are in their teens, cognitive and motor disabilities persist. The oldest affected individual whom the authors are aware of is age 47 years [Authors, personal communication].
Autonomic nervous system dysfunction, including difficulty with temperature regulation and tachypnea
Hearing issues
Bone fractures, often associated with prolonged seizures
Laryngomalacia
Scoliosis
Microcephaly
Cortical visual impairment
Gum hyperplasia secondary to anti-seizure medication
Focal seizures
Bilateral tonic-clonic seizures
Tonic seizures
Seizures are usually partially treatable using sodium channel blockers (see
EEG and MRI brain findings are similar to
Focal seizures
Focal seizures evolving to bilateral tonic-clonic seizures
Bilateral tonic-clonic seizures
Seizures are usually treatable using sodium channel blockers (see
Absence seizures
Generalized tonic-clonic seizures
Generalized myoclonic seizures
Febrile seizures
Seizures are usually not treatable using sodium channel blockers, which may aggravate symptoms of individuals with
Some individuals have language delays and behavioral issues.
Individuals with this phenotype typically do not have epilepsy. However, it is important to note that developmental delay may precede seizure onset in
Attention-deficit/hyperactivity disorder
Autism spectrum disorder
Microcephaly
It is unknown whether life span in the entire spectrum of
Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
• Developmental and epileptic encephalopathy (DEE)
• Mild-to-moderate developmental and epileptic encephalopathy (mild/modDEE, also referred to as intermediate epilepsy or IE)
• Self-limited familial infantile epilepsy (SeLFIE, also referred to as benign familial infantile epilepsy or BFIE)
• Neurodevelopmental disorder with generalized epilepsy (NDDwGE)
• Neurodevelopmental disorder without epilepsy (NDDwoE)
• Focal clonic seizures evolving to bilateral convulsive seizures
• Generalized tonic-clonic seizures
• Tonic seizures
• Infantile spasms
• Myoclonic seizures
• Autonomic nervous system dysfunction, including difficulty with temperature regulation and tachypnea
• Hearing issues
• Bone fractures, often associated with prolonged seizures
• Laryngomalacia
• Scoliosis
• Microcephaly
• Cortical visual impairment
• Gum hyperplasia secondary to anti-seizure medication
• Focal seizures
• Bilateral tonic-clonic seizures
• Tonic seizures
• Focal seizures
• Focal seizures evolving to bilateral tonic-clonic seizures
• Bilateral tonic-clonic seizures
• Absence seizures
• Generalized tonic-clonic seizures
• Generalized myoclonic seizures
• Febrile seizures
• Attention-deficit/hyperactivity disorder
• Autism spectrum disorder
• Microcephaly
Initial seizure type varies, and most affected individuals develop additional seizure types over time, including the following:
Focal clonic seizures evolving to bilateral convulsive seizures
Generalized tonic-clonic seizures
Tonic seizures
Infantile spasms
Myoclonic seizures
Focal seizures in
Although both convulsive and nonconvulsive status epilepticus appear to be common [
Seizure frequencies range from hundreds per day to fewer than one per month. Most affected individuals have refractory seizures and require polytherapy (see
Approximately half of affected children learn to sit and walk unassisted; the remainder are nonambulatory. Ataxia and sudden loss of mobility are common in those who are ambulatory.
Most individuals diagnosed with this disorder are younger than age 20 years. For the several individuals who are in their teens, cognitive and motor disabilities persist. The oldest affected individual whom the authors are aware of is age 47 years [Authors, personal communication].
Autonomic nervous system dysfunction, including difficulty with temperature regulation and tachypnea
Hearing issues
Bone fractures, often associated with prolonged seizures
Laryngomalacia
Scoliosis
Microcephaly
Cortical visual impairment
Gum hyperplasia secondary to anti-seizure medication
• Focal clonic seizures evolving to bilateral convulsive seizures
• Generalized tonic-clonic seizures
• Tonic seizures
• Infantile spasms
• Myoclonic seizures
• Autonomic nervous system dysfunction, including difficulty with temperature regulation and tachypnea
• Hearing issues
• Bone fractures, often associated with prolonged seizures
• Laryngomalacia
• Scoliosis
• Microcephaly
• Cortical visual impairment
• Gum hyperplasia secondary to anti-seizure medication
Focal seizures
Bilateral tonic-clonic seizures
Tonic seizures
Seizures are usually partially treatable using sodium channel blockers (see
EEG and MRI brain findings are similar to
• Focal seizures
• Bilateral tonic-clonic seizures
• Tonic seizures
Focal seizures
Focal seizures evolving to bilateral tonic-clonic seizures
Bilateral tonic-clonic seizures
Seizures are usually treatable using sodium channel blockers (see
• Focal seizures
• Focal seizures evolving to bilateral tonic-clonic seizures
• Bilateral tonic-clonic seizures
Absence seizures
Generalized tonic-clonic seizures
Generalized myoclonic seizures
Febrile seizures
Seizures are usually not treatable using sodium channel blockers, which may aggravate symptoms of individuals with
Some individuals have language delays and behavioral issues.
• Absence seizures
• Generalized tonic-clonic seizures
• Generalized myoclonic seizures
• Febrile seizures
Individuals with this phenotype typically do not have epilepsy. However, it is important to note that developmental delay may precede seizure onset in
Attention-deficit/hyperactivity disorder
Autism spectrum disorder
Microcephaly
• Attention-deficit/hyperactivity disorder
• Autism spectrum disorder
• Microcephaly
## Prognosis
It is unknown whether life span in the entire spectrum of
Since many adults with disabilities have not undergone advanced genetic testing, it is likely that adults with this condition are underrecognized and underreported.
## Genotype-Phenotype Correlations
Affected individuals with LoF variants mostly have
Several recurrent variants are associated with specific phenotypes (see
The variants c.2549G>A (p.Arg850Gln) and c.5614C>T (p.Arg1872Trp) are associated with
The variants c.4423G>A (p.Gly1475Arg), c.4850G>A (p.Arg1617Gln), c.5615G>A (p.Arg1872Gln), and c.5630G>T (p.Asn1877Ser) are associated with
The variant c.4447G>A (p.Glu1483Lys) is associated with
All individuals with GoF variants have epilepsy, whereas 50%-70% of individuals with LoF variants have epilepsy [
• Affected individuals with LoF variants mostly have
• Several recurrent variants are associated with specific phenotypes (see
• The variants c.2549G>A (p.Arg850Gln) and c.5614C>T (p.Arg1872Trp) are associated with
• The variants c.4423G>A (p.Gly1475Arg), c.4850G>A (p.Arg1617Gln), c.5615G>A (p.Arg1872Gln), and c.5630G>T (p.Asn1877Ser) are associated with
• The variant c.4447G>A (p.Glu1483Lys) is associated with
• The variants c.2549G>A (p.Arg850Gln) and c.5614C>T (p.Arg1872Trp) are associated with
• The variants c.4423G>A (p.Gly1475Arg), c.4850G>A (p.Arg1617Gln), c.5615G>A (p.Arg1872Gln), and c.5630G>T (p.Asn1877Ser) are associated with
• The variant c.4447G>A (p.Glu1483Lys) is associated with
• All individuals with GoF variants have epilepsy, whereas 50%-70% of individuals with LoF variants have epilepsy [
• The variants c.2549G>A (p.Arg850Gln) and c.5614C>T (p.Arg1872Trp) are associated with
• The variants c.4423G>A (p.Gly1475Arg), c.4850G>A (p.Arg1617Gln), c.5615G>A (p.Arg1872Gln), and c.5630G>T (p.Asn1877Ser) are associated with
• The variant c.4447G>A (p.Glu1483Lys) is associated with
## Penetrance
Penetrance for
## Nomenclature
Alternate naming conventions for
## Prevalence
The prevalence of
The frequency of
A study evaluating the incidence of
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Because the phenotypic features associated with
See OMIM Phenotypic Series for genes associated with:
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•
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•
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•
•
## 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
EEG to assess EEG background, epileptiform activity, & seizure type (when indicated)
Baseline brain MRI, if not performed already
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
Gross motor & fine motor skills
Tone abnormalities
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
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; SUDEP = sudden unexpected death in epilepsy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Sodium channel blockers represent a targeted treatment option 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 (see
Treatment of Manifestations in Individuals with
Standardized treatment w/ASM by experienced neurologist
Counsel on SUDEP risk & monitoring for seizures, particularly in persons at higher risk, incl those w/
Many ASMs may be effective; studies suggest that persons w/focal epilepsy phenotypes (
The effectiveness of sodium channel blockers is consistent w/activating effects of
Many affected persons are maintained on multiple ASMs w/incomplete seizure control. Vigorous attempts to control seizures w/drug polytherapy are warranted, as children w/DEE are at risk for SUDEP as well as prolonged acute seizures that may cause permanent injury.
Levetiracetam (Keppra
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Eval by sleep &/or ENT specialist for any sleep issues incl sleep apnea
Polysomnography should be considered if obstructive or central sleep apnea is suspected.
Sleep deprivation & illness can exacerbate
Because of ↑ risk of SUDEP, some families use oxygen monitoring during sleep.
Swallow eval
Eval by pulmonary & GI
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; GoF = gain of function;
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
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
Recommended Surveillance for Individuals with
Monitor seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Query for factors that ↑ SUDEP risk, incl generalized tonic-clonic seizures & nighttime seizures.
Assess seizure monitoring strategies.
OT = occupational therapy; PT = physical therapy; SUDEP = sudden unexpected death in epilepsy
Several families of affected individuals report worsening of seizures, encephalopathy, and/or developmental regression with levetiracetam (Keppra
See
NBI-921352, a Na
Search
• EEG to assess EEG background, epileptiform activity, & seizure type (when indicated)
• Baseline brain MRI, if not performed already
• 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
• Gross motor & fine motor skills
• Tone abnormalities
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• 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 neurologist
• Counsel on SUDEP risk & monitoring for seizures, particularly in persons at higher risk, incl those w/
• Many ASMs may be effective; studies suggest that persons w/focal epilepsy phenotypes (
• The effectiveness of sodium channel blockers is consistent w/activating effects of
• Many affected persons are maintained on multiple ASMs w/incomplete seizure control. Vigorous attempts to control seizures w/drug polytherapy are warranted, as children w/DEE are at risk for SUDEP as well as prolonged acute seizures that may cause permanent injury.
• Levetiracetam (Keppra
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Eval by sleep &/or ENT specialist for any sleep issues incl sleep apnea
• Polysomnography should be considered if obstructive or central sleep apnea is suspected.
• Sleep deprivation & illness can exacerbate
• Because of ↑ risk of SUDEP, some families use oxygen monitoring during sleep.
• Swallow eval
• Eval by pulmonary & GI
• 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 seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Query for factors that ↑ SUDEP risk, incl generalized tonic-clonic seizures & nighttime seizures.
• Assess seizure monitoring strategies.
## 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
EEG to assess EEG background, epileptiform activity, & seizure type (when indicated)
Baseline brain MRI, if not performed already
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
Gross motor & fine motor skills
Tone abnormalities
Mobility, ADL, & need for adaptive devices
Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
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; SUDEP = sudden unexpected death in epilepsy
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• EEG to assess EEG background, epileptiform activity, & seizure type (when indicated)
• Baseline brain MRI, if not performed already
• 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
• Gross motor & fine motor skills
• Tone abnormalities
• Mobility, ADL, & need for adaptive devices
• Need for PT (to improve gross motor skills) &/or OT (to improve fine motor skills)
• 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
Sodium channel blockers represent a targeted treatment option 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 (see
Treatment of Manifestations in Individuals with
Standardized treatment w/ASM by experienced neurologist
Counsel on SUDEP risk & monitoring for seizures, particularly in persons at higher risk, incl those w/
Many ASMs may be effective; studies suggest that persons w/focal epilepsy phenotypes (
The effectiveness of sodium channel blockers is consistent w/activating effects of
Many affected persons are maintained on multiple ASMs w/incomplete seizure control. Vigorous attempts to control seizures w/drug polytherapy are warranted, as children w/DEE are at risk for SUDEP as well as prolonged acute seizures that may cause permanent injury.
Levetiracetam (Keppra
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Eval by sleep &/or ENT specialist for any sleep issues incl sleep apnea
Polysomnography should be considered if obstructive or central sleep apnea is suspected.
Sleep deprivation & illness can exacerbate
Because of ↑ risk of SUDEP, some families use oxygen monitoring during sleep.
Swallow eval
Eval by pulmonary & GI
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; GoF = gain of function;
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
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 w/ASM by experienced neurologist
• Counsel on SUDEP risk & monitoring for seizures, particularly in persons at higher risk, incl those w/
• Many ASMs may be effective; studies suggest that persons w/focal epilepsy phenotypes (
• The effectiveness of sodium channel blockers is consistent w/activating effects of
• Many affected persons are maintained on multiple ASMs w/incomplete seizure control. Vigorous attempts to control seizures w/drug polytherapy are warranted, as children w/DEE are at risk for SUDEP as well as prolonged acute seizures that may cause permanent injury.
• Levetiracetam (Keppra
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Eval by sleep &/or ENT specialist for any sleep issues incl sleep apnea
• Polysomnography should be considered if obstructive or central sleep apnea is suspected.
• Sleep deprivation & illness can exacerbate
• Because of ↑ risk of SUDEP, some families use oxygen monitoring during sleep.
• Swallow eval
• Eval by pulmonary & GI
• 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
## Targeted Therapy
Sodium channel blockers represent a targeted treatment option for
## 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
Treatment of Manifestations in Individuals with
Standardized treatment w/ASM by experienced neurologist
Counsel on SUDEP risk & monitoring for seizures, particularly in persons at higher risk, incl those w/
Many ASMs may be effective; studies suggest that persons w/focal epilepsy phenotypes (
The effectiveness of sodium channel blockers is consistent w/activating effects of
Many affected persons are maintained on multiple ASMs w/incomplete seizure control. Vigorous attempts to control seizures w/drug polytherapy are warranted, as children w/DEE are at risk for SUDEP as well as prolonged acute seizures that may cause permanent injury.
Levetiracetam (Keppra
Education of parents/caregivers
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Eval by sleep &/or ENT specialist for any sleep issues incl sleep apnea
Polysomnography should be considered if obstructive or central sleep apnea is suspected.
Sleep deprivation & illness can exacerbate
Because of ↑ risk of SUDEP, some families use oxygen monitoring during sleep.
Swallow eval
Eval by pulmonary & GI
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; GoF = gain of function;
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
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 w/ASM by experienced neurologist
• Counsel on SUDEP risk & monitoring for seizures, particularly in persons at higher risk, incl those w/
• Many ASMs may be effective; studies suggest that persons w/focal epilepsy phenotypes (
• The effectiveness of sodium channel blockers is consistent w/activating effects of
• Many affected persons are maintained on multiple ASMs w/incomplete seizure control. Vigorous attempts to control seizures w/drug polytherapy are warranted, as children w/DEE are at risk for SUDEP as well as prolonged acute seizures that may cause permanent injury.
• Levetiracetam (Keppra
• Education of parents/caregivers
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Eval by sleep &/or ENT specialist for any sleep issues incl sleep apnea
• Polysomnography should be considered if obstructive or central sleep apnea is suspected.
• Sleep deprivation & illness can exacerbate
• Because of ↑ risk of SUDEP, some families use oxygen monitoring during sleep.
• Swallow eval
• Eval by pulmonary & GI
• 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
##
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.
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 individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with
Monitor seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
Query for factors that ↑ SUDEP risk, incl generalized tonic-clonic seizures & nighttime seizures.
Assess seizure monitoring strategies.
OT = occupational therapy; PT = physical therapy; SUDEP = sudden unexpected death in epilepsy
• Monitor seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
• Query for factors that ↑ SUDEP risk, incl generalized tonic-clonic seizures & nighttime seizures.
• Assess seizure monitoring strategies.
## Agents/Circumstances to Avoid
Several families of affected individuals report worsening of seizures, encephalopathy, and/or developmental regression with levetiracetam (Keppra
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
NBI-921352, a Na
Search
## Genetic Counseling
Some individuals diagnosed with an
Some individuals diagnosed with an
2% (3/166) of individuals with
10% (3/29) of individuals with
47% (7/15) of individuals with
33% (5/15) of individuals with
60% (9/15) of individuals with
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 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.
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with an
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 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.
• Some individuals diagnosed with an
• Some individuals diagnosed with an
• 2% (3/166) of individuals with
• 10% (3/29) of individuals with
• 47% (7/15) of individuals with
• 33% (5/15) of individuals with
• 60% (9/15) of individuals with
• 2% (3/166) of individuals with
• 10% (3/29) of individuals with
• 47% (7/15) of individuals with
• 33% (5/15) of individuals with
• 60% (9/15) of individuals with
• 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 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.
• * 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.* 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.
• * A parent with somatic and germline mosaicism for an
• The family history of some individuals diagnosed with an
• 2% (3/166) of individuals with
• 10% (3/29) of individuals with
• 47% (7/15) of individuals with
• 33% (5/15) of individuals with
• 60% (9/15) of individuals with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* 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.
• * A parent with somatic and germline mosaicism for an
• 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 parents of affected individuals.
## Mode of Inheritance
## Risk to Family Members
Some individuals diagnosed with an
Some individuals diagnosed with an
2% (3/166) of individuals with
10% (3/29) of individuals with
47% (7/15) of individuals with
33% (5/15) of individuals with
60% (9/15) of individuals with
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 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.
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with an
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 an
• Some individuals diagnosed with an
• 2% (3/166) of individuals with
• 10% (3/29) of individuals with
• 47% (7/15) of individuals with
• 33% (5/15) of individuals with
• 60% (9/15) of individuals with
• 2% (3/166) of individuals with
• 10% (3/29) of individuals with
• 47% (7/15) of individuals with
• 33% (5/15) of individuals with
• 60% (9/15) of individuals with
• 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 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.
• * 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.* 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.
• * A parent with somatic and germline mosaicism for an
• The family history of some individuals diagnosed with an
• 2% (3/166) of individuals with
• 10% (3/29) of individuals with
• 47% (7/15) of individuals with
• 33% (5/15) of individuals with
• 60% (9/15) of individuals with
• The proband has a
• The proband inherited a pathogenic variant from a parent with germline (or somatic and germline) mosaicism.* 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.
• * A parent with somatic and germline mosaicism for an
• 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
The optimal time for determination of genetic risk and discussion of the availability of prenatal/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
Canada
Canada
•
•
•
•
•
•
•
•
•
• Canada
•
•
• Canada
•
•
•
•
•
## Molecular Genetics
SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SCN8A-Related Epilepsy and/or Neurodevelopmental Disorders (
Most pathogenic variants associated with
Gain of function in
Loss of function in
There are several alternatively spliced exons: 6A (adult) and 6N (neonatal) that encode segment 3/4 of domain I, as well as alternatively spliced exons 21A and 21N that encode segment 3/4 of domain III.
Exon 21N is a "poison" exon that contains an in-frame stop codon and encodes a truncated protein terminating in domain III that does not have channel activity. Therefore, the reference sequence for missing exon 21 should not be used for sequence comparisons:
The most complete full-length reference transcript contains exon 6N and exon 21A:
Highly Recurrent
Variants listed in the table have been provided by the authors.
Variants known to be present in >15 individuals
• Gain of function in
• Loss of function in
• There are several alternatively spliced exons: 6A (adult) and 6N (neonatal) that encode segment 3/4 of domain I, as well as alternatively spliced exons 21A and 21N that encode segment 3/4 of domain III.
• Exon 21N is a "poison" exon that contains an in-frame stop codon and encodes a truncated protein terminating in domain III that does not have channel activity. Therefore, the reference sequence for missing exon 21 should not be used for sequence comparisons:
• The most complete full-length reference transcript contains exon 6N and exon 21A:
## Molecular Pathogenesis
Most pathogenic variants associated with
Gain of function in
Loss of function in
There are several alternatively spliced exons: 6A (adult) and 6N (neonatal) that encode segment 3/4 of domain I, as well as alternatively spliced exons 21A and 21N that encode segment 3/4 of domain III.
Exon 21N is a "poison" exon that contains an in-frame stop codon and encodes a truncated protein terminating in domain III that does not have channel activity. Therefore, the reference sequence for missing exon 21 should not be used for sequence comparisons:
The most complete full-length reference transcript contains exon 6N and exon 21A:
Highly Recurrent
Variants listed in the table have been provided by the authors.
Variants known to be present in >15 individuals
• Gain of function in
• Loss of function in
• There are several alternatively spliced exons: 6A (adult) and 6N (neonatal) that encode segment 3/4 of domain I, as well as alternatively spliced exons 21A and 21N that encode segment 3/4 of domain III.
• Exon 21N is a "poison" exon that contains an in-frame stop codon and encodes a truncated protein terminating in domain III that does not have channel activity. Therefore, the reference sequence for missing exon 21 should not be used for sequence comparisons:
• The most complete full-length reference transcript contains exon 6N and exon 21A:
## Chapter Notes
Contact
The Hammer lab identified the first case of
We thank Wishes for Elliott (
Michael F Hammer, PhD (2016-present)Heather C Mefford, MD, PhD; St Jude Children's Research Hospital (2016-2023)Miriam H Meisler, PhD; University of Michigan (2016-2023)John M Schreiber, MD (2023-present)Jacy L Wagnon, PhD; University of Michigan (2016-2023)Maya Xia, BA (2023-present)
6 April 2023 (gm) Comprehensive updated posted live
25 August 2016 (bp) Review posted live
29 September 2015 (mfh) Original submission
• 6 April 2023 (gm) Comprehensive updated posted live
• 25 August 2016 (bp) Review posted live
• 29 September 2015 (mfh) Original submission
## Author Notes
Contact
The Hammer lab identified the first case of
## Acknowledgments
We thank Wishes for Elliott (
## Author History
Michael F Hammer, PhD (2016-present)Heather C Mefford, MD, PhD; St Jude Children's Research Hospital (2016-2023)Miriam H Meisler, PhD; University of Michigan (2016-2023)John M Schreiber, MD (2023-present)Jacy L Wagnon, PhD; University of Michigan (2016-2023)Maya Xia, BA (2023-present)
## Revision History
6 April 2023 (gm) Comprehensive updated posted live
25 August 2016 (bp) Review posted live
29 September 2015 (mfh) Original submission
• 6 April 2023 (gm) Comprehensive updated posted live
• 25 August 2016 (bp) Review posted live
• 29 September 2015 (mfh) Original submission
## Key Sections in this
## References
## Literature Cited
Intron-exon organization of
Adapted from
Positions of
Data from
|
[] |
25/8/2016
|
6/4/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
scs
|
scs
|
[
"Acrocephalosyndactyly Type III",
"Acrocephalosyndactyly Type III",
"Twist-related protein 1",
"TWIST1",
"Saethre-Chotzen Syndrome"
] |
Saethre-Chotzen Syndrome
|
Emily R Gallagher, Chootima Ratisoontorn, Michael L Cunningham
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Summary Classic Saethre-Chotzen syndrome (SCS) is characterized by coronal synostosis (unilateral or bilateral), facial asymmetry (particularly in individuals with unicoronal synostosis), strabismus, ptosis, and characteristic appearance of the ear (small pinna with a prominent superior and/or inferior crus). Syndactyly of digits two and three of the hand is variably present. Cognitive development is usually normal, although those with a large genomic deletion are at an increased risk for intellectual challenges. Less common manifestations of SCS include other skeletal findings (parietal foramina, vertebral segmentation defects, radioulnar synostosis, maxillary hypoplasia, ocular hypertelorism, hallux valgus, duplicated or curved distal hallux), hypertelorism, palatal anomalies, obstructive sleep apnea, increased intracranial pressure, short stature, and congenital heart malformations. The diagnosis of SCS is established in a proband with typical clinical findings and a heterozygous pathogenic (or likely pathogenic) variant in SCS is inherited in an autosomal dominant manner. Many individuals diagnosed with SCS have an affected parent; the proportion of cases caused by a
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## Diagnosis
Saethre-Chotzen syndrome (SCS)
Craniosynostosis (premature fusion of one or more sutures of the calvarium)
The coronal suture is the most commonly affected, although any or all sutures can be affected.
Craniosynostosis often presents with an abnormal skull shape (e.g., brachycephaly [short, broad skull], acrocephaly [tall skull], anterior plagiocephaly [flat skull]).
Low frontal hairline, ptosis, strabismus, facial asymmetry
Small ears with a prominent crus, hearing loss
Parietal foramina
Vertebral anomalies
Limb anomalies [
Partial cutaneous syndactyly of the second and third digits of the hand
Note: Although the degree of syndactyly or its presence is highly variable, it is effectively diagnostic in the presence of the first three features: craniosynostosis, low frontal hairline (...), and small ears (...).
Radioulnar synostosis
Brachydactyly
Hallux valgus
Duplicated distal phalanx of the hallux
Triangular epiphyses of the hallux
The diagnosis of SCS
Note: 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 SCS is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of SCS, 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 craniosynostosis,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Saethre-Chotzen 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
Note that most reported deletions and duplications are large enough to likely be detected by CMA; however, gene-targeted deletion/duplication analysis does have a higher resolution.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
CMA should be considered in individuals with features of SCS and developmental delay.
• Craniosynostosis (premature fusion of one or more sutures of the calvarium)
• The coronal suture is the most commonly affected, although any or all sutures can be affected.
• Craniosynostosis often presents with an abnormal skull shape (e.g., brachycephaly [short, broad skull], acrocephaly [tall skull], anterior plagiocephaly [flat skull]).
• The coronal suture is the most commonly affected, although any or all sutures can be affected.
• Craniosynostosis often presents with an abnormal skull shape (e.g., brachycephaly [short, broad skull], acrocephaly [tall skull], anterior plagiocephaly [flat skull]).
• Low frontal hairline, ptosis, strabismus, facial asymmetry
• Small ears with a prominent crus, hearing loss
• Parietal foramina
• Vertebral anomalies
• Limb anomalies [
• Partial cutaneous syndactyly of the second and third digits of the hand
• Note: Although the degree of syndactyly or its presence is highly variable, it is effectively diagnostic in the presence of the first three features: craniosynostosis, low frontal hairline (...), and small ears (...).
• Radioulnar synostosis
• Brachydactyly
• Hallux valgus
• Duplicated distal phalanx of the hallux
• Triangular epiphyses of the hallux
• Partial cutaneous syndactyly of the second and third digits of the hand
• Note: Although the degree of syndactyly or its presence is highly variable, it is effectively diagnostic in the presence of the first three features: craniosynostosis, low frontal hairline (...), and small ears (...).
• Radioulnar synostosis
• Brachydactyly
• Hallux valgus
• Duplicated distal phalanx of the hallux
• Triangular epiphyses of the hallux
• The coronal suture is the most commonly affected, although any or all sutures can be affected.
• Craniosynostosis often presents with an abnormal skull shape (e.g., brachycephaly [short, broad skull], acrocephaly [tall skull], anterior plagiocephaly [flat skull]).
• Partial cutaneous syndactyly of the second and third digits of the hand
• Note: Although the degree of syndactyly or its presence is highly variable, it is effectively diagnostic in the presence of the first three features: craniosynostosis, low frontal hairline (...), and small ears (...).
• Radioulnar synostosis
• Brachydactyly
• Hallux valgus
• Duplicated distal phalanx of the hallux
• Triangular epiphyses of the hallux
• For an introduction to multigene panels click
## Suggestive Findings
Saethre-Chotzen syndrome (SCS)
Craniosynostosis (premature fusion of one or more sutures of the calvarium)
The coronal suture is the most commonly affected, although any or all sutures can be affected.
Craniosynostosis often presents with an abnormal skull shape (e.g., brachycephaly [short, broad skull], acrocephaly [tall skull], anterior plagiocephaly [flat skull]).
Low frontal hairline, ptosis, strabismus, facial asymmetry
Small ears with a prominent crus, hearing loss
Parietal foramina
Vertebral anomalies
Limb anomalies [
Partial cutaneous syndactyly of the second and third digits of the hand
Note: Although the degree of syndactyly or its presence is highly variable, it is effectively diagnostic in the presence of the first three features: craniosynostosis, low frontal hairline (...), and small ears (...).
Radioulnar synostosis
Brachydactyly
Hallux valgus
Duplicated distal phalanx of the hallux
Triangular epiphyses of the hallux
• Craniosynostosis (premature fusion of one or more sutures of the calvarium)
• The coronal suture is the most commonly affected, although any or all sutures can be affected.
• Craniosynostosis often presents with an abnormal skull shape (e.g., brachycephaly [short, broad skull], acrocephaly [tall skull], anterior plagiocephaly [flat skull]).
• The coronal suture is the most commonly affected, although any or all sutures can be affected.
• Craniosynostosis often presents with an abnormal skull shape (e.g., brachycephaly [short, broad skull], acrocephaly [tall skull], anterior plagiocephaly [flat skull]).
• Low frontal hairline, ptosis, strabismus, facial asymmetry
• Small ears with a prominent crus, hearing loss
• Parietal foramina
• Vertebral anomalies
• Limb anomalies [
• Partial cutaneous syndactyly of the second and third digits of the hand
• Note: Although the degree of syndactyly or its presence is highly variable, it is effectively diagnostic in the presence of the first three features: craniosynostosis, low frontal hairline (...), and small ears (...).
• Radioulnar synostosis
• Brachydactyly
• Hallux valgus
• Duplicated distal phalanx of the hallux
• Triangular epiphyses of the hallux
• Partial cutaneous syndactyly of the second and third digits of the hand
• Note: Although the degree of syndactyly or its presence is highly variable, it is effectively diagnostic in the presence of the first three features: craniosynostosis, low frontal hairline (...), and small ears (...).
• Radioulnar synostosis
• Brachydactyly
• Hallux valgus
• Duplicated distal phalanx of the hallux
• Triangular epiphyses of the hallux
• The coronal suture is the most commonly affected, although any or all sutures can be affected.
• Craniosynostosis often presents with an abnormal skull shape (e.g., brachycephaly [short, broad skull], acrocephaly [tall skull], anterior plagiocephaly [flat skull]).
• Partial cutaneous syndactyly of the second and third digits of the hand
• Note: Although the degree of syndactyly or its presence is highly variable, it is effectively diagnostic in the presence of the first three features: craniosynostosis, low frontal hairline (...), and small ears (...).
• Radioulnar synostosis
• Brachydactyly
• Hallux valgus
• Duplicated distal phalanx of the hallux
• Triangular epiphyses of the hallux
## Establishing the Diagnosis
The diagnosis of SCS
Note: 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 SCS is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of SCS, 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 craniosynostosis,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Saethre-Chotzen 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
Note that most reported deletions and duplications are large enough to likely be detected by CMA; however, gene-targeted deletion/duplication analysis does have a higher resolution.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
CMA should be considered in individuals with features of SCS and developmental delay.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of SCS, 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 craniosynostosis,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Saethre-Chotzen 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
Note that most reported deletions and duplications are large enough to likely be detected by CMA; however, gene-targeted deletion/duplication analysis does have a higher resolution.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
CMA should be considered in individuals with features of SCS and developmental delay.
## Clinical Characteristics
With the ability to detect pathogenic variants in
It is important to note that other cranial sutures (i.e., sagittal, lambdoid, and metopic) can undergo premature fusion in individuals with SCS.
However, individuals with SCS with no evidence of pathologic suture fusion have been described; thus, craniosynostosis is not an obligatory finding.
There may be a family history of abnormal skull shape, but affected relatives may not have been diagnosed with a craniosynostosis syndrome.
Whereas mild-to-moderate developmental delay and intellectual disability have been reported in some individuals with SCS, normal cognitive development is more common. However, those with a large genomic deletion involving
Findings variably present include the following:
Maxillary hypoplasia, ocular hypertelorism, and lacrimal duct stenosis
Palatal anomalies, including narrow palate, bifid uvula, and cleft palate [
Conductive, mixed, and profound sensorineural hearing loss [
Obstructive sleep apnea (OSA). Mild OSA, defined by changes in nocturnal oxygen saturation, was diagnosed in 5% of individuals with SCS in one recent study [
Increased intracranial pressure (ICP). A recent study found that 21% of individuals with SCS had increased ICP based on the finding of papilledema that persisted more than one year after surgery [
Skeletal concerns such as segmentation defects of the vertebrae, parietal foramina, radioulnar synostosis, duplication of the distal hallux, and hallux valgus
Congenital heart malformation
Short stature
Most pathogenic variants causing SCS are intragenic and cause haploinsufficiency of the protein product, Twist-related protein 1. No specific genotype-phenotype correlations have been identified except for the following.
The vast majority of individuals with single-nucleotide variants have normal intelligence. The risk for developmental delay in individuals with deletions involving
Precise penetrance data are not available; however, wide phenotypic variability and incomplete penetrance are well described [
Robinow-Sorauf syndrome is now known to be caused by pathogenic variants in
SCS is one of the more common forms of syndromic craniosynostosis. Prevalence estimates range from 1:25,000 to 1:50,000 [
Variability of the SCS phenotype may result in underdiagnosis.
• It is important to note that other cranial sutures (i.e., sagittal, lambdoid, and metopic) can undergo premature fusion in individuals with SCS.
• However, individuals with SCS with no evidence of pathologic suture fusion have been described; thus, craniosynostosis is not an obligatory finding.
• There may be a family history of abnormal skull shape, but affected relatives may not have been diagnosed with a craniosynostosis syndrome.
• Whereas mild-to-moderate developmental delay and intellectual disability have been reported in some individuals with SCS, normal cognitive development is more common. However, those with a large genomic deletion involving
• Maxillary hypoplasia, ocular hypertelorism, and lacrimal duct stenosis
• Palatal anomalies, including narrow palate, bifid uvula, and cleft palate [
• Conductive, mixed, and profound sensorineural hearing loss [
• Obstructive sleep apnea (OSA). Mild OSA, defined by changes in nocturnal oxygen saturation, was diagnosed in 5% of individuals with SCS in one recent study [
• Increased intracranial pressure (ICP). A recent study found that 21% of individuals with SCS had increased ICP based on the finding of papilledema that persisted more than one year after surgery [
• Skeletal concerns such as segmentation defects of the vertebrae, parietal foramina, radioulnar synostosis, duplication of the distal hallux, and hallux valgus
• Congenital heart malformation
• Short stature
## Clinical Description
With the ability to detect pathogenic variants in
It is important to note that other cranial sutures (i.e., sagittal, lambdoid, and metopic) can undergo premature fusion in individuals with SCS.
However, individuals with SCS with no evidence of pathologic suture fusion have been described; thus, craniosynostosis is not an obligatory finding.
There may be a family history of abnormal skull shape, but affected relatives may not have been diagnosed with a craniosynostosis syndrome.
Whereas mild-to-moderate developmental delay and intellectual disability have been reported in some individuals with SCS, normal cognitive development is more common. However, those with a large genomic deletion involving
Findings variably present include the following:
Maxillary hypoplasia, ocular hypertelorism, and lacrimal duct stenosis
Palatal anomalies, including narrow palate, bifid uvula, and cleft palate [
Conductive, mixed, and profound sensorineural hearing loss [
Obstructive sleep apnea (OSA). Mild OSA, defined by changes in nocturnal oxygen saturation, was diagnosed in 5% of individuals with SCS in one recent study [
Increased intracranial pressure (ICP). A recent study found that 21% of individuals with SCS had increased ICP based on the finding of papilledema that persisted more than one year after surgery [
Skeletal concerns such as segmentation defects of the vertebrae, parietal foramina, radioulnar synostosis, duplication of the distal hallux, and hallux valgus
Congenital heart malformation
Short stature
• It is important to note that other cranial sutures (i.e., sagittal, lambdoid, and metopic) can undergo premature fusion in individuals with SCS.
• However, individuals with SCS with no evidence of pathologic suture fusion have been described; thus, craniosynostosis is not an obligatory finding.
• There may be a family history of abnormal skull shape, but affected relatives may not have been diagnosed with a craniosynostosis syndrome.
• Whereas mild-to-moderate developmental delay and intellectual disability have been reported in some individuals with SCS, normal cognitive development is more common. However, those with a large genomic deletion involving
• Maxillary hypoplasia, ocular hypertelorism, and lacrimal duct stenosis
• Palatal anomalies, including narrow palate, bifid uvula, and cleft palate [
• Conductive, mixed, and profound sensorineural hearing loss [
• Obstructive sleep apnea (OSA). Mild OSA, defined by changes in nocturnal oxygen saturation, was diagnosed in 5% of individuals with SCS in one recent study [
• Increased intracranial pressure (ICP). A recent study found that 21% of individuals with SCS had increased ICP based on the finding of papilledema that persisted more than one year after surgery [
• Skeletal concerns such as segmentation defects of the vertebrae, parietal foramina, radioulnar synostosis, duplication of the distal hallux, and hallux valgus
• Congenital heart malformation
• Short stature
## Genotype-Phenotype Correlations
Most pathogenic variants causing SCS are intragenic and cause haploinsufficiency of the protein product, Twist-related protein 1. No specific genotype-phenotype correlations have been identified except for the following.
The vast majority of individuals with single-nucleotide variants have normal intelligence. The risk for developmental delay in individuals with deletions involving
## Penetrance
Precise penetrance data are not available; however, wide phenotypic variability and incomplete penetrance are well described [
## Nomenclature
Robinow-Sorauf syndrome is now known to be caused by pathogenic variants in
## Prevalence
SCS is one of the more common forms of syndromic craniosynostosis. Prevalence estimates range from 1:25,000 to 1:50,000 [
Variability of the SCS phenotype may result in underdiagnosis.
## Genetically Related (Allelic) Disorders
Pathogenic variants in the TWIST box, the highly conserved C-terminus that binds and inhibits RUNX2 transactivation, are associated with isolated sagittal or unilateral coronal synostosis, not SCS [
Blepharophimosis or ptosis with or without craniosynostosis resembling
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of Saethre-Chotzen Syndrome (SCS)
Low-set frontal hairline
Downward-sloping palpebral fissures
Ptosis
Ear abnormalities
Interdigital webbing
In Muenke syndrome:
Higher prevalence of DD (35%, vs 5% in SCS)
SNHL (34%, vs rare in SCS)
Coronal synostosis is 2nd most common form of single-suture fusion (after sagittal synostosis).
Isolated coronal fusion is ~10x more common than SCS.
Radial ray defect, usually w/oligodactyly (↓ # of digits), aplasia or hypoplasia of the thumb, &/or aplasia or hypoplasia of the radius
Growth restriction
Poikiloderma
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; MOI = mode of inheritance; SNHL = sensorineural hearing loss
Muenke syndrome is defined by the presence of the specific
In their study of 39 families (71 affected individuals) ascertained on the basis of coronal synostosis,
Isolated coronal synostosis refers to coronal suture fusion with no evidence of other malformations.
In an analysis of 186 individuals with isolated single-suture craniosynostosis, 7.5% had at least one rare deletion or duplication found using CMA [
• Low-set frontal hairline
• Downward-sloping palpebral fissures
• Ptosis
• Ear abnormalities
• Interdigital webbing
• Higher prevalence of DD (35%, vs 5% in SCS)
• SNHL (34%, vs rare in SCS)
• Coronal synostosis is 2nd most common form of single-suture fusion (after sagittal synostosis).
• Isolated coronal fusion is ~10x more common than SCS.
• Radial ray defect, usually w/oligodactyly (↓ # of digits), aplasia or hypoplasia of the thumb, &/or aplasia or hypoplasia of the radius
• Growth restriction
• Poikiloderma
## Management
To establish the extent of disease and needs in an individual diagnosed with Saethre-Chotzen syndrome (SCS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SCS
At age ~2 yrs, ↑ mineralization of vertebrae allows for better interpretation of flexion/extension views of cervical spine in eval for functional instability.
Such screening is appropriate before initiating activities that put the spine at risk (e.g., surgeries w/long duration, gymnastics, football, soccer).
Treatment of Manifestations in Individuals with SCS
Typical cranioplasty occurs in 1st yr of life.
In some individuals midfacial surgery is needed during childhood to address dental malocclusion, swallowing difficulties, or respiratory problems.
Orthodontic treatment &/or orthognathic surgery may be required at or near completion of facial growth.
In most cases, cranioplasty precedes palatal repair.
Ptosis & strabismus should be corrected in early childhood to prevent amblyopia, either w/patching or surgery. If papilledema is detected, consider cranioplasty.
Recommended Surveillance for Individuals with SCS
Ophthalmologic evaluation
Brian imaging (MRI or CT scan)
Annual, if synostosis is not treated
If ↑ ICP a concern, perform imaging (preferably MRI) for additional assessment
Clinical exam
Preoperative CT scan
Annual starting at age 12 mos
Frequency after age 6 yrs based on symptoms of palatal dysfunction
Annual through age 6 yrs, then as needed
Up to every 6 mos in patients w/cleft palate or known hearing loss
Annual for preschool-age children, then as indicated
If screening suggests DD, comprehensive assessment & referral to early intervention
If cervical spine abnormality with instability is present in an individual, activities that put the spine at risk should be limited.
See
Search
• At age ~2 yrs, ↑ mineralization of vertebrae allows for better interpretation of flexion/extension views of cervical spine in eval for functional instability.
• Such screening is appropriate before initiating activities that put the spine at risk (e.g., surgeries w/long duration, gymnastics, football, soccer).
• Typical cranioplasty occurs in 1st yr of life.
• In some individuals midfacial surgery is needed during childhood to address dental malocclusion, swallowing difficulties, or respiratory problems.
• Orthodontic treatment &/or orthognathic surgery may be required at or near completion of facial growth.
• Ophthalmologic evaluation
• Brian imaging (MRI or CT scan)
• Annual, if synostosis is not treated
• If ↑ ICP a concern, perform imaging (preferably MRI) for additional assessment
• Clinical exam
• Preoperative CT scan
• Annual starting at age 12 mos
• Frequency after age 6 yrs based on symptoms of palatal dysfunction
• Annual through age 6 yrs, then as needed
• Up to every 6 mos in patients w/cleft palate or known hearing loss
• Annual for preschool-age children, then as indicated
• If screening suggests DD, comprehensive assessment & referral to early intervention
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Saethre-Chotzen syndrome (SCS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SCS
At age ~2 yrs, ↑ mineralization of vertebrae allows for better interpretation of flexion/extension views of cervical spine in eval for functional instability.
Such screening is appropriate before initiating activities that put the spine at risk (e.g., surgeries w/long duration, gymnastics, football, soccer).
• At age ~2 yrs, ↑ mineralization of vertebrae allows for better interpretation of flexion/extension views of cervical spine in eval for functional instability.
• Such screening is appropriate before initiating activities that put the spine at risk (e.g., surgeries w/long duration, gymnastics, football, soccer).
## Treatment of Manifestations
Treatment of Manifestations in Individuals with SCS
Typical cranioplasty occurs in 1st yr of life.
In some individuals midfacial surgery is needed during childhood to address dental malocclusion, swallowing difficulties, or respiratory problems.
Orthodontic treatment &/or orthognathic surgery may be required at or near completion of facial growth.
In most cases, cranioplasty precedes palatal repair.
Ptosis & strabismus should be corrected in early childhood to prevent amblyopia, either w/patching or surgery. If papilledema is detected, consider cranioplasty.
• Typical cranioplasty occurs in 1st yr of life.
• In some individuals midfacial surgery is needed during childhood to address dental malocclusion, swallowing difficulties, or respiratory problems.
• Orthodontic treatment &/or orthognathic surgery may be required at or near completion of facial growth.
## Surveillance
Recommended Surveillance for Individuals with SCS
Ophthalmologic evaluation
Brian imaging (MRI or CT scan)
Annual, if synostosis is not treated
If ↑ ICP a concern, perform imaging (preferably MRI) for additional assessment
Clinical exam
Preoperative CT scan
Annual starting at age 12 mos
Frequency after age 6 yrs based on symptoms of palatal dysfunction
Annual through age 6 yrs, then as needed
Up to every 6 mos in patients w/cleft palate or known hearing loss
Annual for preschool-age children, then as indicated
If screening suggests DD, comprehensive assessment & referral to early intervention
• Ophthalmologic evaluation
• Brian imaging (MRI or CT scan)
• Annual, if synostosis is not treated
• If ↑ ICP a concern, perform imaging (preferably MRI) for additional assessment
• Clinical exam
• Preoperative CT scan
• Annual starting at age 12 mos
• Frequency after age 6 yrs based on symptoms of palatal dysfunction
• Annual through age 6 yrs, then as needed
• Up to every 6 mos in patients w/cleft palate or known hearing loss
• Annual for preschool-age children, then as indicated
• If screening suggests DD, comprehensive assessment & referral to early intervention
## Agents/Circumstances to Avoid
If cervical spine abnormality with instability is present in an individual, activities that put the spine at risk should be limited.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Saethre-Chotzen syndrome (SCS) is inherited in an autosomal dominant manner.
Many individuals diagnosed with SCS have an affected parent.
A proband with SCS may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Complete examination for subtle features (ptosis, mild brachydactyly / 2-3 syndactyly) even in the absence of any calvarial pathology
Molecular genetic testing of
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 SCS may appear to be negative because of failure to recognize the disorder in family members (wide intrafamilial phenotypic variability is observed in SCS) or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If a parent has SCS and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%.
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.
The widely variable phenotypic manifestations 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 use of prenatal testing to be a personal decision, discussion of these issues may be helpful.
• Many individuals diagnosed with SCS have an affected parent.
• A proband with SCS may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• Complete examination for subtle features (ptosis, mild brachydactyly / 2-3 syndactyly) even in the absence of any calvarial pathology
• Molecular genetic testing of
• Complete examination for subtle features (ptosis, mild brachydactyly / 2-3 syndactyly) even in the absence of any calvarial pathology
• Molecular genetic testing of
• 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 SCS may appear to be negative because of failure to recognize the disorder in family members (wide intrafamilial phenotypic variability is observed in SCS) or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Complete examination for subtle features (ptosis, mild brachydactyly / 2-3 syndactyly) even in the absence of any calvarial pathology
• Molecular genetic testing of
• If a parent has SCS and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%.
• 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.
• The widely variable phenotypic manifestations of
## Mode of Inheritance
Saethre-Chotzen syndrome (SCS) is inherited in an autosomal dominant manner.
## Risk to Family Members
Many individuals diagnosed with SCS have an affected parent.
A proband with SCS may have the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
Complete examination for subtle features (ptosis, mild brachydactyly / 2-3 syndactyly) even in the absence of any calvarial pathology
Molecular genetic testing of
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 SCS may appear to be negative because of failure to recognize the disorder in family members (wide intrafamilial phenotypic variability is observed in SCS) or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
If a parent has SCS and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%.
If the proband has a known
If the parents have not been tested for the
• Many individuals diagnosed with SCS have an affected parent.
• A proband with SCS may have the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• Complete examination for subtle features (ptosis, mild brachydactyly / 2-3 syndactyly) even in the absence of any calvarial pathology
• Molecular genetic testing of
• Complete examination for subtle features (ptosis, mild brachydactyly / 2-3 syndactyly) even in the absence of any calvarial pathology
• Molecular genetic testing of
• 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 SCS may appear to be negative because of failure to recognize the disorder in family members (wide intrafamilial phenotypic variability is observed in SCS) or reduced penetrance. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband.
• Complete examination for subtle features (ptosis, mild brachydactyly / 2-3 syndactyly) even in the absence of any calvarial pathology
• Molecular genetic testing of
• If a parent has SCS and/or is known to have the pathogenic variant identified in the proband, the risk to sibs is 50%.
• If the proband has a known
• 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 widely variable phenotypic manifestations 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.
• The widely variable phenotypic manifestations of
## 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 11082
Chattanooga TN 37401
United Kingdom
•
• PO Box 11082
• Chattanooga TN 37401
•
•
•
•
•
•
• United Kingdom
•
•
•
## Molecular Genetics
Saethre-Chotzen Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Saethre-Chotzen Syndrome (
Several genes and gene families including
All of the disease-associated variants are located within the coding region; no splice variants, intronic variants, or changes within the second exon have been reported. No apparent mutational "hot spot" has been identified.
Nonsense variants that preclude translation of the DNA binding domain and the HLH domain have been identified from the 5' end of the coding sequence to the end of the HLH motif.
Missense variants are clustered within the functional domains.
Four persons have been identified with pathogenic variants in the C-terminus, known as the TWIST box, a highly conserved region that binds and inhibits RUNX2 activation [
Functional haploinsufficiency of TWIST1, whether due to mutation in the DNA binding, HLH, or TWIST box domains, results in disinhibition of RUNX2 and enhances osteogenesis.
The basic domain that mediates specific DNA binding to a consensus hexanucleotide E-box (CANNTG)
The HLH domains containing two amphipathic helices that act as dimerization domains (dimerization is required for DNA binding)
A loop region that separates the two helices, spacing them appropriately for DNA binding and causing formation of a bipartite DNA-binding groove by the basic domain
Nonsense and frameshift variants have been associated with disease.
Missense variants involving the helical domains lead to a loss of heterodimer formation that alters nuclear translocation.
In-frame insertion or missense variants within the loop domain alter dimer formation, but not the nuclear location of the protein.
These data suggest that protein degradation and altered subcellular localization account for the loss of functional Twist-related protein 1 from the abnormal allele in individuals with SCS. This model also supports the finding that the coronal sutures are predominantly fused in SCS, since these sutures have a higher level of gene expression of downstream activators, as shown in
• Nonsense variants that preclude translation of the DNA binding domain and the HLH domain have been identified from the 5' end of the coding sequence to the end of the HLH motif.
• Missense variants are clustered within the functional domains.
• Four persons have been identified with pathogenic variants in the C-terminus, known as the TWIST box, a highly conserved region that binds and inhibits RUNX2 activation [
• Functional haploinsufficiency of TWIST1, whether due to mutation in the DNA binding, HLH, or TWIST box domains, results in disinhibition of RUNX2 and enhances osteogenesis.
• The basic domain that mediates specific DNA binding to a consensus hexanucleotide E-box (CANNTG)
• The HLH domains containing two amphipathic helices that act as dimerization domains (dimerization is required for DNA binding)
• A loop region that separates the two helices, spacing them appropriately for DNA binding and causing formation of a bipartite DNA-binding groove by the basic domain
• Nonsense and frameshift variants have been associated with disease.
• Missense variants involving the helical domains lead to a loss of heterodimer formation that alters nuclear translocation.
• In-frame insertion or missense variants within the loop domain alter dimer formation, but not the nuclear location of the protein.
## Molecular Pathogenesis
Several genes and gene families including
All of the disease-associated variants are located within the coding region; no splice variants, intronic variants, or changes within the second exon have been reported. No apparent mutational "hot spot" has been identified.
Nonsense variants that preclude translation of the DNA binding domain and the HLH domain have been identified from the 5' end of the coding sequence to the end of the HLH motif.
Missense variants are clustered within the functional domains.
Four persons have been identified with pathogenic variants in the C-terminus, known as the TWIST box, a highly conserved region that binds and inhibits RUNX2 activation [
Functional haploinsufficiency of TWIST1, whether due to mutation in the DNA binding, HLH, or TWIST box domains, results in disinhibition of RUNX2 and enhances osteogenesis.
The basic domain that mediates specific DNA binding to a consensus hexanucleotide E-box (CANNTG)
The HLH domains containing two amphipathic helices that act as dimerization domains (dimerization is required for DNA binding)
A loop region that separates the two helices, spacing them appropriately for DNA binding and causing formation of a bipartite DNA-binding groove by the basic domain
Nonsense and frameshift variants have been associated with disease.
Missense variants involving the helical domains lead to a loss of heterodimer formation that alters nuclear translocation.
In-frame insertion or missense variants within the loop domain alter dimer formation, but not the nuclear location of the protein.
These data suggest that protein degradation and altered subcellular localization account for the loss of functional Twist-related protein 1 from the abnormal allele in individuals with SCS. This model also supports the finding that the coronal sutures are predominantly fused in SCS, since these sutures have a higher level of gene expression of downstream activators, as shown in
• Nonsense variants that preclude translation of the DNA binding domain and the HLH domain have been identified from the 5' end of the coding sequence to the end of the HLH motif.
• Missense variants are clustered within the functional domains.
• Four persons have been identified with pathogenic variants in the C-terminus, known as the TWIST box, a highly conserved region that binds and inhibits RUNX2 activation [
• Functional haploinsufficiency of TWIST1, whether due to mutation in the DNA binding, HLH, or TWIST box domains, results in disinhibition of RUNX2 and enhances osteogenesis.
• The basic domain that mediates specific DNA binding to a consensus hexanucleotide E-box (CANNTG)
• The HLH domains containing two amphipathic helices that act as dimerization domains (dimerization is required for DNA binding)
• A loop region that separates the two helices, spacing them appropriately for DNA binding and causing formation of a bipartite DNA-binding groove by the basic domain
• Nonsense and frameshift variants have been associated with disease.
• Missense variants involving the helical domains lead to a loss of heterodimer formation that alters nuclear translocation.
• In-frame insertion or missense variants within the loop domain alter dimer formation, but not the nuclear location of the protein.
## Chapter Notes
24 January 2019 (ha) Comprehensive update posted live
14 June 2012 (cd) Revision: mutation scanning no longer available clinically
21 June 2011 (me) Comprehensive update posted live
27 December 2007 (me) Comprehensive update posted live
1 August 2005 (me) Comprehensive update posted live
30 July 2004 (mc) Revision: testing methods
16 May 2003 (me) Review posted live
21 January 2003 (mc) Original submission
• 24 January 2019 (ha) Comprehensive update posted live
• 14 June 2012 (cd) Revision: mutation scanning no longer available clinically
• 21 June 2011 (me) Comprehensive update posted live
• 27 December 2007 (me) Comprehensive update posted live
• 1 August 2005 (me) Comprehensive update posted live
• 30 July 2004 (mc) Revision: testing methods
• 16 May 2003 (me) Review posted live
• 21 January 2003 (mc) Original submission
## Revision History
24 January 2019 (ha) Comprehensive update posted live
14 June 2012 (cd) Revision: mutation scanning no longer available clinically
21 June 2011 (me) Comprehensive update posted live
27 December 2007 (me) Comprehensive update posted live
1 August 2005 (me) Comprehensive update posted live
30 July 2004 (mc) Revision: testing methods
16 May 2003 (me) Review posted live
21 January 2003 (mc) Original submission
• 24 January 2019 (ha) Comprehensive update posted live
• 14 June 2012 (cd) Revision: mutation scanning no longer available clinically
• 21 June 2011 (me) Comprehensive update posted live
• 27 December 2007 (me) Comprehensive update posted live
• 1 August 2005 (me) Comprehensive update posted live
• 30 July 2004 (mc) Revision: testing methods
• 16 May 2003 (me) Review posted live
• 21 January 2003 (mc) Original submission
## References
## Literature Cited
|
[
"P Bourgeois, AL Bolcato-Bellemin, JM Danse, A Bloch-Zupan, K Yoshiba, C Stoetzel, F Perrin-Schmitt. The variable expressivity and incomplete penetrance of the twist-null heterozygous mouse phenotype resemble those of human Saethre-Chotzen syndrome.. Hum Mol Genet 1998;7:945-57",
"J Cai, BK Goodman, AS Patel, JB Mulliken, L Van Maldergem, GE Hoganson, WA Paznekas, Z Ben-Neriah, R Sheffer, ML Cunningham, DL Daentl, EW Jabs. Increased risk for developmental delay in Saethre-Chotzen syndrome is associated with TWIST deletions: an improved strategy for TWIST mutation screening.. Hum Genet 2003a;114:68-76",
"J Cai, BA Shoo, T Sorauf, EW Jabs. A novel mutation in the TWIST gene, implicated in Saethre-Chotzen syndrome, is found in the original case of Robinow-Sorauf syndrome.. Clin Genet 2003b;64:79-82",
"EA Carver, KF Oram, T Gridley. Craniosynostosis in Twist heterozygous mice: a model for Saethre-Chotzen syndrome.. Anat Rec 2002;268:90-2",
"MM Cohen, S Kreiborg. Birth prevalence studies of the Crouzon syndrome: comparison of direct and indirect methods.. Clin Genet. 1992;41:12-15",
"J Connerney, V Andreeva, Y Leshem, MA Mercado, K Dowell, X Yang, V Linder, RE Friesel, DB Spicer. Twist1 homodimers enhance FGF responsiveness of the cranial sutures and promote suture closure.. Dev Biol 2008;318:323-34",
"IM de Heer, A de Klein, AM van den Ouweland, C Vermeij-Keers, CH Wouters, JM Vaandrager, SE Hovius, JM Hoogeboom. Clinical and genetic analysis of patients with Saethre-Chotzen syndrome.. Plast Reconstr Surg 2005;115:1894-902",
"IM De Heer, AJ Hoogeboom, HJ Eussen, JM Vaandrager, A De Klein. Deletion of the TWIST gene in a large five-generation family.. Clin Genet 2004;65:396-9",
"T de Jong, N Bannink, HH Bredero-Boelhouwer, MLC van Veelen, MC Bartels, LJ Hoeve, AJM Hoogeboom, EB Wolvius, MH Lequin, JJNM van der Muelen, LNA van Adrichem, JM Vaandrager, EM Ongkosuwito, KFM Joosten, IMJ Mathijssen. Long-term functional outcome in 167 patients with syndromic craniosynostosis; defining a syndrome-specific risk profile.. J Plast Reconstr Aesthet Surg. 2010;63:1635-41",
"H Dollfus, P Biswas, G Kumaramanickavel, C Stoetzel, R Quillet, J Biswas, E Lajeunie, D Renier, F Perrin-Schmitt. Saethre-Chotzen syndrome: notable intrafamilial phenotypic variability in a large family with Q28X TWIST mutation.. Am J Med Genet 2002;109:218-25",
"V el Ghouzzi, M Le Merrer, F Perrin-Schmitt, E Lajeunie, P Benit, D Renier, P Bourgeois, AL Bolcato-Bellemin, A Munnich, J Bonaventure. Mutations of the TWIST gene in the Saethre-Chotzen syndrome.. Nat Genet 1997;15:42-6",
"V El Ghouzzi, L Legeai-Mallet, S Aresta, C Benoist, A Munnich, J de Gunzburg, J Bonaventure. Saethre-Chotzen mutations cause TWIST protein degradation or impaired nuclear location.. Hum Mol Genet 2000;9:813-9",
"R Foo, Y Guo, DM McDonald-McGinn, EH Zackai, LA Whitaker, SP Bartlett. The natural history of patients treated for TWIST1-confirmed Saethre-Chotzen syndrome.. Plast Reconstr Surg. 2009;124:2085-95",
"H Fryssira, P Makrythanasis, A Kattamis, K Stokidis, B Menten, K Kosaki, P Willems, E Kanavakis. Severe developmental delay in a patient with 7p21.1-p14.3 microdeletion spanning the TWIST gene and the HOXA gene cluster.. Mol Syndromol. 2011;2:45-9",
"KW Gripp, CA Stolle, L Celle, DM McDonald-McGinn, LA Whitaker, EH Zackai. TWIST gene mutation in a patient with radial aplasia and craniosynostosis: further evidence for heterogeneity of Baller-Gerold syndrome.. Am J Med Genet 1999;82:170-6",
"KW Gripp, EH Zackai, CA Stolle. Mutations in the human TWIST gene.. Hum Mutat 2000;15:479",
"TD Howard, WA Paznekas, ED Green, LC Chiang, N Ma, RI Ortiz de Luna, C Garcia Delgado, M Gonzalez-Ramos, AD Kline, EW Jabs. Mutations in TWIST, a basic helix-loop-helix transcription factor, in Saethre-Chotzen syndrome.. Nat Genet. 1997;15:36-41",
"W Kress, C Schropp, G Lieb, B Petersen, M Busse-Ratzka, J Kunz, E Reinhart, WD Schafer, J Sold, F Hoppe, J Pahnke, A Trusen, N Sorensen, J Krauss, H Collmann. Saethre-Chotzen syndrome caused by TWIST 1 gene mutations: functional differentiation from Muenke coronal synostosis syndrome.. Eur J Hum Genet 2006;14:39-48",
"S Lee, M Seto, K Sie, M Cunningham. A child with Saethre-Chotzen syndrome, sensorineural hearing loss, and a TWIST mutation.. Cleft Palate Craniofac J 2002;39:110-4",
"HC Mefford, N Shafer, F Antonacci, JM Tsai, SS Park, AV Hing, MJ Rieder, MD Smyth, ML Speltz, EE Eichler, ML Cunningham. Copy number variation analysis in single-suture craniosynostosis: multiple rare variants Including RUNX2 duplication in two cousins with metopic craniosynostosis.. Am J Med Genet Part A 2010;152A:2203-10",
"H Miraoui, PJ Marie. Pivotal role of Twist in skeletal biology and pathology.. Gene 2010;468:1-7",
"M Muenke, KW Gripp, DM McDonald-McGinn, K Gaudenz, LA Whitaker, SP Bartlett, RI Markowitz, NH Robin, N Nwokoro, JJ Mulvihill, HW Losken, JB Mulliken, AE Guttmacher, RS Wilroy, LA Clarke, G Hollway, LC Ades, EA Haan, JC Mulley, MM Cohen, GA Bellus, CA Francomano, DM Moloney, SA Wall, AO Wilkie. A unique point mutation in the fibroblast growth factor receptor 3 gene (FGFR3) defines a new craniosynostosis syndrome.. Am J Hum Genet 1997;60:555-64",
"B Paumard-Hernández, J Berges-Soria, E Barroso, CI Rivera-Pedroza, V Pérez-Carrizosa, S Benito-Sanz, E López-Messa, F Santos, II García-Recuero, A Romance, JM Ballesta-Martínez, V López-González, Á Campos-Barros, J Cruz, E Guillén-Navarro, J Sánchez Del Pozo, P Lapunzina, S García-Miñaur, KE Heath. Expanding the mutation spectrum in 182 Spanish probands with craniosynostosis: identification and characterization of novel TCF12 variants.. Eur J Hum Genet. 2015;23:907-14",
"WA Paznekas, ML Cunningham, TD Howard, BR Korf, MH Lipson, AW Grix, M Feingold, R Goldberg, Z Borochowitz, K Aleck, J Mulliken, M Yin, EW Jabs. Genetic heterogeneity of Saethre-Chotzen syndrome, due to TWIST and FGFR mutations.. Am J Hum Genet 1998;62:1370-80",
"WA Peña, A Slavotinek, S Oberoi. Saethre-Chotzen syndrome: a case report.. Cleft Palate Craniofac J. 2010;47:318-21",
"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 Roscioli, G Elakis, TC Cox, DJ Moon, H Venselaar, AM Turner, T Le, E Hackett, E Haan, A Colley, D Mowat, L Worgan, EP Kirk, R Sachdev, E Thompson, M Gabbett, J McGaughran, K Gibson, M Gattas, ML Freckmann, J Dixon, L Hoefsloot, M Field, A Hackett, B Kamien, M Edwards, LC Adès, FA Collins, MJ Wilson, R Savarirayan, TY Tan, DJ Amor, G McGillivray, SM White, IA Glass, DJ David, PJ Anderson, M Gianoutsos, MF Buckley. Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients.. Am J Med Genet C Semin Med Genet. 2013;163C:259-70",
"ML Seto, AV Hing, J Chang, M Hu, KA Kapp-Simon, PK Patel, BK Burton, AA Kane, MD Smyth, R Hopper, RG Ellenbogen, K Stevenson, ML Speltz, ML Cunningham. Isolated sagittal and coronal craniosynostosis associated with TWIST box mutations.. Am J Med Genet A 2007;143A:678-86",
"ML Seto, SJ Lee, RW Sze, ML Cunningham. Another TWIST on Baller-Gerold syndrome.. Am J Med Genet 2001;104:323-30",
"S Shetty, KM Boycott, TL Gillan, K Bowser, JS Parboosingh, B McInnes, JE Chernos, FP Bernier. Cytogenetic and molecular characterization of a de-novo cryptic deletion of 7p21 associated with an apparently balanced translocation and complex craniosynostosis.. Clin Dysmorphol 2007;16:253-6",
"JM Stoler, GF Rogers, JB Mulliken. The frequency of palatal anomalies in Saethre-Chotzen syndrome.. Cleft Palate Craniofac J. 2009;46:280-4",
"Y Tahiri, N Bastidas, DM McDonald-McGinn, C Birgfeld, EH Zackai, J Taylor, SP Bartlett. New pattern of sutural synostosis associated with TWIST gene mutation and Saethre-Chotzen syndrome: peace sign synostosis.. J Craniofac Surg. 2015;26:1564-7",
"V Touliatou, A Mavrou, A Kolialexi, E Kanavakis, S Kitsiou-Tzeli. Saethre-Chotzen syndrome with severe developmental delay associated with deletion of chromosomic region 7p15→pter.. Genet Couns 2007;18:295-301",
"A Trusen, M Beissert, H Collmann, K Darge. The pattern of skeletal anomalies in the cervical spine, hands and feet in patients with Saethre-Chotzen syndrome and Muenke-type mutation.. Pediatr Radiol 2003;33:168-72"
] |
16/5/2003
|
24/1/2019
|
14/6/2012
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sd-thes
|
sd-thes
|
[
"Phenotypic Diarrhea of Infancy",
"Syndromic Diarrhea/Tricho-Hepato-Enteric Syndrome (SD/THE)",
"THES",
"THES",
"Syndromic Diarrhea/Tricho-Hepato-Enteric Syndrome (SD/THE)",
"Phenotypic Diarrhea of Infancy",
"Tricho-Hepato-Enteric Syndrome",
"Superkiller complex protein 2",
"Superkiller complex protein 3",
"SKIC2",
"SKIC3",
"Trichohepatoenteric Syndrome"
] |
Trichohepatoenteric Syndrome
|
Alexandre Fabre, Patrice Bourgeois, Charlène Chaix, Karine Bertaux, Olivier Goulet, Catherine Badens
|
Summary Trichohepatoenteric syndrome (THES), generally considered to be a neonatal enteropathy, is characterized by intractable diarrhea (seen in almost all affected children), woolly hair (seen in all), intrauterine growth restriction, facial dysmorphism, and short stature. Additional findings include poorly characterized immunodeficiency, recurrent infections, skin abnormalities, and liver disease. Mild intellectual disability (ID) is seen in about 50% of affected individuals. Less common findings include congenital heart defects and platelet anomalies. To date 52 affected individuals have been reported. The diagnosis of THES is established in a proband with biallelic pathogenic variants in either THES 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
To date, no diagnostic algorithm for trichohepatoenteric syndrome (THES) has been published.
THES
* The association of neonatal intractable diarrhea and IUGR suggests the diagnosis of THES.
The diagnosis of THES
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 THES is broad, children with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of THES, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders with diarrhea, hepatic disease, and immunodeficiency,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Trichohepatoenteric 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.
n=6:
n=12:
• For an introduction to multigene panels click
## Suggestive Findings
THES
* The association of neonatal intractable diarrhea and IUGR suggests the diagnosis of THES.
## Establishing the Diagnosis
The diagnosis of THES
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 THES is broad, children with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of THES, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders with diarrhea, hepatic disease, and immunodeficiency,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Trichohepatoenteric 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.
n=6:
n=12:
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of THES, 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 with diarrhea, hepatic disease, and immunodeficiency,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Trichohepatoenteric 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.
n=6:
n=12:
## Clinical Characteristics
Trichohepatoenteric syndrome (THES) is considered a syndrome of neonatal enteropathy [
Very rarely, the clinical presentation can resemble so-called very early-onset inflammatory bowel disease (VEOIBD).
In the only instance in which immunodeficiency was reported to be the major clinical finding, the child never manifested the characteristic diarrhea [
Intrauterine growth restriction (IUGR) / small for gestational age (SGA). Most children are below the 10th centile at birth either for height or for weight [
Short stature. Despite adequate nutrition, the last recorded height in more than 50% of affected individuals was below the 3rd centile [
Although to date no adult with THES has been described in detail, the heights in the three older individuals for whom that information was available were the following:
148 cm (-2.36 SD) in a woman age 27 years [
171 cm (-0.74 SD) in a man age 18 years [
-5 SD in a woman age 17 years [
Nine of 15 individuals with THES had a transient hemophagocytic syndrome / macrophage activation syndrome [
Infection was implicated in the death of seven of 21 affected individuals.
Pathology showed iron overload and sometimes hemochromatosis [
Brain MRI – when performed – appears normal [
Hypothyroidism. n=3/15 affected individuals [
Dental abnormalities:
Peg teeth. n=2 [
Narrow pointed teeth and dental dysplasia. n=2 [
Inguinal hernia. n=2 [
One individual each:
Small kidneys [
Perthe syndrome [
Glaucoma [
Polycystic kidney [
Thymus atrophy (in an individual without a molecular diagnosis) [
Current data suggest that individuals with biallelic pathogenic variants in either
Because most pathogenic variants are private, genotype/phenotype correlations are difficult.
Of note, the phenotypes were indistinguishable in the five individuals with the recurrent
THES is rare. To date about 50 affected individuals have been reported.
The best estimate of prevalence is 1:1,000,000 births, based on the French cohort of
Affected individuals have been reported worldwide.
As with all autosomal recessive disorders, the prevalence may be increased in highly consanguineous populations.
• Intrauterine growth restriction (IUGR) / small for gestational age (SGA). Most children are below the 10th centile at birth either for height or for weight [
• Short stature. Despite adequate nutrition, the last recorded height in more than 50% of affected individuals was below the 3rd centile [
• Although to date no adult with THES has been described in detail, the heights in the three older individuals for whom that information was available were the following:
• 148 cm (-2.36 SD) in a woman age 27 years [
• 171 cm (-0.74 SD) in a man age 18 years [
• -5 SD in a woman age 17 years [
• 148 cm (-2.36 SD) in a woman age 27 years [
• 171 cm (-0.74 SD) in a man age 18 years [
• -5 SD in a woman age 17 years [
• 148 cm (-2.36 SD) in a woman age 27 years [
• 171 cm (-0.74 SD) in a man age 18 years [
• -5 SD in a woman age 17 years [
• Hypothyroidism. n=3/15 affected individuals [
• Dental abnormalities:
• Peg teeth. n=2 [
• Narrow pointed teeth and dental dysplasia. n=2 [
• Peg teeth. n=2 [
• Narrow pointed teeth and dental dysplasia. n=2 [
• Inguinal hernia. n=2 [
• Peg teeth. n=2 [
• Narrow pointed teeth and dental dysplasia. n=2 [
• Small kidneys [
• Perthe syndrome [
• Glaucoma [
• Polycystic kidney [
• Thymus atrophy (in an individual without a molecular diagnosis) [
## Clinical Description
Trichohepatoenteric syndrome (THES) is considered a syndrome of neonatal enteropathy [
Very rarely, the clinical presentation can resemble so-called very early-onset inflammatory bowel disease (VEOIBD).
In the only instance in which immunodeficiency was reported to be the major clinical finding, the child never manifested the characteristic diarrhea [
Intrauterine growth restriction (IUGR) / small for gestational age (SGA). Most children are below the 10th centile at birth either for height or for weight [
Short stature. Despite adequate nutrition, the last recorded height in more than 50% of affected individuals was below the 3rd centile [
Although to date no adult with THES has been described in detail, the heights in the three older individuals for whom that information was available were the following:
148 cm (-2.36 SD) in a woman age 27 years [
171 cm (-0.74 SD) in a man age 18 years [
-5 SD in a woman age 17 years [
Nine of 15 individuals with THES had a transient hemophagocytic syndrome / macrophage activation syndrome [
Infection was implicated in the death of seven of 21 affected individuals.
Pathology showed iron overload and sometimes hemochromatosis [
Brain MRI – when performed – appears normal [
Hypothyroidism. n=3/15 affected individuals [
Dental abnormalities:
Peg teeth. n=2 [
Narrow pointed teeth and dental dysplasia. n=2 [
Inguinal hernia. n=2 [
One individual each:
Small kidneys [
Perthe syndrome [
Glaucoma [
Polycystic kidney [
Thymus atrophy (in an individual without a molecular diagnosis) [
• Intrauterine growth restriction (IUGR) / small for gestational age (SGA). Most children are below the 10th centile at birth either for height or for weight [
• Short stature. Despite adequate nutrition, the last recorded height in more than 50% of affected individuals was below the 3rd centile [
• Although to date no adult with THES has been described in detail, the heights in the three older individuals for whom that information was available were the following:
• 148 cm (-2.36 SD) in a woman age 27 years [
• 171 cm (-0.74 SD) in a man age 18 years [
• -5 SD in a woman age 17 years [
• 148 cm (-2.36 SD) in a woman age 27 years [
• 171 cm (-0.74 SD) in a man age 18 years [
• -5 SD in a woman age 17 years [
• 148 cm (-2.36 SD) in a woman age 27 years [
• 171 cm (-0.74 SD) in a man age 18 years [
• -5 SD in a woman age 17 years [
• Hypothyroidism. n=3/15 affected individuals [
• Dental abnormalities:
• Peg teeth. n=2 [
• Narrow pointed teeth and dental dysplasia. n=2 [
• Peg teeth. n=2 [
• Narrow pointed teeth and dental dysplasia. n=2 [
• Inguinal hernia. n=2 [
• Peg teeth. n=2 [
• Narrow pointed teeth and dental dysplasia. n=2 [
• Small kidneys [
• Perthe syndrome [
• Glaucoma [
• Polycystic kidney [
• Thymus atrophy (in an individual without a molecular diagnosis) [
## Phenotype Correlations by Gene
Current data suggest that individuals with biallelic pathogenic variants in either
## Genotype-Phenotype Correlations
Because most pathogenic variants are private, genotype/phenotype correlations are difficult.
Of note, the phenotypes were indistinguishable in the five individuals with the recurrent
## Prevalence
THES is rare. To date about 50 affected individuals have been reported.
The best estimate of prevalence is 1:1,000,000 births, based on the French cohort of
Affected individuals have been reported worldwide.
As with all autosomal recessive disorders, the prevalence may be increased in highly consanguineous populations.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Monogenic Disorders with Intractable Diarrhea to Consider in the Differential Diagnosis of Trichohepatoenteric Syndrome
AR = autosomal recessive; IPEX =
See
## Management
To establish the extent of disease and needs in an individual diagnosed with trichohepatoenteric syndrome (THES), the following evaluations are recommended:
Nutritional evaluation by a specialist pediatric nutritionist
Immunologic assessment with serum IgG, IgM, IgA; immunophenotyping; if immunization has been performed before, evaluation of the level of specific antibodies to detect a rapid loss of protective antibodies, which would require immunoglobulin supplementation
Liver assessment: ultrasound evaluation; assessment of liver enzymes (ALT/AST, GGT); in case of abnormalities, consult a pediatric hepatologist for recommendations on additional investigations
Cardiac evaluation for congenital malformations
Age-appropriate assessment of cognitive development, speech and language development, and psychosocial skills
Consultation with a clinical geneticist and/or genetic counselor
No specific treatment is available. The goals of the treatment are to promote maximal weight gain and linear growth, to reduce the burden of infections, and to provide individual management of intellectual disability.
To date nine individuals have been reported in whom PN was unnecessary [
When early-onset manifestations are those of inflammatory bowel disease (IBD), infections should be ruled out and routine management of IBD with steroids, azathioprine, and anti-TNF (tumor necrosis factor) antibody can be considered; however, this routine IBD management may result in only transient improvement, or no improvement [
Of note, hematopoietic stem cell transplantation (HSCT) – reported twice to date – has been unsuccessful: one individual succumbed to infection [
Although there are no consensus guidelines, the following surveillance is recommended:
For children not receiving parenteral nutrition, close monitoring of nutritional status by a pediatric nutritionist to assure prompt intervention should nutritional deficiency become a concern
Yearly assessment of the following main features:
Diarrhea. If the nature of the diarrhea changes (e.g., appearance of bloody diarrhea), investigation of possible inflammatory bowel disease (IBD) is warranted [
Liver function. Ultrasound examination and measurement of liver enzymes (AST, ALT, GGT), International Normalized Ratio (INR), and bilirubin
Serum concentration of IgG, IgM, IgA, and immunoglobulin functionality (i.e., immunophenotyping) even if results at the time of initial evaluation were normal. Consultation with an immunologist is warranted if immunoglobulin levels are low or if normal immunoglobulin levels are associated with a loss of specific protective antibody.
TSH level for evidence of hypothyroidism
Assessment of cognitive development, speech and language, and psychosocial skills for evidence of intellectual disability at ages 2, 4, 8, 12, and 15 years unless concerns appear earlier
As evolution of the dermatologic features (mostly hypo- or hyperpigmented patches and hair abnormalities) is unknown, regular evaluation by a dermatologist seems reasonable.
See
Search
• Nutritional evaluation by a specialist pediatric nutritionist
• Immunologic assessment with serum IgG, IgM, IgA; immunophenotyping; if immunization has been performed before, evaluation of the level of specific antibodies to detect a rapid loss of protective antibodies, which would require immunoglobulin supplementation
• Liver assessment: ultrasound evaluation; assessment of liver enzymes (ALT/AST, GGT); in case of abnormalities, consult a pediatric hepatologist for recommendations on additional investigations
• Cardiac evaluation for congenital malformations
• Age-appropriate assessment of cognitive development, speech and language development, and psychosocial skills
• Consultation with a clinical geneticist and/or genetic counselor
• For children not receiving parenteral nutrition, close monitoring of nutritional status by a pediatric nutritionist to assure prompt intervention should nutritional deficiency become a concern
• Yearly assessment of the following main features:
• Diarrhea. If the nature of the diarrhea changes (e.g., appearance of bloody diarrhea), investigation of possible inflammatory bowel disease (IBD) is warranted [
• Liver function. Ultrasound examination and measurement of liver enzymes (AST, ALT, GGT), International Normalized Ratio (INR), and bilirubin
• Serum concentration of IgG, IgM, IgA, and immunoglobulin functionality (i.e., immunophenotyping) even if results at the time of initial evaluation were normal. Consultation with an immunologist is warranted if immunoglobulin levels are low or if normal immunoglobulin levels are associated with a loss of specific protective antibody.
• TSH level for evidence of hypothyroidism
• Diarrhea. If the nature of the diarrhea changes (e.g., appearance of bloody diarrhea), investigation of possible inflammatory bowel disease (IBD) is warranted [
• Liver function. Ultrasound examination and measurement of liver enzymes (AST, ALT, GGT), International Normalized Ratio (INR), and bilirubin
• Serum concentration of IgG, IgM, IgA, and immunoglobulin functionality (i.e., immunophenotyping) even if results at the time of initial evaluation were normal. Consultation with an immunologist is warranted if immunoglobulin levels are low or if normal immunoglobulin levels are associated with a loss of specific protective antibody.
• TSH level for evidence of hypothyroidism
• Assessment of cognitive development, speech and language, and psychosocial skills for evidence of intellectual disability at ages 2, 4, 8, 12, and 15 years unless concerns appear earlier
• As evolution of the dermatologic features (mostly hypo- or hyperpigmented patches and hair abnormalities) is unknown, regular evaluation by a dermatologist seems reasonable.
• Diarrhea. If the nature of the diarrhea changes (e.g., appearance of bloody diarrhea), investigation of possible inflammatory bowel disease (IBD) is warranted [
• Liver function. Ultrasound examination and measurement of liver enzymes (AST, ALT, GGT), International Normalized Ratio (INR), and bilirubin
• Serum concentration of IgG, IgM, IgA, and immunoglobulin functionality (i.e., immunophenotyping) even if results at the time of initial evaluation were normal. Consultation with an immunologist is warranted if immunoglobulin levels are low or if normal immunoglobulin levels are associated with a loss of specific protective antibody.
• TSH level for evidence of hypothyroidism
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with trichohepatoenteric syndrome (THES), the following evaluations are recommended:
Nutritional evaluation by a specialist pediatric nutritionist
Immunologic assessment with serum IgG, IgM, IgA; immunophenotyping; if immunization has been performed before, evaluation of the level of specific antibodies to detect a rapid loss of protective antibodies, which would require immunoglobulin supplementation
Liver assessment: ultrasound evaluation; assessment of liver enzymes (ALT/AST, GGT); in case of abnormalities, consult a pediatric hepatologist for recommendations on additional investigations
Cardiac evaluation for congenital malformations
Age-appropriate assessment of cognitive development, speech and language development, and psychosocial skills
Consultation with a clinical geneticist and/or genetic counselor
• Nutritional evaluation by a specialist pediatric nutritionist
• Immunologic assessment with serum IgG, IgM, IgA; immunophenotyping; if immunization has been performed before, evaluation of the level of specific antibodies to detect a rapid loss of protective antibodies, which would require immunoglobulin supplementation
• Liver assessment: ultrasound evaluation; assessment of liver enzymes (ALT/AST, GGT); in case of abnormalities, consult a pediatric hepatologist for recommendations on additional investigations
• Cardiac evaluation for congenital malformations
• Age-appropriate assessment of cognitive development, speech and language development, and psychosocial skills
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
No specific treatment is available. The goals of the treatment are to promote maximal weight gain and linear growth, to reduce the burden of infections, and to provide individual management of intellectual disability.
To date nine individuals have been reported in whom PN was unnecessary [
When early-onset manifestations are those of inflammatory bowel disease (IBD), infections should be ruled out and routine management of IBD with steroids, azathioprine, and anti-TNF (tumor necrosis factor) antibody can be considered; however, this routine IBD management may result in only transient improvement, or no improvement [
Of note, hematopoietic stem cell transplantation (HSCT) – reported twice to date – has been unsuccessful: one individual succumbed to infection [
## Surveillance
Although there are no consensus guidelines, the following surveillance is recommended:
For children not receiving parenteral nutrition, close monitoring of nutritional status by a pediatric nutritionist to assure prompt intervention should nutritional deficiency become a concern
Yearly assessment of the following main features:
Diarrhea. If the nature of the diarrhea changes (e.g., appearance of bloody diarrhea), investigation of possible inflammatory bowel disease (IBD) is warranted [
Liver function. Ultrasound examination and measurement of liver enzymes (AST, ALT, GGT), International Normalized Ratio (INR), and bilirubin
Serum concentration of IgG, IgM, IgA, and immunoglobulin functionality (i.e., immunophenotyping) even if results at the time of initial evaluation were normal. Consultation with an immunologist is warranted if immunoglobulin levels are low or if normal immunoglobulin levels are associated with a loss of specific protective antibody.
TSH level for evidence of hypothyroidism
Assessment of cognitive development, speech and language, and psychosocial skills for evidence of intellectual disability at ages 2, 4, 8, 12, and 15 years unless concerns appear earlier
As evolution of the dermatologic features (mostly hypo- or hyperpigmented patches and hair abnormalities) is unknown, regular evaluation by a dermatologist seems reasonable.
• For children not receiving parenteral nutrition, close monitoring of nutritional status by a pediatric nutritionist to assure prompt intervention should nutritional deficiency become a concern
• Yearly assessment of the following main features:
• Diarrhea. If the nature of the diarrhea changes (e.g., appearance of bloody diarrhea), investigation of possible inflammatory bowel disease (IBD) is warranted [
• Liver function. Ultrasound examination and measurement of liver enzymes (AST, ALT, GGT), International Normalized Ratio (INR), and bilirubin
• Serum concentration of IgG, IgM, IgA, and immunoglobulin functionality (i.e., immunophenotyping) even if results at the time of initial evaluation were normal. Consultation with an immunologist is warranted if immunoglobulin levels are low or if normal immunoglobulin levels are associated with a loss of specific protective antibody.
• TSH level for evidence of hypothyroidism
• Diarrhea. If the nature of the diarrhea changes (e.g., appearance of bloody diarrhea), investigation of possible inflammatory bowel disease (IBD) is warranted [
• Liver function. Ultrasound examination and measurement of liver enzymes (AST, ALT, GGT), International Normalized Ratio (INR), and bilirubin
• Serum concentration of IgG, IgM, IgA, and immunoglobulin functionality (i.e., immunophenotyping) even if results at the time of initial evaluation were normal. Consultation with an immunologist is warranted if immunoglobulin levels are low or if normal immunoglobulin levels are associated with a loss of specific protective antibody.
• TSH level for evidence of hypothyroidism
• Assessment of cognitive development, speech and language, and psychosocial skills for evidence of intellectual disability at ages 2, 4, 8, 12, and 15 years unless concerns appear earlier
• As evolution of the dermatologic features (mostly hypo- or hyperpigmented patches and hair abnormalities) is unknown, regular evaluation by a dermatologist seems reasonable.
• Diarrhea. If the nature of the diarrhea changes (e.g., appearance of bloody diarrhea), investigation of possible inflammatory bowel disease (IBD) is warranted [
• Liver function. Ultrasound examination and measurement of liver enzymes (AST, ALT, GGT), International Normalized Ratio (INR), and bilirubin
• Serum concentration of IgG, IgM, IgA, and immunoglobulin functionality (i.e., immunophenotyping) even if results at the time of initial evaluation were normal. Consultation with an immunologist is warranted if immunoglobulin levels are low or if normal immunoglobulin levels are associated with a loss of specific protective antibody.
• TSH level for evidence of hypothyroidism
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Trichohepatoenteric syndrome (THES) 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 THES syndrome are obligate heterozygotes (carriers) for a pathogenic variant in
To date, no individuals with THES syndrome have had children; however, many affected individuals have not yet reached reproductive age.
Carrier testing for relatives at risk 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 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.
• The offspring of an individual with THES syndrome are obligate heterozygotes (carriers) for a pathogenic variant in
• To date, no individuals with THES syndrome have had children; however, many affected individuals have not yet reached reproductive age.
• 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
Trichohepatoenteric syndrome (THES) 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 THES syndrome are obligate heterozygotes (carriers) for a pathogenic variant in
To date, no individuals with THES syndrome have had children; however, many affected individuals have not yet reached reproductive age.
• 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 THES syndrome are obligate heterozygotes (carriers) for a pathogenic variant in
• To date, no individuals with THES syndrome have had children; however, many affected individuals have not yet reached reproductive age.
## Carrier Detection
Carrier testing for relatives at risk 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 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
Trichohepatoenteric Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Trichohepatoenteric Syndrome (
Trichohepatoenteric syndrome (THES) is caused by loss of function of either protein in the human Ski complex: SKIC3 (a TPR-containing protein) or SKIC2 (an RNA helicase). The Ski complex, a heterotetrameric cytoplasmic cofactor of the RNA exosome in eukaryotic and archeal (prokaryotic) cells, is required for exosome-mediated RNA surveillance including the regulation of normal mRNA and decay of nonfunctional mRNA [
Subsequently
The protein contains 20 TRP repeated domains. TPR repeats (which mediate protein-protein interactions and the assembly of multiprotein complexes) are a component of the SKI complex involved in exosome-mediated RNA decay.
## Molecular Pathogenesis
Trichohepatoenteric syndrome (THES) is caused by loss of function of either protein in the human Ski complex: SKIC3 (a TPR-containing protein) or SKIC2 (an RNA helicase). The Ski complex, a heterotetrameric cytoplasmic cofactor of the RNA exosome in eukaryotic and archeal (prokaryotic) cells, is required for exosome-mediated RNA surveillance including the regulation of normal mRNA and decay of nonfunctional mRNA [
Subsequently
The protein contains 20 TRP repeated domains. TPR repeats (which mediate protein-protein interactions and the assembly of multiprotein complexes) are a component of the SKI complex involved in exosome-mediated RNA decay.
##
##
The protein contains 20 TRP repeated domains. TPR repeats (which mediate protein-protein interactions and the assembly of multiprotein complexes) are a component of the SKI complex involved in exosome-mediated RNA decay.
## Chapter Notes
We deeply thank Cécile Mouradian, from the CRB-TAC, for DNA extraction and transfer, as well as for excellent cell culture and technical help. We also thank the reviewers for their useful comments.
11 January 2018 (bp) Review posted live
29 December 2016 (af) Original submission
• 11 January 2018 (bp) Review posted live
• 29 December 2016 (af) Original submission
## Acknowledgments
We deeply thank Cécile Mouradian, from the CRB-TAC, for DNA extraction and transfer, as well as for excellent cell culture and technical help. We also thank the reviewers for their useful comments.
## Revision History
11 January 2018 (bp) Review posted live
29 December 2016 (af) Original submission
• 11 January 2018 (bp) Review posted live
• 29 December 2016 (af) Original submission
## References
## Literature Cited
|
[] |
11/1/2018
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sds
|
sds
|
[
"Shwachman-Bodian-Diamond Syndrome",
"Shwachman-Bodian-Diamond Syndrome",
"DnaJ homolog subfamily C member 21",
"Elongation factor-like GTPase 1",
"Ribosome maturation protein SBDS",
"Signal recognition particle subunit SRP54",
"DNAJC21",
"EFL1",
"SBDS",
"SRP54",
"Shwachman-Diamond Syndrome"
] |
Shwachman-Diamond Syndrome
|
Adam Nelson, Kasiani Myers
|
Summary Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); and bone abnormalities. In almost all affected children, persistent or intermittent neutropenia is an early finding. Short stature and recurrent infections are common. The diagnosis of SDS is established in a proband with the classic clinical findings of exocrine pancreatic dysfunction and bone marrow dysfunction and/or biallelic pathogenic variants in SDS is inherited in an autosomal recessive (most commonly) or an autosomal dominant manner. Once the SDS-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 Shwachman-Diamond syndrome (SDS) have been published.
SDS
Low serum concentrations of the pancreatic enzymes trypsinogen and/or isoamylase for age. Note: Measurement of trypsinogen concentration should be used in children age 3 years [
Low levels of fecal elastase
Evidence of pancreatic lipomatosis on imaging. Note: Pancreatic imaging can be normal early in the disease [
Abnormal fecal fat balance study of a 72-hour stool collection (with exclusion of intestinal mucosal disease or cholestatic liver disease)
Neutropenia (absolute neutrophil count <1,500 neutrophils/mm
Anemia or macrocytosis not explained by other causes (e.g., iron or B
Thrombocytopenia (platelet count <150,000 platelets/mm
Bone marrow examination: hypocellularity for age, myelodysplasia, leukemia, characteristic cytogenic abnormalities (e.g., deletion of 20q11, monosomy 7, isochromosome 7)
Short stature (postnatal, proportionate)
Skeletal abnormalities: delayed epiphyseal ossification, metaphyseal dysplasia, congenital thoracic dystrophy
Congenital cardiac anomalies
Ear malformations / hearing loss
Eczematous-like skin rash or ichthyosis
Hepatomegaly with or without elevation of serum aminotransferase concentrations
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
Note: (1) Numerous pathogenic variants in
When the diagnosis of SDS is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Note: Because the complex
Molecular Genetic Testing Used in Shwachman-Diamond 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, and multiplex ligation-dependent probe amplification (MLPA) and a gene-targeted microarray designed to detect single-exon deletions or duplications. Assay design is complicated by the presence of pseudogene
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Rare pathogenic variants such as c.297_300delAAGA are also likely the consequence of gene conversion with
Approximately 8% of
Rare whole-exon deletions [
Fewer than 10% of individuals with a clinical diagnosis of SDS do not have pathogenic variants identified in any of the known genes, suggesting that pathogenic variants in other gene(s) may also be causative.
• Low serum concentrations of the pancreatic enzymes trypsinogen and/or isoamylase for age. Note: Measurement of trypsinogen concentration should be used in children age 3 years [
• Low levels of fecal elastase
• Evidence of pancreatic lipomatosis on imaging. Note: Pancreatic imaging can be normal early in the disease [
• Abnormal fecal fat balance study of a 72-hour stool collection (with exclusion of intestinal mucosal disease or cholestatic liver disease)
• Neutropenia (absolute neutrophil count <1,500 neutrophils/mm
• Anemia or macrocytosis not explained by other causes (e.g., iron or B
• Thrombocytopenia (platelet count <150,000 platelets/mm
• Bone marrow examination: hypocellularity for age, myelodysplasia, leukemia, characteristic cytogenic abnormalities (e.g., deletion of 20q11, monosomy 7, isochromosome 7)
• Short stature (postnatal, proportionate)
• Skeletal abnormalities: delayed epiphyseal ossification, metaphyseal dysplasia, congenital thoracic dystrophy
• Congenital cardiac anomalies
• Ear malformations / hearing loss
• Eczematous-like skin rash or ichthyosis
• Hepatomegaly with or without elevation of serum aminotransferase concentrations
## Suggestive Findings
SDS
Low serum concentrations of the pancreatic enzymes trypsinogen and/or isoamylase for age. Note: Measurement of trypsinogen concentration should be used in children age 3 years [
Low levels of fecal elastase
Evidence of pancreatic lipomatosis on imaging. Note: Pancreatic imaging can be normal early in the disease [
Abnormal fecal fat balance study of a 72-hour stool collection (with exclusion of intestinal mucosal disease or cholestatic liver disease)
Neutropenia (absolute neutrophil count <1,500 neutrophils/mm
Anemia or macrocytosis not explained by other causes (e.g., iron or B
Thrombocytopenia (platelet count <150,000 platelets/mm
Bone marrow examination: hypocellularity for age, myelodysplasia, leukemia, characteristic cytogenic abnormalities (e.g., deletion of 20q11, monosomy 7, isochromosome 7)
Short stature (postnatal, proportionate)
Skeletal abnormalities: delayed epiphyseal ossification, metaphyseal dysplasia, congenital thoracic dystrophy
Congenital cardiac anomalies
Ear malformations / hearing loss
Eczematous-like skin rash or ichthyosis
Hepatomegaly with or without elevation of serum aminotransferase concentrations
• Low serum concentrations of the pancreatic enzymes trypsinogen and/or isoamylase for age. Note: Measurement of trypsinogen concentration should be used in children age 3 years [
• Low levels of fecal elastase
• Evidence of pancreatic lipomatosis on imaging. Note: Pancreatic imaging can be normal early in the disease [
• Abnormal fecal fat balance study of a 72-hour stool collection (with exclusion of intestinal mucosal disease or cholestatic liver disease)
• Neutropenia (absolute neutrophil count <1,500 neutrophils/mm
• Anemia or macrocytosis not explained by other causes (e.g., iron or B
• Thrombocytopenia (platelet count <150,000 platelets/mm
• Bone marrow examination: hypocellularity for age, myelodysplasia, leukemia, characteristic cytogenic abnormalities (e.g., deletion of 20q11, monosomy 7, isochromosome 7)
• Short stature (postnatal, proportionate)
• Skeletal abnormalities: delayed epiphyseal ossification, metaphyseal dysplasia, congenital thoracic dystrophy
• Congenital cardiac anomalies
• Ear malformations / hearing loss
• Eczematous-like skin rash or ichthyosis
• Hepatomegaly with or without elevation of serum aminotransferase concentrations
## 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 genetic testing approaches can include a combination of
For an introduction to multigene panels click
Note: (1) Numerous pathogenic variants in
When the diagnosis of SDS is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Note: Because the complex
Molecular Genetic Testing Used in Shwachman-Diamond 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, and multiplex ligation-dependent probe amplification (MLPA) and a gene-targeted microarray designed to detect single-exon deletions or duplications. Assay design is complicated by the presence of pseudogene
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Rare pathogenic variants such as c.297_300delAAGA are also likely the consequence of gene conversion with
Approximately 8% of
Rare whole-exon deletions [
Fewer than 10% of individuals with a clinical diagnosis of SDS do not have pathogenic variants identified in any of the known genes, suggesting that pathogenic variants in other gene(s) may also be causative.
## Option 1
For an introduction to multigene panels click
Note: (1) Numerous pathogenic variants in
## Option 2
When the diagnosis of SDS is not considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Note: Because the complex
Molecular Genetic Testing Used in Shwachman-Diamond 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, and multiplex ligation-dependent probe amplification (MLPA) and a gene-targeted microarray designed to detect single-exon deletions or duplications. Assay design is complicated by the presence of pseudogene
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Rare pathogenic variants such as c.297_300delAAGA are also likely the consequence of gene conversion with
Approximately 8% of
Rare whole-exon deletions [
Fewer than 10% of individuals with a clinical diagnosis of SDS do not have pathogenic variants identified in any of the known genes, suggesting that pathogenic variants in other gene(s) may also be causative.
## Clinical Characteristics
Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); and bone abnormalities. To date, more than 500 individuals have been identified with biallelic pathogenic variants in
Shwachman-Diamond Syndrome: Frequency of Select Features
More commonly, SDS presents in infancy with poor weight gain and poor growth secondary to exocrine pancreatic dysfunction. However, the presentation of SDS varies greatly, with nearly half of individuals in the North American SDS Registry presenting without neutropenia or steatorrhea [
Pancreatic histopathology reveals few acinar cells and extensive fatty infiltration. Pancreatic imaging studies by ultrasound or CT examination may reveal small pancreas size for age. In individuals with
Although anemia and thrombocytopenia are also seen in the majority of individuals with SDS, these findings may be intermittent or clinically asymptomatic. Severe aplastic anemia with pancytopenia occurs in a subset of individuals. The French Severe Chronic Neutropenia Registry found that 41/102 (40%) individuals with SDS demonstrated significant hematologic manifestations, including those with intermittent severe cytopenias and 21 with persistent severe cytopenias (nine classified as malignant, nine as nonmalignant, and three progressing from nonmalignant to malignant) [
The risk for MDS or progression to leukemia, typically AML, is significant in individuals with SDS; however, data remain limited, with specific reports varying by definition of MDS and cohort age. In one 25-year survey, seven of 21 individuals with SDS developed MDS; five of these seven developed AML [
Of note, the above findings contrast with other reports from the Israeli Inherited Bone Marrow Failure Registry (3 individuals) [
The risk for malignant transformation involving dysplasia or AML is considered to be lifelong, with AML generally associated with poor outcome [
Individuals with SDS may develop characteristic cytogenetic clonal changes such as deletion of 20q11 and isochromosome 7 in the absence of overt MDS or AML. It has been suggested that these changes may persist and fluctuate over time without high risk of progression to MDS/AML [
Survival remains poor for individuals that develop MDS/AML [
Recent evidence has suggested acquired pathogenic variants in hematopoietic cells in individuals with SDS can either alleviate ribosomal defects or increase leukemogenic potential via disruption of cellular checkpoints; somatic biallelic loss-of-function
To date, other reported malignancies in individuals with SDS have been rare, including isolated reports of bilateral breast cancer [
Cross-sectional and longitudinal data from
Delayed appearance of secondary ossification centers, causing bone age to appear to be delayed;
Variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates;
Generalized osteopenia.
Of note, the epiphyseal maturation defects tended to normalize with age and the metaphyseal changes tended to progress (worsen) with age [
Further skeletal findings can include rib and joint abnormalities, the latter of which can result from asymmetric growth and can be sufficiently severe to warrant surgical intervention.
Additionally, low-turnover osteoporosis has been reported as a feature of SDS.
Ichthyosis and eczematous lesions
Oral disease, including delayed dental development, increased dental caries in both primary and permanent teeth, and recurrent oral ulcerations [
Endocrine dysfunction, including congenital hypopituitarism [
Congenital anomalies, including cardiac (septal defects, patent ductus arteriosus), gastrointestinal, urinary tract / kidney, eye, or ear anomalies [
Vision abnormalities, including rod-cone dystrophy [
Inflammatory conditions, including juvenille idiopathic arthritis, chronic recurrent multifocal osteomyeltitis, scleroderma, and other inflammtory eye conditions [
No phenotype correlations by gene have been identified.
No genotype-phenotype correlations have been observed for any of the genes associated with SDS [
Previously used terms for SDS:
Shwachman's syndrome
Congenital lipomatosis of the pancreas
Shwachman-Bodian syndrome
It has been estimated that SDS occurs in one in 77,000 births based on the observation that it is approximately 1/20th as frequent as cystic fibrosis in North America [
SDS occurs in diverse populations, including those with European, Indian, Indigenous American, Chinese, Japanese, and African ancestry.
• Delayed appearance of secondary ossification centers, causing bone age to appear to be delayed;
• Variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates;
• Generalized osteopenia.
• Ichthyosis and eczematous lesions
• Oral disease, including delayed dental development, increased dental caries in both primary and permanent teeth, and recurrent oral ulcerations [
• Endocrine dysfunction, including congenital hypopituitarism [
• Congenital anomalies, including cardiac (septal defects, patent ductus arteriosus), gastrointestinal, urinary tract / kidney, eye, or ear anomalies [
• Vision abnormalities, including rod-cone dystrophy [
• Inflammatory conditions, including juvenille idiopathic arthritis, chronic recurrent multifocal osteomyeltitis, scleroderma, and other inflammtory eye conditions [
• Shwachman's syndrome
• Congenital lipomatosis of the pancreas
• Shwachman-Bodian syndrome
## Clinical Description
Shwachman-Diamond syndrome (SDS) is characterized by exocrine pancreatic dysfunction with malabsorption, malnutrition, and growth failure; hematologic abnormalities with single- or multilineage cytopenias and susceptibility to myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML); and bone abnormalities. To date, more than 500 individuals have been identified with biallelic pathogenic variants in
Shwachman-Diamond Syndrome: Frequency of Select Features
More commonly, SDS presents in infancy with poor weight gain and poor growth secondary to exocrine pancreatic dysfunction. However, the presentation of SDS varies greatly, with nearly half of individuals in the North American SDS Registry presenting without neutropenia or steatorrhea [
Pancreatic histopathology reveals few acinar cells and extensive fatty infiltration. Pancreatic imaging studies by ultrasound or CT examination may reveal small pancreas size for age. In individuals with
Although anemia and thrombocytopenia are also seen in the majority of individuals with SDS, these findings may be intermittent or clinically asymptomatic. Severe aplastic anemia with pancytopenia occurs in a subset of individuals. The French Severe Chronic Neutropenia Registry found that 41/102 (40%) individuals with SDS demonstrated significant hematologic manifestations, including those with intermittent severe cytopenias and 21 with persistent severe cytopenias (nine classified as malignant, nine as nonmalignant, and three progressing from nonmalignant to malignant) [
The risk for MDS or progression to leukemia, typically AML, is significant in individuals with SDS; however, data remain limited, with specific reports varying by definition of MDS and cohort age. In one 25-year survey, seven of 21 individuals with SDS developed MDS; five of these seven developed AML [
Of note, the above findings contrast with other reports from the Israeli Inherited Bone Marrow Failure Registry (3 individuals) [
The risk for malignant transformation involving dysplasia or AML is considered to be lifelong, with AML generally associated with poor outcome [
Individuals with SDS may develop characteristic cytogenetic clonal changes such as deletion of 20q11 and isochromosome 7 in the absence of overt MDS or AML. It has been suggested that these changes may persist and fluctuate over time without high risk of progression to MDS/AML [
Survival remains poor for individuals that develop MDS/AML [
Recent evidence has suggested acquired pathogenic variants in hematopoietic cells in individuals with SDS can either alleviate ribosomal defects or increase leukemogenic potential via disruption of cellular checkpoints; somatic biallelic loss-of-function
To date, other reported malignancies in individuals with SDS have been rare, including isolated reports of bilateral breast cancer [
Cross-sectional and longitudinal data from
Delayed appearance of secondary ossification centers, causing bone age to appear to be delayed;
Variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates;
Generalized osteopenia.
Of note, the epiphyseal maturation defects tended to normalize with age and the metaphyseal changes tended to progress (worsen) with age [
Further skeletal findings can include rib and joint abnormalities, the latter of which can result from asymmetric growth and can be sufficiently severe to warrant surgical intervention.
Additionally, low-turnover osteoporosis has been reported as a feature of SDS.
Ichthyosis and eczematous lesions
Oral disease, including delayed dental development, increased dental caries in both primary and permanent teeth, and recurrent oral ulcerations [
Endocrine dysfunction, including congenital hypopituitarism [
Congenital anomalies, including cardiac (septal defects, patent ductus arteriosus), gastrointestinal, urinary tract / kidney, eye, or ear anomalies [
Vision abnormalities, including rod-cone dystrophy [
Inflammatory conditions, including juvenille idiopathic arthritis, chronic recurrent multifocal osteomyeltitis, scleroderma, and other inflammtory eye conditions [
• Delayed appearance of secondary ossification centers, causing bone age to appear to be delayed;
• Variable widening and irregularity of the metaphyses in early childhood, followed by progressive thickening and irregularity of the growth plates;
• Generalized osteopenia.
• Ichthyosis and eczematous lesions
• Oral disease, including delayed dental development, increased dental caries in both primary and permanent teeth, and recurrent oral ulcerations [
• Endocrine dysfunction, including congenital hypopituitarism [
• Congenital anomalies, including cardiac (septal defects, patent ductus arteriosus), gastrointestinal, urinary tract / kidney, eye, or ear anomalies [
• Vision abnormalities, including rod-cone dystrophy [
• Inflammatory conditions, including juvenille idiopathic arthritis, chronic recurrent multifocal osteomyeltitis, scleroderma, and other inflammtory eye conditions [
## Phenotype Correlations by Gene
No phenotype correlations by gene have been identified.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been observed for any of the genes associated with SDS [
## Nomenclature
Previously used terms for SDS:
Shwachman's syndrome
Congenital lipomatosis of the pancreas
Shwachman-Bodian syndrome
• Shwachman's syndrome
• Congenital lipomatosis of the pancreas
• Shwachman-Bodian syndrome
## Prevalence
It has been estimated that SDS occurs in one in 77,000 births based on the observation that it is approximately 1/20th as frequent as cystic fibrosis in North America [
SDS occurs in diverse populations, including those with European, Indian, Indigenous American, Chinese, Japanese, and African ancestry.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
Heterozygous
## Differential Diagnosis
Features of Shwachman-Diamond syndrome (SDS) (e.g., poor growth and transient neutropenia) may have multiple causes in young children (see
Genes of Interest in the Differential Diagnosis of Shwachman-Diamond Syndrome
↑ sweat chloride values
No primary bone marrow failure
Abnormally shortened telomere length
Variable cellularity of bone marrow w/↓ precursors
No primary exocrine pancreatic dysfunction
Severe neutropenia
On hematologic testing: isolated neutropenia
Progressive pancytopenia w/positive chromosome breakage studies
Variable cellularity of bone marrow w/↓ precursors
No primary exocrine pancreatic dysfunction
Severe neutropenia
On hematologic testing: early myeloid arrest at promyelocyte/myelocyte stage, w/atypical nuclei & cytoplasmic vacuolization
Progressive macrocytic anemia w/reticulocytopenia
Normal cellularity bone marrow w/markedly ↓ or absent erythroid precursors
No primary exocrine pancreatic dysfunction
Short at birth, w/abnormal long-bone growth
↑ incidence of scoliosis, abnormal pubertal growth spurt, & global dysfunction of skeletal growth (axial & appendicular)
Gastrointestinal features due to complications of infection (vs exocrine pancreatic insufficiency in SDS)
Anomalies & severe developmental delay
No hematologic abnormalities
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; mt = mitochondrial; SDS = Shwachman-Diamond syndrome; XL = X-linked
Listed genes represent more commonly associated genes.
Fanconi anemia (FA) is inherited in an autosomal recessive manner, an autosomal dominant manner (
Most often, Diamond-Blackfan anemia (DBA) is inherited in an autosomal dominant manner.
• ↑ sweat chloride values
• No primary bone marrow failure
• Abnormally shortened telomere length
• Variable cellularity of bone marrow w/↓ precursors
• No primary exocrine pancreatic dysfunction
• Severe neutropenia
• On hematologic testing: isolated neutropenia
• Progressive pancytopenia w/positive chromosome breakage studies
• Variable cellularity of bone marrow w/↓ precursors
• No primary exocrine pancreatic dysfunction
• Severe neutropenia
• On hematologic testing: early myeloid arrest at promyelocyte/myelocyte stage, w/atypical nuclei & cytoplasmic vacuolization
• Progressive macrocytic anemia w/reticulocytopenia
• Normal cellularity bone marrow w/markedly ↓ or absent erythroid precursors
• No primary exocrine pancreatic dysfunction
• Short at birth, w/abnormal long-bone growth
• ↑ incidence of scoliosis, abnormal pubertal growth spurt, & global dysfunction of skeletal growth (axial & appendicular)
• Gastrointestinal features due to complications of infection (vs exocrine pancreatic insufficiency in SDS)
• Anomalies & severe developmental delay
• No hematologic abnormalities
## Management
Clinical practice guidelines for Shwachman-Diamond syndrome (SDS) have been published [
To establish the extent of disease and needs in an individual diagnosed with SDS, the evaluations summarized in
Shwachman-Diamond Syndrome: Recommended Evaluations Following Initial Diagnosis
Assessment of weight & height
Assessment of nutritional status
Measurement of fat-soluble vitamins (vitamin A, 25-hydroxyvitamin D, vitamin E) or their related metabolites
Measurement of prothrombin time (to detect vitamin K deficiency)
CBC w/white cell differential & platelet count
Measurement of iron, folate, & vitamin B
Bone marrow exam w/biopsy & cytogenetic studies
Measurement of immunoglobulins
Lymphocyte subpopulations
Assessment of pubertal development
Assessment for clinical manifestations of hypopituitarism & diabetes
Clinical exam for skin & dental manifestations, cardiac anomalies, ocular or ear anomalies
Assessment for recurrent urinary tract infections
Community or
Social work involvement for parental support
Home nursing referral
CBC = complete blood count; MOI = mode of inheritance; SDS = Shwachman-Diamond syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Supportive care to improve quality of life, maximize function, and reduce complications by a multidisciplinary team is highly recommended. This can include specialists in hematology, gastroenterology, clinical genetics, orthopedics, endocrinology, immunology, dentistry, child development, psychology, and social work as needed [
Shwachman-Diamond Syndrome: Treatment of Manifestations
HSCT for severe bone marrow failure, MDS, or AML
Chemotherapy can be utilized as a bridge to HSCT in persons w/AML; however, sustaining complete remission is challenging & prompt HSCT remains imperative.
Early referral to pediatric pulmonary & orthopedic specialists for asphyxiating thoracic dystrophy due to rib cage restriction
Consultation w/orthopedic surgeon familiar w/SDS for those w/skeletal dysplasia, asymmetric growth, & joint deformities
Surgical intervention as needed for other severe rib & joint abnormalities
Consider treatment for low bone density if indicated by bone densitometry.
Mgmt of dental manifestations, mouth ulcers, & gingivitis per dentist
Home care should include aggressive dental hygiene w/topical fluoride treatments to help prevent dental decay.
AML = acute myelogenous leukemia; G-CSF = granulocyte-colony stimulation factor; HSCT = hematopoietic stem cell transplantation; MDS = myelodysplastic syndrome; SDS = Shwachman-Diamond syndrome
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations – given the intermittent nature of some features of SDS and the evolution of the phenotype over time – the evaluations in
Shwachman-Diamond Syndrome: Recommended Surveillance
Assessment of nutritional status
Measurement of serum concentration of fat-soluble vitamins to evaluate effectiveness of or need for pancreatic enzyme therapy
At least every 3-6 mos
More frequently if peripheral blood counts are changing or infections are recurrent & debilitating
Every 1-3 yrs
More frequently if changes in bone marrow function or cellularity are observed
Before puberty, during puberty, & thereafter based on individual findings
Note: Results must be interpreted in context of stature & pubertal status.
Every 12 mos
More frequently in those w/neutropenia &/or frequent infections
Assess growth.
Assess for clinical signs/symptoms of additional endocrine manifestations.
CBC = complete blood count
Prolonged use of cytokine and hematopoietic growth factors such as granulocyte-colony stimulation factor is cautioned against in view of their potential contribution to leukemic transformation [
Some drugs (e.g., cyclophosphamide and busulfan) used in standard hematopoietic stem cell transplantation (HSCT) preparative regimens may not be suitable because of possible cardiac toxicity [
Molecular genetic testing if the pathogenic variants in the family are known;
Testing for exocrine pancreatic dysfunction and evidence of bone marrow failure with single- or multilineage cytopenia if the pathogenic variants in the family are not known.
See
For pregnancies in women with SDS, high-risk pregnancy care including consultation with a hematologist is recommended [
Search
• Assessment of weight & height
• Assessment of nutritional status
• Measurement of fat-soluble vitamins (vitamin A, 25-hydroxyvitamin D, vitamin E) or their related metabolites
• Measurement of prothrombin time (to detect vitamin K deficiency)
• CBC w/white cell differential & platelet count
• Measurement of iron, folate, & vitamin B
• Bone marrow exam w/biopsy & cytogenetic studies
• Measurement of immunoglobulins
• Lymphocyte subpopulations
• Assessment of pubertal development
• Assessment for clinical manifestations of hypopituitarism & diabetes
• Clinical exam for skin & dental manifestations, cardiac anomalies, ocular or ear anomalies
• Assessment for recurrent urinary tract infections
• Community or
• Social work involvement for parental support
• Home nursing referral
• HSCT for severe bone marrow failure, MDS, or AML
• Chemotherapy can be utilized as a bridge to HSCT in persons w/AML; however, sustaining complete remission is challenging & prompt HSCT remains imperative.
• Early referral to pediatric pulmonary & orthopedic specialists for asphyxiating thoracic dystrophy due to rib cage restriction
• Consultation w/orthopedic surgeon familiar w/SDS for those w/skeletal dysplasia, asymmetric growth, & joint deformities
• Surgical intervention as needed for other severe rib & joint abnormalities
• Consider treatment for low bone density if indicated by bone densitometry.
• Mgmt of dental manifestations, mouth ulcers, & gingivitis per dentist
• Home care should include aggressive dental hygiene w/topical fluoride treatments to help prevent dental decay.
• Assessment of nutritional status
• Measurement of serum concentration of fat-soluble vitamins to evaluate effectiveness of or need for pancreatic enzyme therapy
• At least every 3-6 mos
• More frequently if peripheral blood counts are changing or infections are recurrent & debilitating
• Every 1-3 yrs
• More frequently if changes in bone marrow function or cellularity are observed
• Before puberty, during puberty, & thereafter based on individual findings
• Note: Results must be interpreted in context of stature & pubertal status.
• Every 12 mos
• More frequently in those w/neutropenia &/or frequent infections
• Assess growth.
• Assess for clinical signs/symptoms of additional endocrine manifestations.
• Molecular genetic testing if the pathogenic variants in the family are known;
• Testing for exocrine pancreatic dysfunction and evidence of bone marrow failure with single- or multilineage cytopenia 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 SDS, the evaluations summarized in
Shwachman-Diamond Syndrome: Recommended Evaluations Following Initial Diagnosis
Assessment of weight & height
Assessment of nutritional status
Measurement of fat-soluble vitamins (vitamin A, 25-hydroxyvitamin D, vitamin E) or their related metabolites
Measurement of prothrombin time (to detect vitamin K deficiency)
CBC w/white cell differential & platelet count
Measurement of iron, folate, & vitamin B
Bone marrow exam w/biopsy & cytogenetic studies
Measurement of immunoglobulins
Lymphocyte subpopulations
Assessment of pubertal development
Assessment for clinical manifestations of hypopituitarism & diabetes
Clinical exam for skin & dental manifestations, cardiac anomalies, ocular or ear anomalies
Assessment for recurrent urinary tract infections
Community or
Social work involvement for parental support
Home nursing referral
CBC = complete blood count; MOI = mode of inheritance; SDS = Shwachman-Diamond syndrome
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Assessment of weight & height
• Assessment of nutritional status
• Measurement of fat-soluble vitamins (vitamin A, 25-hydroxyvitamin D, vitamin E) or their related metabolites
• Measurement of prothrombin time (to detect vitamin K deficiency)
• CBC w/white cell differential & platelet count
• Measurement of iron, folate, & vitamin B
• Bone marrow exam w/biopsy & cytogenetic studies
• Measurement of immunoglobulins
• Lymphocyte subpopulations
• Assessment of pubertal development
• Assessment for clinical manifestations of hypopituitarism & diabetes
• Clinical exam for skin & dental manifestations, cardiac anomalies, ocular or ear anomalies
• Assessment for recurrent urinary tract infections
• 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 by a multidisciplinary team is highly recommended. This can include specialists in hematology, gastroenterology, clinical genetics, orthopedics, endocrinology, immunology, dentistry, child development, psychology, and social work as needed [
Shwachman-Diamond Syndrome: Treatment of Manifestations
HSCT for severe bone marrow failure, MDS, or AML
Chemotherapy can be utilized as a bridge to HSCT in persons w/AML; however, sustaining complete remission is challenging & prompt HSCT remains imperative.
Early referral to pediatric pulmonary & orthopedic specialists for asphyxiating thoracic dystrophy due to rib cage restriction
Consultation w/orthopedic surgeon familiar w/SDS for those w/skeletal dysplasia, asymmetric growth, & joint deformities
Surgical intervention as needed for other severe rib & joint abnormalities
Consider treatment for low bone density if indicated by bone densitometry.
Mgmt of dental manifestations, mouth ulcers, & gingivitis per dentist
Home care should include aggressive dental hygiene w/topical fluoride treatments to help prevent dental decay.
AML = acute myelogenous leukemia; G-CSF = granulocyte-colony stimulation factor; HSCT = hematopoietic stem cell transplantation; MDS = myelodysplastic syndrome; SDS = Shwachman-Diamond syndrome
• HSCT for severe bone marrow failure, MDS, or AML
• Chemotherapy can be utilized as a bridge to HSCT in persons w/AML; however, sustaining complete remission is challenging & prompt HSCT remains imperative.
• Early referral to pediatric pulmonary & orthopedic specialists for asphyxiating thoracic dystrophy due to rib cage restriction
• Consultation w/orthopedic surgeon familiar w/SDS for those w/skeletal dysplasia, asymmetric growth, & joint deformities
• Surgical intervention as needed for other severe rib & joint abnormalities
• Consider treatment for low bone density if indicated by bone densitometry.
• Mgmt of dental manifestations, mouth ulcers, & gingivitis per dentist
• Home care should include aggressive dental hygiene w/topical fluoride treatments to help prevent dental decay.
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations – given the intermittent nature of some features of SDS and the evolution of the phenotype over time – the evaluations in
Shwachman-Diamond Syndrome: Recommended Surveillance
Assessment of nutritional status
Measurement of serum concentration of fat-soluble vitamins to evaluate effectiveness of or need for pancreatic enzyme therapy
At least every 3-6 mos
More frequently if peripheral blood counts are changing or infections are recurrent & debilitating
Every 1-3 yrs
More frequently if changes in bone marrow function or cellularity are observed
Before puberty, during puberty, & thereafter based on individual findings
Note: Results must be interpreted in context of stature & pubertal status.
Every 12 mos
More frequently in those w/neutropenia &/or frequent infections
Assess growth.
Assess for clinical signs/symptoms of additional endocrine manifestations.
CBC = complete blood count
• Assessment of nutritional status
• Measurement of serum concentration of fat-soluble vitamins to evaluate effectiveness of or need for pancreatic enzyme therapy
• At least every 3-6 mos
• More frequently if peripheral blood counts are changing or infections are recurrent & debilitating
• Every 1-3 yrs
• More frequently if changes in bone marrow function or cellularity are observed
• Before puberty, during puberty, & thereafter based on individual findings
• Note: Results must be interpreted in context of stature & pubertal status.
• Every 12 mos
• More frequently in those w/neutropenia &/or frequent infections
• Assess growth.
• Assess for clinical signs/symptoms of additional endocrine manifestations.
## Agents/Circumstances to Avoid
Prolonged use of cytokine and hematopoietic growth factors such as granulocyte-colony stimulation factor is cautioned against in view of their potential contribution to leukemic transformation [
Some drugs (e.g., cyclophosphamide and busulfan) used in standard hematopoietic stem cell transplantation (HSCT) preparative regimens may not be suitable because of possible cardiac toxicity [
## Evaluation of Relatives at Risk
Molecular genetic testing if the pathogenic variants in the family are known;
Testing for exocrine pancreatic dysfunction and evidence of bone marrow failure with single- or multilineage cytopenia if the pathogenic variants in the family are not known.
See
• Molecular genetic testing if the pathogenic variants in the family are known;
• Testing for exocrine pancreatic dysfunction and evidence of bone marrow failure with single- or multilineage cytopenia if the pathogenic variants in the family are not known.
## Pregnancy Management
For pregnancies in women with SDS, high-risk pregnancy care including consultation with a hematologist is recommended [
## Therapies Under Investigation
Search
## Genetic Counseling
Shwachman-Diamond syndrome (SDS) caused by pathogenic variants in
The parents of an affected child are usually heterozygous for an SDS-related pathogenic variant. Occasionally, only one parent is a carrier and the affected child has one inherited and one
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 SDS-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.
Heterozygotes (carriers) are asymptomatic. See
If both parents are known to be heterozygous for an SDS-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 an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
The clinical spectrum of SDS is broad and varies among affected sibs [
When the proband has one inherited and one
Heterozygotes (carriers) are clinically asymptomatic. See
The offspring of an individual with autosomal recessive SDS are obligate heterozygotes (carriers) for a pathogenic variant in one of the genes associated with SDS.
In the rare event that the reproductive partner of the proband is a carrier, offspring are at a 50% risk of being affected and a 50% risk of being carriers.
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
Note that carriers are clinically asymptomatic.
Although it has been suggested that carriers (heterozygotes) with one pathogenic
Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogenous leukemia (AML) did not reveal any
To date, most individuals diagnosed with
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 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 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 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 of having SDS-related pathogenic variant(s).
Once the SDS-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 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 usually heterozygous for an SDS-related pathogenic variant. Occasionally, only one parent is a carrier and the affected child has one inherited and one
• 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 SDS-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.
• Heterozygotes (carriers) are asymptomatic. See
• 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 SDS-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 an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• The clinical spectrum of SDS is broad and varies among affected sibs [
• When the proband has one inherited and one
• Heterozygotes (carriers) are clinically asymptomatic. See
• The offspring of an individual with autosomal recessive SDS are obligate heterozygotes (carriers) for a pathogenic variant in one of the genes associated with SDS.
• In the rare event that the reproductive partner of the proband is a carrier, offspring are at a 50% risk of being affected and a 50% risk of being carriers.
• Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
• Note that carriers are clinically asymptomatic.
• Although it has been suggested that carriers (heterozygotes) with one pathogenic
• Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogenous leukemia (AML) did not reveal any
• Although it has been suggested that carriers (heterozygotes) with one pathogenic
• Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogenous leukemia (AML) did not reveal any
• Although it has been suggested that carriers (heterozygotes) with one pathogenic
• Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogenous leukemia (AML) did not reveal any
• To date, most individuals diagnosed with
• 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 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 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 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 of having SDS-related pathogenic variant(s).
## Mode of Inheritance
Shwachman-Diamond syndrome (SDS) caused by pathogenic variants in
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of an affected child are usually heterozygous for an SDS-related pathogenic variant. Occasionally, only one parent is a carrier and the affected child has one inherited and one
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 SDS-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.
Heterozygotes (carriers) are asymptomatic. See
If both parents are known to be heterozygous for an SDS-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 an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
The clinical spectrum of SDS is broad and varies among affected sibs [
When the proband has one inherited and one
Heterozygotes (carriers) are clinically asymptomatic. See
The offspring of an individual with autosomal recessive SDS are obligate heterozygotes (carriers) for a pathogenic variant in one of the genes associated with SDS.
In the rare event that the reproductive partner of the proband is a carrier, offspring are at a 50% risk of being affected and a 50% risk of being carriers.
Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
Note that carriers are clinically asymptomatic.
Although it has been suggested that carriers (heterozygotes) with one pathogenic
Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogenous leukemia (AML) did not reveal any
• The parents of an affected child are usually heterozygous for an SDS-related pathogenic variant. Occasionally, only one parent is a carrier and the affected child has one inherited and one
• 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 SDS-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.
• Heterozygotes (carriers) are asymptomatic. See
• 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 SDS-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 an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier.
• The clinical spectrum of SDS is broad and varies among affected sibs [
• When the proband has one inherited and one
• Heterozygotes (carriers) are clinically asymptomatic. See
• The offspring of an individual with autosomal recessive SDS are obligate heterozygotes (carriers) for a pathogenic variant in one of the genes associated with SDS.
• In the rare event that the reproductive partner of the proband is a carrier, offspring are at a 50% risk of being affected and a 50% risk of being carriers.
• Carrier testing for at-risk relatives requires prior identification of the pathogenic variants in the family.
• Note that carriers are clinically asymptomatic.
• Although it has been suggested that carriers (heterozygotes) with one pathogenic
• Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogenous leukemia (AML) did not reveal any
• Although it has been suggested that carriers (heterozygotes) with one pathogenic
• Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogenous leukemia (AML) did not reveal any
• Although it has been suggested that carriers (heterozygotes) with one pathogenic
• Sequence analysis of DNA obtained from bone marrow samples from 77 persons with acute myelogenous leukemia (AML) did not reveal any
## Autosomal Dominant Inheritance – Risk to Family Members
To date, most individuals diagnosed with
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 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 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 is known to have the
If the
If the parents have not been tested for the
• To date, most individuals diagnosed with
• 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 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 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 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 of having SDS-related pathogenic variant(s).
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 SDS-related pathogenic variant(s).
## Prenatal Testing and Preimplantation Genetic Testing
Once the SDS-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 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
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• Italy
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•
## Molecular Genetics
Shwachman-Diamond Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Shwachman-Diamond Syndrome (
Schwachman-Diamond syndrome (SDS) is caused by pathogenic variants in
Ribosome maturation protein SBDS (SBDS), encoded by
SBDS has also been implicated in mitochondrial function. Reduced expression of
Some residual activity of SBDS may be required for development. Despite the relatively common occurrence of the null allele c.183_184delinsCT (p.Lys62Ter), no homozygotes have been reported. This is consistent with the observations of a mouse model in which complete loss of both
Deletion of the yeast
EFL1 is a partner for SBDS and is involved in the formation of mature ribosomes. EFL1 interacts with the 60S ribosomal subunit to prevent premature association of the ribosomal subunits in the nucleus.
Signal recognition particle subunit SRP54 (SRP54), encoded by
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Likely the consequence of gene conversion with
## Molecular Pathogenesis
Schwachman-Diamond syndrome (SDS) is caused by pathogenic variants in
Ribosome maturation protein SBDS (SBDS), encoded by
SBDS has also been implicated in mitochondrial function. Reduced expression of
Some residual activity of SBDS may be required for development. Despite the relatively common occurrence of the null allele c.183_184delinsCT (p.Lys62Ter), no homozygotes have been reported. This is consistent with the observations of a mouse model in which complete loss of both
Deletion of the yeast
EFL1 is a partner for SBDS and is involved in the formation of mature ribosomes. EFL1 interacts with the 60S ribosomal subunit to prevent premature association of the ribosomal subunits in the nucleus.
Signal recognition particle subunit SRP54 (SRP54), encoded by
Pathogenic Variants Referenced in This
Variants listed in the table have been provided by the authors.
Variant designation that does not conform to current naming conventions
Likely the consequence of gene conversion with
## Chapter Notes
The authors would like to thank individuals with Shwachman-Diamond syndrome and their families and caregivers, as well as Dr Peter Durie, Dr Akiko Shimamura, and Dr Stella Davies.
Peter R Durie, MD, FRCPC; University of Toronto (2008-2014)Kasiani Myers, MD (2014-present)Adam Nelson, MBBS (2018-present)Johanna M Rommens, PhD; University of Toronto (2008-2014)
19 September 2024 (sw) Comprehensive update posted live
18 October 2018 (ha) Comprehensive update posted live
11 September 2014 (me) Comprehensive update posted live
17 July 2008 (me) Review posted live
7 January 2008 (jr) Original submission
• 19 September 2024 (sw) Comprehensive update posted live
• 18 October 2018 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 17 July 2008 (me) Review posted live
• 7 January 2008 (jr) Original submission
## Acknowledgments
The authors would like to thank individuals with Shwachman-Diamond syndrome and their families and caregivers, as well as Dr Peter Durie, Dr Akiko Shimamura, and Dr Stella Davies.
## Author History
Peter R Durie, MD, FRCPC; University of Toronto (2008-2014)Kasiani Myers, MD (2014-present)Adam Nelson, MBBS (2018-present)Johanna M Rommens, PhD; University of Toronto (2008-2014)
## Revision History
19 September 2024 (sw) Comprehensive update posted live
18 October 2018 (ha) Comprehensive update posted live
11 September 2014 (me) Comprehensive update posted live
17 July 2008 (me) Review posted live
7 January 2008 (jr) Original submission
• 19 September 2024 (sw) Comprehensive update posted live
• 18 October 2018 (ha) Comprehensive update posted live
• 11 September 2014 (me) Comprehensive update posted live
• 17 July 2008 (me) Review posted live
• 7 January 2008 (jr) Original submission
## References
## Literature Cited
|
[] |
17/7/2008
|
19/9/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
sedt
|
sedt
|
[
"TRAPPC2-Related X-Linked Spondyloepiphyseal Dysplasia Tarda",
"TRAPPC2-Related X-Linked Spondyloepiphyseal Dysplasia Tarda",
"Trafficking protein particle complex subunit 2",
"TRAPPC2",
"X-Linked Spondyloepiphyseal Dysplasia Tarda"
] |
X-Linked Spondyloepiphyseal Dysplasia Tarda
|
George E Tiller
|
Summary In adults, X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT) is characterized by disproportionately short stature with short trunk and arm span significantly greater than height. At birth, affected males are normal in length and have normal body proportions. Affected males exhibit linear growth deficiency beginning around age six to eight years. Final adult height is typically 137-163 cm. Progressive joint and back pain with osteoarthritis ensues; hip, knee, and shoulder joints are commonly involved but to a variable degree. Hip replacement is often required as early as age 40 years. Interphalangeal joints are typically spared. Motor and cognitive milestones are normal. The clinical diagnosis of X-linked SEDT can be established in a male proband with characteristic radiographic findings (which typically appear prior to puberty) including: multiple epiphyseal abnormalities, platyspondyly with characteristic superior and inferior "humping" seen on lateral view, scoliosis, hypoplastic odontoid process, short femoral necks, and coxa vara; evidence of premature osteoarthritis appears in young adulthood. The molecular diagnosis of X-linked SEDT can be established in a male proband with suggestive findings and a hemizygous pathogenic variant in By definition, X-linked SEDT is inherited in an X-linked manner. When performed, molecular genetic testing of all mothers of affected sons determined that regardless of family history all were carriers of a pathogenic variant in
|
## Diagnosis
No consensus clinical diagnostic criteria for X-linked spondyloepiphyseal dysplasia tarda have been published.
X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT)
Disproportionate short stature in adolescence or adulthood and a relatively short trunk and barrel-shaped chest. Upper- to lower-body segment ratio is usually about 0.8. Arm span typically exceeds height by 10-20 cm. Short neck, dorsal kyphosis, and lumbar hyperlordosis may be evident by puberty.
Early-onset osteoarthritis, especially in the hip joints
A family history consistent with X-linked recessive inheritance. A positive family history is contributory but not necessary.
Absence of cleft palate and retinal detachment (frequently present in SED congenita; see
The clinical diagnosis of X-linked SEDT
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 following radiographic findings may not be manifest in an affected male in early childhood and typically appear prior to puberty (
Multiple epiphyseal abnormalities
Platyspondyly (flattened vertebral bodies) with characteristic superior and inferior "humping" seen on lateral view; narrow disc spaces in adulthood
Scoliosis / kyphoscoliosis
Hypoplastic odontoid process
Short femoral necks
Coxa vara
Evidence of premature osteoarthritis beginning in young adulthood
Radiographs of symptomatic males should be reviewed by a radiologist experienced with bone dysplasias.
Testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in X-linked Spondyloepiphyseal Dysplasia Tarda
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.
Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysis
It is unknown whether negative molecular analysis reflects locus heterogeneity or clinical misdiagnosis.
• Disproportionate short stature in adolescence or adulthood and a relatively short trunk and barrel-shaped chest. Upper- to lower-body segment ratio is usually about 0.8. Arm span typically exceeds height by 10-20 cm. Short neck, dorsal kyphosis, and lumbar hyperlordosis may be evident by puberty.
• Early-onset osteoarthritis, especially in the hip joints
• A family history consistent with X-linked recessive inheritance. A positive family history is contributory but not necessary.
• Absence of cleft palate and retinal detachment (frequently present in SED congenita; see
• Multiple epiphyseal abnormalities
• Platyspondyly (flattened vertebral bodies) with characteristic superior and inferior "humping" seen on lateral view; narrow disc spaces in adulthood
• Scoliosis / kyphoscoliosis
• Hypoplastic odontoid process
• Short femoral necks
• Coxa vara
• Evidence of premature osteoarthritis beginning in young adulthood
• For an introduction to multigene panels click
## Suggestive Findings
X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT)
Disproportionate short stature in adolescence or adulthood and a relatively short trunk and barrel-shaped chest. Upper- to lower-body segment ratio is usually about 0.8. Arm span typically exceeds height by 10-20 cm. Short neck, dorsal kyphosis, and lumbar hyperlordosis may be evident by puberty.
Early-onset osteoarthritis, especially in the hip joints
A family history consistent with X-linked recessive inheritance. A positive family history is contributory but not necessary.
Absence of cleft palate and retinal detachment (frequently present in SED congenita; see
• Disproportionate short stature in adolescence or adulthood and a relatively short trunk and barrel-shaped chest. Upper- to lower-body segment ratio is usually about 0.8. Arm span typically exceeds height by 10-20 cm. Short neck, dorsal kyphosis, and lumbar hyperlordosis may be evident by puberty.
• Early-onset osteoarthritis, especially in the hip joints
• A family history consistent with X-linked recessive inheritance. A positive family history is contributory but not necessary.
• Absence of cleft palate and retinal detachment (frequently present in SED congenita; see
## Establishing the Diagnosis
The clinical diagnosis of X-linked SEDT
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 following radiographic findings may not be manifest in an affected male in early childhood and typically appear prior to puberty (
Multiple epiphyseal abnormalities
Platyspondyly (flattened vertebral bodies) with characteristic superior and inferior "humping" seen on lateral view; narrow disc spaces in adulthood
Scoliosis / kyphoscoliosis
Hypoplastic odontoid process
Short femoral necks
Coxa vara
Evidence of premature osteoarthritis beginning in young adulthood
Radiographs of symptomatic males should be reviewed by a radiologist experienced with bone dysplasias.
Testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in X-linked Spondyloepiphyseal Dysplasia Tarda
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.
Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysis
It is unknown whether negative molecular analysis reflects locus heterogeneity or clinical misdiagnosis.
• Multiple epiphyseal abnormalities
• Platyspondyly (flattened vertebral bodies) with characteristic superior and inferior "humping" seen on lateral view; narrow disc spaces in adulthood
• Scoliosis / kyphoscoliosis
• Hypoplastic odontoid process
• Short femoral necks
• Coxa vara
• Evidence of premature osteoarthritis beginning in young adulthood
• For an introduction to multigene panels click
## Radiographic Findings
The following radiographic findings may not be manifest in an affected male in early childhood and typically appear prior to puberty (
Multiple epiphyseal abnormalities
Platyspondyly (flattened vertebral bodies) with characteristic superior and inferior "humping" seen on lateral view; narrow disc spaces in adulthood
Scoliosis / kyphoscoliosis
Hypoplastic odontoid process
Short femoral necks
Coxa vara
Evidence of premature osteoarthritis beginning in young adulthood
Radiographs of symptomatic males should be reviewed by a radiologist experienced with bone dysplasias.
• Multiple epiphyseal abnormalities
• Platyspondyly (flattened vertebral bodies) with characteristic superior and inferior "humping" seen on lateral view; narrow disc spaces in adulthood
• Scoliosis / kyphoscoliosis
• Hypoplastic odontoid process
• Short femoral necks
• Coxa vara
• Evidence of premature osteoarthritis beginning in young adulthood
## Molecular Genetic Testing
Testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in X-linked Spondyloepiphyseal Dysplasia Tarda
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.
Males initially suspected on sequence analysis of having a deletion in whom the deletion is subsequently confirmed by deletion/duplication analysis
It is unknown whether negative molecular analysis reflects locus heterogeneity or clinical misdiagnosis.
• For an introduction to multigene panels click
## Clinical Characteristics
Affected males achieve normal motor and cognitive milestones. Life span and intelligence appear normal.
Data are inadequate to reliably correlate clinical severity to a specific
Spondyloepiphyseal dysplasia is a general term that describes the radiographic abnormalities seen in several skeletal dysplasias, including
SED tarda commonly refers to the X-linked recessive form of the disorder, although rare autosomal dominant and autosomal recessive "tarda" forms have been described.
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The prevalence is 1:150,000-1:200,000 [
Pathogenic variants in
## Clinical Description
Affected males achieve normal motor and cognitive milestones. Life span and intelligence appear normal.
## Genotype-Phenotype Correlations
Data are inadequate to reliably correlate clinical severity to a specific
## Nomenclature
Spondyloepiphyseal dysplasia is a general term that describes the radiographic abnormalities seen in several skeletal dysplasias, including
SED tarda commonly refers to the X-linked recessive form of the disorder, although rare autosomal dominant and autosomal recessive "tarda" forms have been described.
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
The prevalence is 1:150,000-1:200,000 [
Pathogenic variants in
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT) is distinguished from other forms of spondyloepiphyseal dysplasia (SED) by its later onset and X-linked inheritance (see
Forms of Spondyloepiphyseal Dysplasia of Interest in the Differential Diagnosis of X-Linked Spondyloepiphyseal Dysplasia Tarda
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; MPS = mucopolysaccharidosis; SED = spondyloepiphyseal dysplasia; SEDT = spondyloepiphyseal dysplasia tarda
Rare instances of autosomal recessive inheritance in SEDC have been reported (see
Stickler syndrome caused by pathogenic variants in
## Management
To establish the extent of disease and needs in an individual diagnosed with X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with X-linked Spondyloepiphyseal Dysplasia Tarda
Flexion-extension radiographs of cervical spine
Flexion-extension MRI if instability & compression seen on radiographs or interpretation on radiographs is limited (e.g., in young persons w/delayed ossification in upper cervical spine)
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with X-linked Spondyloepiphyseal Dysplasia Tarda
Treatment per orthopedic surgeon
Spine surgery (correction of scoliosis or kyphosis) may be indicated.
Chronic pain management
Surgical intervention may incl joint replacement (hip, knee, shoulder).
Recommended Surveillance for Individuals with X-linked Spondyloepiphyseal Dysplasia Tarda
The following should be avoided:
In individuals with odontoid hypoplasia, extreme neck flexion and extension
Activities and occupations that place undue stress on the spine and weight-bearing joints
If the
See
Search
• Flexion-extension radiographs of cervical spine
• Flexion-extension MRI if instability & compression seen on radiographs or interpretation on radiographs is limited (e.g., in young persons w/delayed ossification in upper cervical spine)
• Treatment per orthopedic surgeon
• Spine surgery (correction of scoliosis or kyphosis) may be indicated.
• Chronic pain management
• Surgical intervention may incl joint replacement (hip, knee, shoulder).
• In individuals with odontoid hypoplasia, extreme neck flexion and extension
• Activities and occupations that place undue stress on the spine and weight-bearing joints
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with X-linked Spondyloepiphyseal Dysplasia Tarda
Flexion-extension radiographs of cervical spine
Flexion-extension MRI if instability & compression seen on radiographs or interpretation on radiographs is limited (e.g., in young persons w/delayed ossification in upper cervical spine)
MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Flexion-extension radiographs of cervical spine
• Flexion-extension MRI if instability & compression seen on radiographs or interpretation on radiographs is limited (e.g., in young persons w/delayed ossification in upper cervical spine)
## Treatment of Manifestations
Treatment of Manifestations in Individuals with X-linked Spondyloepiphyseal Dysplasia Tarda
Treatment per orthopedic surgeon
Spine surgery (correction of scoliosis or kyphosis) may be indicated.
Chronic pain management
Surgical intervention may incl joint replacement (hip, knee, shoulder).
• Treatment per orthopedic surgeon
• Spine surgery (correction of scoliosis or kyphosis) may be indicated.
• Chronic pain management
• Surgical intervention may incl joint replacement (hip, knee, shoulder).
## Surveillance
Recommended Surveillance for Individuals with X-linked Spondyloepiphyseal Dysplasia Tarda
## Agents/Circumstances to Avoid
The following should be avoided:
In individuals with odontoid hypoplasia, extreme neck flexion and extension
Activities and occupations that place undue stress on the spine and weight-bearing joints
• In individuals with odontoid hypoplasia, extreme neck flexion and extension
• Activities and occupations that place undue stress on the spine and weight-bearing joints
## Evaluation of Relatives at Risk
If the
See
## Therapies Under Investigation
Search
## Genetic Counseling
By definition, X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT) is inherited in an X-linked manner.
The father of a male proband with X-linked SEDT will not have the disorder nor will he be hemizygous for the causative pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her DNA, she most likely has germline mosaicism. Although no instances of maternal germline mosaicism have been reported, it remains a possibility.
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
In reported individuals for whom molecular genetic testing was available in a research laboratory, all mothers of affected sons were carriers of a
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 carriers and will usually not be affected (see
If the proband represents a simplex case and if the
Identification of female heterozygotes requires either prior identification of the
Note: Females who are heterozygotes (carriers) for X-linked SEDT may develop minimal clinical findings related to the disorder [
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 affected, are carriers, or are at risk of being carriers.
Once the X-linked SEDT-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 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 with X-linked SEDT will not have the disorder nor will he be hemizygous for the causative pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her DNA, she most likely has germline mosaicism. Although no instances of maternal germline mosaicism have been reported, it remains a possibility.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
• In reported individuals for whom molecular genetic testing was available in a research laboratory, all mothers of affected sons were carriers of a
• 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 carriers and will usually not be affected (see
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be carriers and will usually not be affected (see
• 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 carriers and will usually not be affected (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 affected, are carriers, or are at risk of being carriers.
## Mode of Inheritance
By definition, X-linked spondyloepiphyseal dysplasia tarda (X-linked SEDT) is inherited in an X-linked manner.
## Risk to Family Members
The father of a male proband with X-linked SEDT will not have the disorder nor will he be hemizygous for the causative pathogenic variant; therefore, he does not require further evaluation/testing.
In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her DNA, she most likely has germline mosaicism. Although no instances of maternal germline mosaicism have been reported, it remains a possibility.
If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
In reported individuals for whom molecular genetic testing was available in a research laboratory, all mothers of affected sons were carriers of a
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 carriers and will usually not be affected (see
If the proband represents a simplex case and if the
• The father of a male proband with X-linked SEDT will not have the disorder nor will he be hemizygous for the causative pathogenic variant; therefore, he does not require further evaluation/testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier. Note: If a woman has more than one affected child and no other affected relatives and if the familial pathogenic variant cannot be detected in her DNA, she most likely has germline mosaicism. Although no instances of maternal germline mosaicism have been reported, it remains a possibility.
• If a male is the only affected family member (i.e., a simplex case), the mother may be a carrier or the affected male may have a
• In reported individuals for whom molecular genetic testing was available in a research laboratory, all mothers of affected sons were carriers of a
• 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 carriers and will usually not be affected (see
• Males who inherit the pathogenic variant will be affected;
• Females who inherit the pathogenic variant will be carriers and will usually not be affected (see
• 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 carriers and will usually not be affected (see
## Carrier Detection
Identification of female heterozygotes requires either prior identification of the
Note: Females who are heterozygotes (carriers) for X-linked SEDT may develop minimal clinical findings related to the disorder [
## 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 affected, are carriers, or are at risk of being carriers.
• 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 affected, are carriers, or are at risk of being carriers.
## Prenatal Testing and Preimplantation Genetic Testing
Once the X-linked SEDT-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 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
X-Linked Spondyloepiphyseal Dysplasia Tarda: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for X-Linked Spondyloepiphyseal Dysplasia Tarda (
Notable Recurrent
Variants listed in the table have been provided by the author.
## Molecular Pathogenesis
Notable Recurrent
Variants listed in the table have been provided by the author.
## Chapter Notes
George E Tiller, MD, PhD (2001-present)Vickie L Hannig, MS; Vanderbilt University Medical Center (2001-2020)
6 April 2023 (sw) Revision: "
5 November 2020 (sw) Comprehensive update posted live
11 June 2015 (me) Comprehensive update posted live
15 February 2011 (me) Comprehensive update posted live
5 April 2006 (me) Comprehensive update posted live
10 February 2004 (me) Comprehensive update posted live
30 December 2003 (cd) Revision: change in test availability
1 November 2001 (me) Review posted live
16 May 2001 (gt) Original submission
• 6 April 2023 (sw) Revision: "
• 5 November 2020 (sw) Comprehensive update posted live
• 11 June 2015 (me) Comprehensive update posted live
• 15 February 2011 (me) Comprehensive update posted live
• 5 April 2006 (me) Comprehensive update posted live
• 10 February 2004 (me) Comprehensive update posted live
• 30 December 2003 (cd) Revision: change in test availability
• 1 November 2001 (me) Review posted live
• 16 May 2001 (gt) Original submission
## Author History
George E Tiller, MD, PhD (2001-present)Vickie L Hannig, MS; Vanderbilt University Medical Center (2001-2020)
## Revision History
6 April 2023 (sw) Revision: "
5 November 2020 (sw) Comprehensive update posted live
11 June 2015 (me) Comprehensive update posted live
15 February 2011 (me) Comprehensive update posted live
5 April 2006 (me) Comprehensive update posted live
10 February 2004 (me) Comprehensive update posted live
30 December 2003 (cd) Revision: change in test availability
1 November 2001 (me) Review posted live
16 May 2001 (gt) Original submission
• 6 April 2023 (sw) Revision: "
• 5 November 2020 (sw) Comprehensive update posted live
• 11 June 2015 (me) Comprehensive update posted live
• 15 February 2011 (me) Comprehensive update posted live
• 5 April 2006 (me) Comprehensive update posted live
• 10 February 2004 (me) Comprehensive update posted live
• 30 December 2003 (cd) Revision: change in test availability
• 1 November 2001 (me) Review posted live
• 16 May 2001 (gt) Original submission
## References
## Literature Cited
Radiographs of a male age 31 years with SEDT
A. Platyspondyly with superior and inferior humping of vertebral bodies
B. Severe degenerative changes in both hip joints.
|
[
"J Fiedler, M Le Merrer, G Mortier, S Heuertz, L Faivre, RE Brenner. X-linked spondyloepiphyseal dysplasia tarda: Novel and recurrent mutations in 13 European families.. Hum Mutat 2004;24:103",
"J Gécz, MA Hillman, AK Gedeon, TC Cox, E Baker, JC Mulley. Gene structure and expression study of the SEDL gene for spondyloepiphyseal dysplasia tarda.. Genomics 2000;69:242-51",
"AK Gedeon, A Colley, R Jamieson, EM Thompson, J Rogers, D Sillence, GE Tiller, JC Mulley, J Gecz. Identification of the gene (SEDL) causing X-linked spondyloepiphyseal dysplasia tarda.. Nat Genet 1999;22:400-4",
"AK Gedeon, GE Tiller, M Le Merrer, S Heuertz, L Tranebjaerg, D Chitayat, S Robertson, IA Glass, R Savarirayan, WG Cole, DL Rimoin, BG Kousseff, H Ohashi, B Zabel, A Munnich, J Gecz, JC Mulley. The molecular basis of X-linked spondyloepiphyseal dysplasia tarda.. Am J Hum Genet 2001;68:1386-97",
"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",
"Y Matsui, N Yasui, K Ozono, M Yamagata, H Kawabata, H Yoshikawa. Loss of the SEDL gene product (Sedlin) causes X-linked spondyloepiphyseal dysplasia tarda: Identification of a molecular defect in a Japanese family.. Am J Med Genet 2001;99:328-30",
"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",
"MA Shaw, N Brunetti-Pierri, L Kadasi, V Kovacova, L Van Maldergem, D De Brasi, M Salerno, J Gecz. Identification of three novel SEDL mutations, including mutation in the rare, non-canonical splice site of exon 4.. Clin Genet 2003;64:235-42",
"SG Shu, CR Tsai, CS Chi. Spondyloepiphyseal dysplasia tarda: report of one case.. Acta Paediatr Taiwan 2002;43:106-8",
"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",
"GE Tiller, VL Hannig, D Dozier, L Carrel, KC Trevarthen, WR Wilcox, S Mundlos, JL Haines, AK Gedeon, J Gecz. A recurrent RNA-splicing mutation in the SEDL gene causes X-linked spondyloepiphyseal dysplasia tarda.. Am J Hum Genet 2001;68:1398-407",
"S Unger, CR Ferreira, GR Mortier, H Ali, DR Bertola, A Calder, DH Cohn, V Cormier-Daire, KM Girisha, C Hall, D Krakow, O Makitie, S Mundlos, G Nishimura, SP Robertson, R Savarirayan, D Sillence, M Simon, VR Sutton, ML Warman, A Superti-Furga. Nosology of genetic skeletal disorders: 2023 revision.. Am J Med Genet A. 2023",
"R Venditti, T Scanu, M Santoro, G Di Tullio, A Spaar, R Gaibisso, GV Beznoussenko, AA Mironov, A Mironov, L Zelante, MR Piemontese, A Notarangelo, V Malhotra, BM Vertel, C Wilson, MA De Matteis. Sedlin controls the ER export of procollagen by regulating the Sar1 cycle.. Science 2012;337:1668-72",
"MP Whyte, GS Gottesman, MC Eddy, WH McAlister. X-linked recessive spondyloepiphyseal dysplasia tarda. Clinical and radiographic evolution in a 6-generation kindred and review of the literature.. Medicine (Baltimore) 1999;78:9-25",
"R Wynne-Davies, J Gormley. The prevalence of skeletal dysplasias. An estimate of their minimum frequency and the number of patients requiring orthopaedic care.. J Bone Joint Surg Br 1985;67:133-7"
] |
1/11/2001
|
5/11/2020
|
6/4/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
serine-def
|
serine-def
|
[
"Serine Biosynthesis Disorders",
"Serine Synthesis Disorders",
"Serine Biosynthesis Disorders",
"Serine Synthesis Disorders",
"Neu-Laxova Syndrome",
"D-3-phosphoglycerate dehydrogenase",
"Phosphoserine aminotransferase",
"Phosphoserine phosphatase",
"PHGDH",
"PSAT1",
"PSPH",
"Serine Deficiency Disorders"
] |
Serine Deficiency Disorders
|
Saskia N van der Crabben, Tom J de Koning
|
Summary Serine deficiency disorders include a spectrum of disease ranging from lethal prenatal-onset Neu-Laxova syndrome to serine deficiency with infantile, juvenile, or adult onset. Neu-Laxova syndrome is characterized by severe intrauterine growth deficiency, microcephaly, congenital bilateral cataracts, characteristic dysmorphic features, limb anomalies, and collodion-like ichthyosis. Infants are typically stillborn or die in early infancy. Infantile-onset serine deficiency is characterized by seizures, microcephaly, developmental delay, intellectual disability, and spastic quadriplegia. Individuals that present with juvenile-onset serine deficiency have seizures and many develop spastic quadriplegia. Adult-onset serine deficiency is characterized by progressive axonal polyneuropathy with ataxia and possible cognitive impairment. The diagnosis of a serine deficiency disorder is established in a proband with biallelic pathogenic variants in Serine deficiency disorders are inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a serine deficiency-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 inheriting neither of the familial pathogenic variants. Once the serine deficiency-causing pathogenic variants have been identified in an affected family member, carrier testing for at-risk relatives and prenatal and preimplantation genetic testing are possible.
|
Serine Deficiency Disorders: Phenotypic Spectrum
Infantile-onset phenotype: severe neurodevelopmental disorder w/epilepsy & microcephaly
Juvenile-onset phenotype: developmental & behavioral issues & epilepsy
Adult-onset phenotype: progressive axonal neuropathy, variable ataxia &/or cognitive impairment
For other genetic causes of these phenotypes, see
• Infantile-onset phenotype: severe neurodevelopmental disorder w/epilepsy & microcephaly
• Juvenile-onset phenotype: developmental & behavioral issues & epilepsy
• Adult-onset phenotype: progressive axonal neuropathy, variable ataxia &/or cognitive impairment
## Diagnosis
No consensus clinical diagnostic criteria for serine deficiency disorders have been published.
A serine deficiency disorder
Severe intrauterine growth deficiency
Microcephaly
Congenital bilateral cataracts
Dysmorphic features: sloping forehead, proptosis or short palpebral fissures with absent or abnormal eyelids, edematous and/or low-set or malformed ears, depressed nasal ridge, fixed narrow mouth with edematous lips, micrognathia, cleft palate, and short neck
Thin, transparent, and tight skin with collodion-like ichthyosis
Limb anomalies: short limbs, flexion contractures, cutaneous syndactyly, edematous hands and feet, rocker-bottom feet
Neural tube defects
Brain MRI findings: cortical dysplasia with gyral simplification (anterior more than posterior), enlarged ventricles, decreased white matter, and structural abnormalities of the cerebellum [
Seizures
Microcephaly (congenital or postnatal)
Developmental delay
Severe intellectual disability
Spastic quadriplegia
Growth deficiency (prenatal and/or postnatal)
Ocular manifestations: nystagmus, congenital bilateral cataracts
Ichthyosis
Brain MRI findings: severe hypomyelination, white matter attenuation and delayed myelination, nonspecific cerebellar abnormalities
Seizures
Developmental delay
Intellectual disability
Behavioral disorders
Normal brain MRI [
Progressive polyneuropathy
Ataxia in some individuals
Mild cognitive impairment in some individuals
Normal brain MRI [
Cerebrospinal fluid (CSF) serine is very low, usually <13 umol/L, and in most individuals <10 umol/L [
Fasting plasma serine is low, but nonfasting samples can be normal.
CSF 5-methyltetrahydrofolate is very low [
CSF glycine is low to normal; fasting plasma glycine can be low to normal.
Urine amino acids are noninformative; results are usually normal.
Note: Use age-specific reference ranges for CSF and plasma serine; normal serine levels are significantly higher between birth and age three months [
The diagnosis of a serine deficiency disorder
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 Serine Deficiency Disorders
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.
Authors, unpublished data
Data derived from the subscription-based professional view of Human Gene Mutation Database [
To date, large deletions/duplications in
In those with variants of uncertain significance identified on molecular genetic testing, the diagnosis of a serine deficiency disorder can be established by identification of low D-3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase, or phosphoserine phosphatase enzymatic activity. However, due to decreased availability of substrates for the enzymatic reactions, this testing is no longer routinely available.
•
• Severe intrauterine growth deficiency
• Microcephaly
• Congenital bilateral cataracts
• Dysmorphic features: sloping forehead, proptosis or short palpebral fissures with absent or abnormal eyelids, edematous and/or low-set or malformed ears, depressed nasal ridge, fixed narrow mouth with edematous lips, micrognathia, cleft palate, and short neck
• Thin, transparent, and tight skin with collodion-like ichthyosis
• Limb anomalies: short limbs, flexion contractures, cutaneous syndactyly, edematous hands and feet, rocker-bottom feet
• Neural tube defects
• Brain MRI findings: cortical dysplasia with gyral simplification (anterior more than posterior), enlarged ventricles, decreased white matter, and structural abnormalities of the cerebellum [
• Severe intrauterine growth deficiency
• Microcephaly
• Congenital bilateral cataracts
• Dysmorphic features: sloping forehead, proptosis or short palpebral fissures with absent or abnormal eyelids, edematous and/or low-set or malformed ears, depressed nasal ridge, fixed narrow mouth with edematous lips, micrognathia, cleft palate, and short neck
• Thin, transparent, and tight skin with collodion-like ichthyosis
• Limb anomalies: short limbs, flexion contractures, cutaneous syndactyly, edematous hands and feet, rocker-bottom feet
• Neural tube defects
• Brain MRI findings: cortical dysplasia with gyral simplification (anterior more than posterior), enlarged ventricles, decreased white matter, and structural abnormalities of the cerebellum [
•
• Seizures
• Microcephaly (congenital or postnatal)
• Developmental delay
• Severe intellectual disability
• Spastic quadriplegia
• Growth deficiency (prenatal and/or postnatal)
• Ocular manifestations: nystagmus, congenital bilateral cataracts
• Ichthyosis
• Brain MRI findings: severe hypomyelination, white matter attenuation and delayed myelination, nonspecific cerebellar abnormalities
• Seizures
• Microcephaly (congenital or postnatal)
• Developmental delay
• Severe intellectual disability
• Spastic quadriplegia
• Growth deficiency (prenatal and/or postnatal)
• Ocular manifestations: nystagmus, congenital bilateral cataracts
• Ichthyosis
• Brain MRI findings: severe hypomyelination, white matter attenuation and delayed myelination, nonspecific cerebellar abnormalities
•
• Seizures
• Developmental delay
• Intellectual disability
• Behavioral disorders
• Normal brain MRI [
• Seizures
• Developmental delay
• Intellectual disability
• Behavioral disorders
• Normal brain MRI [
•
• Progressive polyneuropathy
• Ataxia in some individuals
• Mild cognitive impairment in some individuals
• Normal brain MRI [
• Progressive polyneuropathy
• Ataxia in some individuals
• Mild cognitive impairment in some individuals
• Normal brain MRI [
• Severe intrauterine growth deficiency
• Microcephaly
• Congenital bilateral cataracts
• Dysmorphic features: sloping forehead, proptosis or short palpebral fissures with absent or abnormal eyelids, edematous and/or low-set or malformed ears, depressed nasal ridge, fixed narrow mouth with edematous lips, micrognathia, cleft palate, and short neck
• Thin, transparent, and tight skin with collodion-like ichthyosis
• Limb anomalies: short limbs, flexion contractures, cutaneous syndactyly, edematous hands and feet, rocker-bottom feet
• Neural tube defects
• Brain MRI findings: cortical dysplasia with gyral simplification (anterior more than posterior), enlarged ventricles, decreased white matter, and structural abnormalities of the cerebellum [
• Seizures
• Microcephaly (congenital or postnatal)
• Developmental delay
• Severe intellectual disability
• Spastic quadriplegia
• Growth deficiency (prenatal and/or postnatal)
• Ocular manifestations: nystagmus, congenital bilateral cataracts
• Ichthyosis
• Brain MRI findings: severe hypomyelination, white matter attenuation and delayed myelination, nonspecific cerebellar abnormalities
• Seizures
• Developmental delay
• Intellectual disability
• Behavioral disorders
• Normal brain MRI [
• Progressive polyneuropathy
• Ataxia in some individuals
• Mild cognitive impairment in some individuals
• Normal brain MRI [
• Cerebrospinal fluid (CSF) serine is very low, usually <13 umol/L, and in most individuals <10 umol/L [
• Fasting plasma serine is low, but nonfasting samples can be normal.
• CSF 5-methyltetrahydrofolate is very low [
• CSF glycine is low to normal; fasting plasma glycine can be low to normal.
• Urine amino acids are noninformative; results are usually normal.
## Suggestive Findings
A serine deficiency disorder
Severe intrauterine growth deficiency
Microcephaly
Congenital bilateral cataracts
Dysmorphic features: sloping forehead, proptosis or short palpebral fissures with absent or abnormal eyelids, edematous and/or low-set or malformed ears, depressed nasal ridge, fixed narrow mouth with edematous lips, micrognathia, cleft palate, and short neck
Thin, transparent, and tight skin with collodion-like ichthyosis
Limb anomalies: short limbs, flexion contractures, cutaneous syndactyly, edematous hands and feet, rocker-bottom feet
Neural tube defects
Brain MRI findings: cortical dysplasia with gyral simplification (anterior more than posterior), enlarged ventricles, decreased white matter, and structural abnormalities of the cerebellum [
Seizures
Microcephaly (congenital or postnatal)
Developmental delay
Severe intellectual disability
Spastic quadriplegia
Growth deficiency (prenatal and/or postnatal)
Ocular manifestations: nystagmus, congenital bilateral cataracts
Ichthyosis
Brain MRI findings: severe hypomyelination, white matter attenuation and delayed myelination, nonspecific cerebellar abnormalities
Seizures
Developmental delay
Intellectual disability
Behavioral disorders
Normal brain MRI [
Progressive polyneuropathy
Ataxia in some individuals
Mild cognitive impairment in some individuals
Normal brain MRI [
Cerebrospinal fluid (CSF) serine is very low, usually <13 umol/L, and in most individuals <10 umol/L [
Fasting plasma serine is low, but nonfasting samples can be normal.
CSF 5-methyltetrahydrofolate is very low [
CSF glycine is low to normal; fasting plasma glycine can be low to normal.
Urine amino acids are noninformative; results are usually normal.
Note: Use age-specific reference ranges for CSF and plasma serine; normal serine levels are significantly higher between birth and age three months [
•
• Severe intrauterine growth deficiency
• Microcephaly
• Congenital bilateral cataracts
• Dysmorphic features: sloping forehead, proptosis or short palpebral fissures with absent or abnormal eyelids, edematous and/or low-set or malformed ears, depressed nasal ridge, fixed narrow mouth with edematous lips, micrognathia, cleft palate, and short neck
• Thin, transparent, and tight skin with collodion-like ichthyosis
• Limb anomalies: short limbs, flexion contractures, cutaneous syndactyly, edematous hands and feet, rocker-bottom feet
• Neural tube defects
• Brain MRI findings: cortical dysplasia with gyral simplification (anterior more than posterior), enlarged ventricles, decreased white matter, and structural abnormalities of the cerebellum [
• Severe intrauterine growth deficiency
• Microcephaly
• Congenital bilateral cataracts
• Dysmorphic features: sloping forehead, proptosis or short palpebral fissures with absent or abnormal eyelids, edematous and/or low-set or malformed ears, depressed nasal ridge, fixed narrow mouth with edematous lips, micrognathia, cleft palate, and short neck
• Thin, transparent, and tight skin with collodion-like ichthyosis
• Limb anomalies: short limbs, flexion contractures, cutaneous syndactyly, edematous hands and feet, rocker-bottom feet
• Neural tube defects
• Brain MRI findings: cortical dysplasia with gyral simplification (anterior more than posterior), enlarged ventricles, decreased white matter, and structural abnormalities of the cerebellum [
•
• Seizures
• Microcephaly (congenital or postnatal)
• Developmental delay
• Severe intellectual disability
• Spastic quadriplegia
• Growth deficiency (prenatal and/or postnatal)
• Ocular manifestations: nystagmus, congenital bilateral cataracts
• Ichthyosis
• Brain MRI findings: severe hypomyelination, white matter attenuation and delayed myelination, nonspecific cerebellar abnormalities
• Seizures
• Microcephaly (congenital or postnatal)
• Developmental delay
• Severe intellectual disability
• Spastic quadriplegia
• Growth deficiency (prenatal and/or postnatal)
• Ocular manifestations: nystagmus, congenital bilateral cataracts
• Ichthyosis
• Brain MRI findings: severe hypomyelination, white matter attenuation and delayed myelination, nonspecific cerebellar abnormalities
•
• Seizures
• Developmental delay
• Intellectual disability
• Behavioral disorders
• Normal brain MRI [
• Seizures
• Developmental delay
• Intellectual disability
• Behavioral disorders
• Normal brain MRI [
•
• Progressive polyneuropathy
• Ataxia in some individuals
• Mild cognitive impairment in some individuals
• Normal brain MRI [
• Progressive polyneuropathy
• Ataxia in some individuals
• Mild cognitive impairment in some individuals
• Normal brain MRI [
• Severe intrauterine growth deficiency
• Microcephaly
• Congenital bilateral cataracts
• Dysmorphic features: sloping forehead, proptosis or short palpebral fissures with absent or abnormal eyelids, edematous and/or low-set or malformed ears, depressed nasal ridge, fixed narrow mouth with edematous lips, micrognathia, cleft palate, and short neck
• Thin, transparent, and tight skin with collodion-like ichthyosis
• Limb anomalies: short limbs, flexion contractures, cutaneous syndactyly, edematous hands and feet, rocker-bottom feet
• Neural tube defects
• Brain MRI findings: cortical dysplasia with gyral simplification (anterior more than posterior), enlarged ventricles, decreased white matter, and structural abnormalities of the cerebellum [
• Seizures
• Microcephaly (congenital or postnatal)
• Developmental delay
• Severe intellectual disability
• Spastic quadriplegia
• Growth deficiency (prenatal and/or postnatal)
• Ocular manifestations: nystagmus, congenital bilateral cataracts
• Ichthyosis
• Brain MRI findings: severe hypomyelination, white matter attenuation and delayed myelination, nonspecific cerebellar abnormalities
• Seizures
• Developmental delay
• Intellectual disability
• Behavioral disorders
• Normal brain MRI [
• Progressive polyneuropathy
• Ataxia in some individuals
• Mild cognitive impairment in some individuals
• Normal brain MRI [
• Cerebrospinal fluid (CSF) serine is very low, usually <13 umol/L, and in most individuals <10 umol/L [
• Fasting plasma serine is low, but nonfasting samples can be normal.
• CSF 5-methyltetrahydrofolate is very low [
• CSF glycine is low to normal; fasting plasma glycine can be low to normal.
• Urine amino acids are noninformative; results are usually normal.
## Establishing the Diagnosis
The diagnosis of a serine deficiency disorder
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 Serine Deficiency Disorders
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.
Authors, unpublished data
Data derived from the subscription-based professional view of Human Gene Mutation Database [
To date, large deletions/duplications in
In those with variants of uncertain significance identified on molecular genetic testing, the diagnosis of a serine deficiency disorder can be established by identification of low D-3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase, or phosphoserine phosphatase enzymatic activity. However, due to decreased availability of substrates for the enzymatic reactions, this testing is no longer routinely available.
## 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
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Serine Deficiency Disorders
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.
Authors, unpublished data
Data derived from the subscription-based professional view of Human Gene Mutation Database [
To date, large deletions/duplications in
##
For an introduction to multigene panels click
##
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Serine Deficiency Disorders
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.
Authors, unpublished data
Data derived from the subscription-based professional view of Human Gene Mutation Database [
To date, large deletions/duplications in
## Other Testing
In those with variants of uncertain significance identified on molecular genetic testing, the diagnosis of a serine deficiency disorder can be established by identification of low D-3-phosphoglycerate dehydrogenase, phosphoserine aminotransferase, or phosphoserine phosphatase enzymatic activity. However, due to decreased availability of substrates for the enzymatic reactions, this testing is no longer routinely available.
## Clinical Characteristics
Serine deficiency disorders include a spectrum of disease ranging from lethal prenatal-onset Neu-Laxova syndrome to adult-onset serine deficiency characterized by progressive polyneuropathy. Several clinical phenotypes can be identified: prenatal onset, infantile onset, juvenile onset, and adult onset. To date, more than 50 individuals have been identified with biallelic pathogenic variants in
Neu-Laxova syndrome is characterized by severe intrauterine growth deficiency, decreased or absent fetal movements, microcephaly, congenital bilateral cataracts, and ichthyosis [
Seizures are refractory to anti-seizure medications in almost all individuals. Some individuals have up to 60-70 clinically evident tonic-clonic seizures a day. In all individuals, seizures significantly improve upon treatment with L-serine; many become seizure free, decreasing the need for chronic anti-seizure medications. Improvement in EEG abnormalities may not occur until after six months of L-serine treatment [Authors, personal observations].
Individuals treated with L-serine prenatally or immediately after birth have normal developmental outcomes [
After initiation of L-serine treatment, well-being improves rapidly, with decreased irritability and improved feeding. However, infants that were symptomatic prior to L-serine treatment continue to have severe neurologic symptoms impacting feeding and weight gain.
Individuals with adult-onset serine deficiency present with progressive axonal polyneuropathy (resembling Charcot-Marie-Tooth disease type 2 on EMG).
Some adults were reported to have ataxia [
In adult-onset serine deficiency, individuals had normal cognitive function to mild cognitive impairment.
Individuals treated with L-serine for many years can develop psychiatric symptoms when L-serine supplements are discontinued [Author, personal communication].
One adult who presented with progressive polyneuropathy and progressive motor disability had surgical treatment for bilateral congenital cataracts at age three months [
The following have been reported in only a limited number of affected individuals: adducted thumbs, inguinal and umbilical hernias, hypogonadism, megaloblastic anemia, and generalized ichthyosis. These features may be seen in individuals with any of the phenotypes [Authors, personal communication].
There is no correlation between the gene involved and the clinical phenotype. All phenotypes (lethal prenatal onset to adult onset) can be observed in individuals with pathogenic variants in
No clear genotype-phenotype correlations for
Preliminary conclusions regarding possible genotype-phenotype correlations for
The prevalence of serine deficiency disorders is not known. It is estimated that there are more than 50 affected individuals reported.
## Clinical Description
Serine deficiency disorders include a spectrum of disease ranging from lethal prenatal-onset Neu-Laxova syndrome to adult-onset serine deficiency characterized by progressive polyneuropathy. Several clinical phenotypes can be identified: prenatal onset, infantile onset, juvenile onset, and adult onset. To date, more than 50 individuals have been identified with biallelic pathogenic variants in
Neu-Laxova syndrome is characterized by severe intrauterine growth deficiency, decreased or absent fetal movements, microcephaly, congenital bilateral cataracts, and ichthyosis [
Seizures are refractory to anti-seizure medications in almost all individuals. Some individuals have up to 60-70 clinically evident tonic-clonic seizures a day. In all individuals, seizures significantly improve upon treatment with L-serine; many become seizure free, decreasing the need for chronic anti-seizure medications. Improvement in EEG abnormalities may not occur until after six months of L-serine treatment [Authors, personal observations].
Individuals treated with L-serine prenatally or immediately after birth have normal developmental outcomes [
After initiation of L-serine treatment, well-being improves rapidly, with decreased irritability and improved feeding. However, infants that were symptomatic prior to L-serine treatment continue to have severe neurologic symptoms impacting feeding and weight gain.
Individuals with adult-onset serine deficiency present with progressive axonal polyneuropathy (resembling Charcot-Marie-Tooth disease type 2 on EMG).
Some adults were reported to have ataxia [
In adult-onset serine deficiency, individuals had normal cognitive function to mild cognitive impairment.
Individuals treated with L-serine for many years can develop psychiatric symptoms when L-serine supplements are discontinued [Author, personal communication].
One adult who presented with progressive polyneuropathy and progressive motor disability had surgical treatment for bilateral congenital cataracts at age three months [
The following have been reported in only a limited number of affected individuals: adducted thumbs, inguinal and umbilical hernias, hypogonadism, megaloblastic anemia, and generalized ichthyosis. These features may be seen in individuals with any of the phenotypes [Authors, personal communication].
## Neu-Laxova Syndrome (Prenatal Onset)
Neu-Laxova syndrome is characterized by severe intrauterine growth deficiency, decreased or absent fetal movements, microcephaly, congenital bilateral cataracts, and ichthyosis [
## Infantile-Onset Serine Deficiency
Seizures are refractory to anti-seizure medications in almost all individuals. Some individuals have up to 60-70 clinically evident tonic-clonic seizures a day. In all individuals, seizures significantly improve upon treatment with L-serine; many become seizure free, decreasing the need for chronic anti-seizure medications. Improvement in EEG abnormalities may not occur until after six months of L-serine treatment [Authors, personal observations].
Individuals treated with L-serine prenatally or immediately after birth have normal developmental outcomes [
After initiation of L-serine treatment, well-being improves rapidly, with decreased irritability and improved feeding. However, infants that were symptomatic prior to L-serine treatment continue to have severe neurologic symptoms impacting feeding and weight gain.
## Juvenile-Onset Serine Deficiency
## Adult-Onset Serine Deficiency
Individuals with adult-onset serine deficiency present with progressive axonal polyneuropathy (resembling Charcot-Marie-Tooth disease type 2 on EMG).
Some adults were reported to have ataxia [
In adult-onset serine deficiency, individuals had normal cognitive function to mild cognitive impairment.
Individuals treated with L-serine for many years can develop psychiatric symptoms when L-serine supplements are discontinued [Author, personal communication].
One adult who presented with progressive polyneuropathy and progressive motor disability had surgical treatment for bilateral congenital cataracts at age three months [
## Other
The following have been reported in only a limited number of affected individuals: adducted thumbs, inguinal and umbilical hernias, hypogonadism, megaloblastic anemia, and generalized ichthyosis. These features may be seen in individuals with any of the phenotypes [Authors, personal communication].
## Phenotype Correlations by Gene
There is no correlation between the gene involved and the clinical phenotype. All phenotypes (lethal prenatal onset to adult onset) can be observed in individuals with pathogenic variants in
## Genotype-Phenotype Correlations
No clear genotype-phenotype correlations for
Preliminary conclusions regarding possible genotype-phenotype correlations for
## Prevalence
The prevalence of serine deficiency disorders is not known. It is estimated that there are more than 50 affected individuals reported.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
ASCT1 transporter deficiency, GOT2 deficiency, and other selected disorders with clinical and/or biochemical features that may resemble serine deficiency disorders are summarized in
Note: Given the first step in the synthesis of L-serine is an oxidation-reduction (redox) reaction (see
Genetic Disorders in the Differential Diagnosis of Serine Deficiency Disorders
Considerable phenotypic overlap w/serine deficiency disorders. Assoc w/DD, microcephaly, spastic tetraplegia, & variable seizures (infantile form may or may not be assoc w/seizures
Hypomyelination & thin corpus callosum on MRI
No associated biochemical abnormalities
Note: As ASCT1 is the major transporter for L-serine in brain tissue, it is possible that a defect of ASCT1 leads to an intracellular deficiency of L-serine.
Early-onset encephalopathy w/progressive microcephaly & early-onset seizures (seizures are pyridoxine & L-serine responsive).
Atrophy & white matter abnormalities w/thin corpus callosum on MRI
Inhibited synthesis of serine results in secondary serine deficiency.
In addition, citrulline may be ↑ & ammonia & lactate are mildly ↑.
Infants w/classic Menkes disease appear healthy until age 1.5-3 mos, when loss of developmental milestones, hypotonia, seizures, & poor weight gain occur. Diagnosis is usually suspected when infants exhibit neurologic findings & characteristic hair changes.
Cerebral & cerebellar atrophy w/ventriculomegaly, delayed myelination, & vascular tortuosity on brain MRI
AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; MOI = mode of inheritance; XL = X-linked
Authors, personal observations
See OMIM Phenotypic Series:
• Considerable phenotypic overlap w/serine deficiency disorders. Assoc w/DD, microcephaly, spastic tetraplegia, & variable seizures (infantile form may or may not be assoc w/seizures
• Hypomyelination & thin corpus callosum on MRI
• No associated biochemical abnormalities
• Note: As ASCT1 is the major transporter for L-serine in brain tissue, it is possible that a defect of ASCT1 leads to an intracellular deficiency of L-serine.
• Early-onset encephalopathy w/progressive microcephaly & early-onset seizures (seizures are pyridoxine & L-serine responsive).
• Atrophy & white matter abnormalities w/thin corpus callosum on MRI
• Inhibited synthesis of serine results in secondary serine deficiency.
• In addition, citrulline may be ↑ & ammonia & lactate are mildly ↑.
• Infants w/classic Menkes disease appear healthy until age 1.5-3 mos, when loss of developmental milestones, hypotonia, seizures, & poor weight gain occur. Diagnosis is usually suspected when infants exhibit neurologic findings & characteristic hair changes.
• Cerebral & cerebellar atrophy w/ventriculomegaly, delayed myelination, & vascular tortuosity on brain MRI
## Management
No clinical practice guidelines for serine deficiency disorders have been published.
To establish the extent of disease and needs in an individual diagnosed with a serine deficiency disorder, the evaluations summarized in
Serine Deficiency Disorders: Recommended Evaluations Following Initial Diagnosis
Neurologic eval
EEG
To incl brain MRI
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.
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)
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
High doses of L-serine are needed to correct the serine deficiency and obtain serine values within the reference ranges in plasma and cerebrospinal fluid (CSF). For young individuals, L-serine doses up to 500-700 mg/kg/day are usually needed to correct the deficiency and obtain satisfactory treatment results.
Usually, L-serine therapy is started at 200-400 mg/kg/day (given orally and divided into 4-6 doses), because in some individuals, transient acoustic startles and myoclonus were observed with larger doses.
The L-serine dose is gradually increased to 500-700 mg/kg/day. A dose of 400 mg/kg/day was insufficient to prevent recurrence of seizures [Authors, personal observations].
In some individuals who did not have a satisfactory response, glycine (200 mg/kg/day given orally and divided into 4-6 doses) was added to L-serine treatment.
In adolescents and adults, lower L-serine doses can be used (100-150 mg/kg/day).
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
Serine Deficiency Disorders: Treatment of Manifestations
See
Standardized treatment w/ASM by experienced neurologist
Treatment w/ASM may not be required after adequate response to L-serine therapy.
Many ASMs may prove to be ineffective; none has been demonstrated effective specifically for this disorder, except L-serine therapy.
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.
Provide family support in transition to adult care.
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 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 consultants should be a part of the child's IEP team to support access to academic material.
Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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, botulinum toxin, or orthopedic procedures.
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
Recommended Surveillance for Individuals with Serine Deficiency Disorders
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & contractures.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Avoid known triggers of seizure activity (e.g., infection, physical stress, emotional stress).
It is appropriate to evaluate newborn sibs and apparently asymptomatic older and younger sibs of a proband to identify as early as possible those who would benefit from prompt initiation of L-serine treatment. Early treatment with L-serine can prevent the onset of neurologic abnormalities.
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 serine deficiency-causing pathogenic variants should be treated with L-serine immediately.
If the pathogenic variants in the family are not known and genetic testing is not possible, biochemical tests should be performed immediately after birth. Some diagnostic centers have reference ranges for umbilical cord blood amino acids; this can be used as the least invasive testing in combination with fasting plasma serine. When this is not feasible CSF serine is most reliable to diagnose serine deficiency.
See
There is very limited experience in the management of pregnancies in women with serine deficiency. The authors are aware of these pregnancies resulting in healthy newborns, but long-term follow up on the outcome of children born to mothers with serine deficiency is lacking. Affected pregnant females were monitored regularly to ensure that plasma serine concentrations remained within the normal range with L-serine therapy and that fetal growth parameters remained within the normal range.
See
Search
• Neurologic eval
• EEG
• To incl brain MRI
• 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.
• 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)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Usually, L-serine therapy is started at 200-400 mg/kg/day (given orally and divided into 4-6 doses), because in some individuals, transient acoustic startles and myoclonus were observed with larger doses.
• The L-serine dose is gradually increased to 500-700 mg/kg/day. A dose of 400 mg/kg/day was insufficient to prevent recurrence of seizures [Authors, personal observations].
• In some individuals who did not have a satisfactory response, glycine (200 mg/kg/day given orally and divided into 4-6 doses) was added to L-serine treatment.
• In adolescents and adults, lower L-serine doses can be used (100-150 mg/kg/day).
• See
• Standardized treatment w/ASM by experienced neurologist
• Treatment w/ASM may not be required after adequate response to L-serine therapy.
• Many ASMs may prove to be ineffective; none has been demonstrated effective specifically for this disorder, except L-serine therapy.
• 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.
• Provide family support in transition to adult care.
• 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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, botulinum toxin, or orthopedic procedures.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & contractures.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• 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 serine deficiency-causing pathogenic variants should be treated with L-serine immediately.
• If the pathogenic variants in the family are not known and genetic testing is not possible, biochemical tests should be performed immediately after birth. Some diagnostic centers have reference ranges for umbilical cord blood amino acids; this can be used as the least invasive testing in combination with fasting plasma serine. When this is not feasible CSF serine is most reliable to diagnose serine deficiency.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a serine deficiency disorder, the evaluations summarized in
Serine Deficiency Disorders: Recommended Evaluations Following Initial Diagnosis
Neurologic eval
EEG
To incl brain MRI
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.
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)
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
• Neurologic eval
• EEG
• To incl brain MRI
• 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.
• 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)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
High doses of L-serine are needed to correct the serine deficiency and obtain serine values within the reference ranges in plasma and cerebrospinal fluid (CSF). For young individuals, L-serine doses up to 500-700 mg/kg/day are usually needed to correct the deficiency and obtain satisfactory treatment results.
Usually, L-serine therapy is started at 200-400 mg/kg/day (given orally and divided into 4-6 doses), because in some individuals, transient acoustic startles and myoclonus were observed with larger doses.
The L-serine dose is gradually increased to 500-700 mg/kg/day. A dose of 400 mg/kg/day was insufficient to prevent recurrence of seizures [Authors, personal observations].
In some individuals who did not have a satisfactory response, glycine (200 mg/kg/day given orally and divided into 4-6 doses) was added to L-serine treatment.
In adolescents and adults, lower L-serine doses can be used (100-150 mg/kg/day).
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
Serine Deficiency Disorders: Treatment of Manifestations
See
Standardized treatment w/ASM by experienced neurologist
Treatment w/ASM may not be required after adequate response to L-serine therapy.
Many ASMs may prove to be ineffective; none has been demonstrated effective specifically for this disorder, except L-serine therapy.
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.
Provide family support in transition to adult care.
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 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 consultants should be a part of the child's IEP team to support access to academic material.
Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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, botulinum toxin, or orthopedic procedures.
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.
• Usually, L-serine therapy is started at 200-400 mg/kg/day (given orally and divided into 4-6 doses), because in some individuals, transient acoustic startles and myoclonus were observed with larger doses.
• The L-serine dose is gradually increased to 500-700 mg/kg/day. A dose of 400 mg/kg/day was insufficient to prevent recurrence of seizures [Authors, personal observations].
• In some individuals who did not have a satisfactory response, glycine (200 mg/kg/day given orally and divided into 4-6 doses) was added to L-serine treatment.
• In adolescents and adults, lower L-serine doses can be used (100-150 mg/kg/day).
• See
• Standardized treatment w/ASM by experienced neurologist
• Treatment w/ASM may not be required after adequate response to L-serine therapy.
• Many ASMs may prove to be ineffective; none has been demonstrated effective specifically for this disorder, except L-serine therapy.
• 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.
• Provide family support in transition to adult care.
• 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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, botulinum toxin, or orthopedic procedures.
## Targeted Therapy
High doses of L-serine are needed to correct the serine deficiency and obtain serine values within the reference ranges in plasma and cerebrospinal fluid (CSF). For young individuals, L-serine doses up to 500-700 mg/kg/day are usually needed to correct the deficiency and obtain satisfactory treatment results.
Usually, L-serine therapy is started at 200-400 mg/kg/day (given orally and divided into 4-6 doses), because in some individuals, transient acoustic startles and myoclonus were observed with larger doses.
The L-serine dose is gradually increased to 500-700 mg/kg/day. A dose of 400 mg/kg/day was insufficient to prevent recurrence of seizures [Authors, personal observations].
In some individuals who did not have a satisfactory response, glycine (200 mg/kg/day given orally and divided into 4-6 doses) was added to L-serine treatment.
In adolescents and adults, lower L-serine doses can be used (100-150 mg/kg/day).
• Usually, L-serine therapy is started at 200-400 mg/kg/day (given orally and divided into 4-6 doses), because in some individuals, transient acoustic startles and myoclonus were observed with larger doses.
• The L-serine dose is gradually increased to 500-700 mg/kg/day. A dose of 400 mg/kg/day was insufficient to prevent recurrence of seizures [Authors, personal observations].
• In some individuals who did not have a satisfactory response, glycine (200 mg/kg/day given orally and divided into 4-6 doses) was added to L-serine treatment.
• In adolescents and adults, lower L-serine doses can be used (100-150 mg/kg/day).
## 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
Serine Deficiency Disorders: Treatment of Manifestations
See
Standardized treatment w/ASM by experienced neurologist
Treatment w/ASM may not be required after adequate response to L-serine therapy.
Many ASMs may prove to be ineffective; none has been demonstrated effective specifically for this disorder, except L-serine therapy.
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.
Provide family support in transition to adult care.
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 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 consultants should be a part of the child's IEP team to support access to academic material.
Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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, botulinum toxin, or orthopedic procedures.
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.
• See
• Standardized treatment w/ASM by experienced neurologist
• Treatment w/ASM may not be required after adequate response to L-serine therapy.
• Many ASMs may prove to be ineffective; none has been demonstrated effective specifically for this disorder, except L-serine therapy.
• 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.
• Provide family support in transition to adult care.
• 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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, botulinum toxin, or orthopedic procedures.
##
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 consultants should be a part of the child's IEP team to support access to academic material.
Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
As a child enters the teen years, a transition plan should 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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.
• Physical, occupational, and speech therapies will be provided in the IEP to the extent that the need affects the child's access to academic material. Beyond that, private supportive therapies based on the affected individual's needs may be considered. Specific recommendations regarding type of therapy can be made by a developmental pediatrician.
• As a child enters the teen years, a transition plan should 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, botulinum toxin, 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 muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, botulinum toxin, or orthopedic procedures.
##
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
Recommended Surveillance for Individuals with Serine Deficiency Disorders
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & contractures.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & contractures.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Agents/Circumstances to Avoid
Avoid known triggers of seizure activity (e.g., infection, physical stress, emotional stress).
## Evaluation of Relatives at Risk
It is appropriate to evaluate newborn sibs and apparently asymptomatic older and younger sibs of a proband to identify as early as possible those who would benefit from prompt initiation of L-serine treatment. Early treatment with L-serine can prevent the onset of neurologic abnormalities.
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 serine deficiency-causing pathogenic variants should be treated with L-serine immediately.
If the pathogenic variants in the family are not known and genetic testing is not possible, biochemical tests should be performed immediately after birth. Some diagnostic centers have reference ranges for umbilical cord blood amino acids; this can be used as the least invasive testing in combination with fasting plasma serine. When this is not feasible CSF serine is most reliable to diagnose serine deficiency.
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 serine deficiency-causing pathogenic variants should be treated with L-serine immediately.
• If the pathogenic variants in the family are not known and genetic testing is not possible, biochemical tests should be performed immediately after birth. Some diagnostic centers have reference ranges for umbilical cord blood amino acids; this can be used as the least invasive testing in combination with fasting plasma serine. When this is not feasible CSF serine is most reliable to diagnose serine deficiency.
## Pregnancy Management
There is very limited experience in the management of pregnancies in women with serine deficiency. The authors are aware of these pregnancies resulting in healthy newborns, but long-term follow up on the outcome of children born to mothers with serine deficiency is lacking. Affected pregnant females were monitored regularly to ensure that plasma serine concentrations remained within the normal range with L-serine therapy and that fetal growth parameters remained within the normal range.
See
## Therapies Under Investigation
Search
## Genetic Counseling
Serine deficiency disorders are inherited in an autosomal recessive manner.
The parents of an affected child 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 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 asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a serine deficiency-causing 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 an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
Sibs who inherit biallelic pathogenic variants are expected to have a clinical phenotype similar to that observed in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with severe serine deficiency are not known to have offspring.
The offspring of an individual with a milder or adult-onset serine deficiency disorder are obligate heterozygotes (carriers) 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 carriers or are at risk of being carriers.
Once the serine deficiency-causing pathogenic variants 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 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
• 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 serine deficiency-causing 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 an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Sibs who inherit biallelic pathogenic variants are expected to have a clinical phenotype similar to that observed in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with severe serine deficiency are not known to have offspring.
• The offspring of an individual with a milder or adult-onset serine deficiency disorder are obligate heterozygotes (carriers) 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 carriers or are at risk of being carriers.
## Mode of Inheritance
Serine deficiency disorders are inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an affected child 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 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 asymptomatic and are not at risk of developing the disorder.
If both parents are known to be heterozygous for a serine deficiency-causing 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 an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
Sibs who inherit biallelic pathogenic variants are expected to have a clinical phenotype similar to that observed in the proband.
Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
Individuals with severe serine deficiency are not known to have offspring.
The offspring of an individual with a milder or adult-onset serine deficiency disorder are obligate heterozygotes (carriers) for a pathogenic variant in
• The parents of an affected child 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 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 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 serine deficiency-causing 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 an asymptomatic carrier, and a 25% chance of inheriting neither of the familial pathogenic variants.
• Sibs who inherit biallelic pathogenic variants are expected to have a clinical phenotype similar to that observed in the proband.
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• Individuals with severe serine deficiency are not known to have offspring.
• The offspring of an individual with a milder or adult-onset serine deficiency disorder are obligate heterozygotes (carriers) for a pathogenic variant in
## 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 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 serine deficiency-causing pathogenic variants 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
Dutch Patient Organization for Inborn Errors of Metabolism
Netherlands
•
•
•
•
•
• Dutch Patient Organization for Inborn Errors of Metabolism
• Netherlands
•
## Molecular Genetics
Serine Deficiency Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Serine Deficiency Disorders (
L-serine is classified as a nonessential amino acid (i.e., humans can synthesize serine from available cellular precursors). However, given L-serine's many important cellular functions, it is considered a conditionally essential amino acid. Synthesis of L-serine from the glycolytic intermediate 3-phopshoglycerate is the major source of L-serine (see
L-serine cellular functions include:
Nucleotide synthesis and cellular proliferation;
Folate and single-carbon metabolism (methylation);
Phosphatidylserine, sphingolipid, and ceramide synthesis;
Synthesis of NMDA receptor agonists glycine and D-serine.
The manifestations of serine deficiency are due to dysfunction of these metabolic pathways. The neurodevelopmental manifestations of prenatal- and infantile-onset serine deficiency, including microcephaly, are due to defective prenatal and postnatal neuronal proliferation and migration. Defective phospholipid synthesis results in hypomyelination and skin abnormalities. Seizures are likely related to disturbances in NMDA receptor activation due to insufficient synthesis of D-serine and potentially glycine.
Treatment with L-serine restores these metabolites and normalizes serine, glycine, 5-methyltetrahydrofolate, and D-serine levels. Phospholipids cannot be quantified after L-serine treatment, but it has been shown that cerebral white matter expands significantly following treatment, serving as a measure of phospholipid synthesis [
• Nucleotide synthesis and cellular proliferation;
• Folate and single-carbon metabolism (methylation);
• Phosphatidylserine, sphingolipid, and ceramide synthesis;
• Synthesis of NMDA receptor agonists glycine and D-serine.
## Molecular Pathogenesis
L-serine is classified as a nonessential amino acid (i.e., humans can synthesize serine from available cellular precursors). However, given L-serine's many important cellular functions, it is considered a conditionally essential amino acid. Synthesis of L-serine from the glycolytic intermediate 3-phopshoglycerate is the major source of L-serine (see
L-serine cellular functions include:
Nucleotide synthesis and cellular proliferation;
Folate and single-carbon metabolism (methylation);
Phosphatidylserine, sphingolipid, and ceramide synthesis;
Synthesis of NMDA receptor agonists glycine and D-serine.
The manifestations of serine deficiency are due to dysfunction of these metabolic pathways. The neurodevelopmental manifestations of prenatal- and infantile-onset serine deficiency, including microcephaly, are due to defective prenatal and postnatal neuronal proliferation and migration. Defective phospholipid synthesis results in hypomyelination and skin abnormalities. Seizures are likely related to disturbances in NMDA receptor activation due to insufficient synthesis of D-serine and potentially glycine.
Treatment with L-serine restores these metabolites and normalizes serine, glycine, 5-methyltetrahydrofolate, and D-serine levels. Phospholipids cannot be quantified after L-serine treatment, but it has been shown that cerebral white matter expands significantly following treatment, serving as a measure of phospholipid synthesis [
• Nucleotide synthesis and cellular proliferation;
• Folate and single-carbon metabolism (methylation);
• Phosphatidylserine, sphingolipid, and ceramide synthesis;
• Synthesis of NMDA receptor agonists glycine and D-serine.
## Chapter Notes
Dr de Koning is actively involved in clinical research regarding individuals with serine deficiency disorders. He would be happy to communicate with persons who have any questions regarding diagnosis of serine deficiency disorders or other considerations.
Dr de Koning is also interested in hearing from clinicians treating families affected by serine deficiency disorders 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 Dr de Koning or Dr van der Crabben to inquire about review of
22 June 2023 (sw) Review posted live
24 October 2022 (svdc) Original submission
• 22 June 2023 (sw) Review posted live
• 24 October 2022 (svdc) Original submission
## Author Notes
Dr de Koning is actively involved in clinical research regarding individuals with serine deficiency disorders. He would be happy to communicate with persons who have any questions regarding diagnosis of serine deficiency disorders or other considerations.
Dr de Koning is also interested in hearing from clinicians treating families affected by serine deficiency disorders 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 Dr de Koning or Dr van der Crabben to inquire about review of
## Revision History
22 June 2023 (sw) Review posted live
24 October 2022 (svdc) Original submission
• 22 June 2023 (sw) Review posted live
• 24 October 2022 (svdc) Original submission
## Key Sections in this
## References
## Literature Cited
Serine synthesis
1 = D-3-phosphoglycerate dehydrogenase (encoded by
|
[] |
22/6/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
setbp1-hd
|
setbp1-hd
|
[
"SETBP1 Disorder",
"SETBP1 Disorder",
"SET-binding protein",
"SETBP1",
"SETBP1 Haploinsufficiency Disorder"
] |
Angela Morgan, Siddharth Srivastava, Jessica Duis, Bregje van Bon
|
Summary The diagnosis of
|
Pathogenic variants in
Spectrum of Phenotypes Associated with
## Diagnosis
No consensus clinical diagnostic criteria for
Motor developmental delay (in 97%)
Developmental delay / mild-to-severe intellectual disability
Learning difficulties
Speech and language disorder (including childhood apraxia of speech)
Generalized hypotonia of infancy
Feeding difficulties
Seizures/epilepsy
Behavior consistent with attention-deficit/hyperactivity disorder including impulsivity
Other behaviors such as anxiety, aggression, sleep disturbances, self-injury and/or autism spectrum disorder
Ophthalmologic findings: refractive errors (hypermetropia, myopia, astigmatism), strabismus)
Digestive problems
Subtle dysmorphic features in several individuals: ptosis, blepharophimosis, broad nasal bridge, hypertelorism, full nasal tip, and a high arched palate. See
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
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.
• Motor developmental delay (in 97%)
• Developmental delay / mild-to-severe intellectual disability
• Learning difficulties
• Speech and language disorder (including childhood apraxia of speech)
• Generalized hypotonia of infancy
• Feeding difficulties
• Seizures/epilepsy
• Behavior consistent with attention-deficit/hyperactivity disorder including impulsivity
• Other behaviors such as anxiety, aggression, sleep disturbances, self-injury and/or autism spectrum disorder
• Ophthalmologic findings: refractive errors (hypermetropia, myopia, astigmatism), strabismus)
• Digestive problems
• Subtle dysmorphic features in several individuals: ptosis, blepharophimosis, broad nasal bridge, hypertelorism, full nasal tip, and a high arched palate. See
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Motor developmental delay (in 97%)
Developmental delay / mild-to-severe intellectual disability
Learning difficulties
Speech and language disorder (including childhood apraxia of speech)
Generalized hypotonia of infancy
Feeding difficulties
Seizures/epilepsy
Behavior consistent with attention-deficit/hyperactivity disorder including impulsivity
Other behaviors such as anxiety, aggression, sleep disturbances, self-injury and/or autism spectrum disorder
Ophthalmologic findings: refractive errors (hypermetropia, myopia, astigmatism), strabismus)
Digestive problems
Subtle dysmorphic features in several individuals: ptosis, blepharophimosis, broad nasal bridge, hypertelorism, full nasal tip, and a high arched palate. See
• Motor developmental delay (in 97%)
• Developmental delay / mild-to-severe intellectual disability
• Learning difficulties
• Speech and language disorder (including childhood apraxia of speech)
• Generalized hypotonia of infancy
• Feeding difficulties
• Seizures/epilepsy
• Behavior consistent with attention-deficit/hyperactivity disorder including impulsivity
• Other behaviors such as anxiety, aggression, sleep disturbances, self-injury and/or autism spectrum disorder
• Ophthalmologic findings: refractive errors (hypermetropia, myopia, astigmatism), strabismus)
• Digestive problems
• Subtle dysmorphic features in several individuals: ptosis, blepharophimosis, broad nasal bridge, hypertelorism, full nasal tip, and a high arched palate. See
## 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
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.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
The most common clinical manifestations of
To date, 47 individuals with
Based on
ADHD = attention-deficit/hyperactivity disorder
Gross motor abilities are generally better than fine motor abilities [
Sitting, crawling, and walking are delayed. Average age of sitting unsupported is six to 15 months, crawling nine to 19 months, and walking 13 to 36 months.
Fine motor development is delayed in about 70% of affected children. In particular, some children have difficulty with handwriting, which can further affect development of written language and/or exacerbate literacy difficulties [
The terms speech disorder and language disorder are often used interchangeably. Although they often co-occur, each can occur independently, providing evidence that they are separate entities.
Speech involves producing sounds in words with the correct breath support, voicing, resonance, articulation, prosody, and accuracy. Language involves meaning, i.e., the understanding and expression of words (vocabulary) and sentences (grammar).
Speech disorders and language disorders can each be further classified clinically.
Children with
Due to the childhood apraxia of speech, some children remain minimally verbal for years and augment their speech and language with sign language, gestures, or augmentative and assistive communication devices [
Speech Disorders: Definitions
Inconsistent error production on consonants & vowels across repeated production of syllables or words
Lengthened & impaired coarticulatory transitions between sounds & syllables
Inappropriate prosody
Children are typically sociable with a strong desire to communicate, yet social language is poorer than for typically developing peers.
Language Disorders: Definitions
The spectrum of intellectual disability (noted in 80% of individuals) ranges from mild to severe.
Children with
Most commonly reported are attention/concentration deficits and hyperactivity, and impulsivity, leading in many instances to a diagnosis of ADHD. Other behavioral problems include anxiety, autism spectrum disorder (ASD), sleep disturbances, self-injury, and other aggressive behaviors. Some children have autism or autistic features and social communication disorders. While many children with
Epilepsy was reported in three individuals, all of whom had generalized seizures [
The following were normal:
Growth parameters in general (e.g., weight, height, head circumference)
MRI findings in 19 of 22 individuals (for whom data were available). Of the remaining three, two had delayed myelination and one had a thin corpus callosum and a rotated hippocampal tail [
The possible relationship of the following findings to
Recurrent ear infections (~25% of infants)
Dry skin and/or eczema (20% of individuals)
Different types of hearing impairment (3 individuals)
Based on current data, life span is not shortened in
To date, 47 individuals with
The prevalence of
• Inconsistent error production on consonants & vowels across repeated production of syllables or words
• Lengthened & impaired coarticulatory transitions between sounds & syllables
• Inappropriate prosody
• Growth parameters in general (e.g., weight, height, head circumference)
• MRI findings in 19 of 22 individuals (for whom data were available). Of the remaining three, two had delayed myelination and one had a thin corpus callosum and a rotated hippocampal tail [
• Recurrent ear infections (~25% of infants)
• Dry skin and/or eczema (20% of individuals)
• Different types of hearing impairment (3 individuals)
## Clinical Description
The most common clinical manifestations of
To date, 47 individuals with
Based on
ADHD = attention-deficit/hyperactivity disorder
Gross motor abilities are generally better than fine motor abilities [
Sitting, crawling, and walking are delayed. Average age of sitting unsupported is six to 15 months, crawling nine to 19 months, and walking 13 to 36 months.
Fine motor development is delayed in about 70% of affected children. In particular, some children have difficulty with handwriting, which can further affect development of written language and/or exacerbate literacy difficulties [
The terms speech disorder and language disorder are often used interchangeably. Although they often co-occur, each can occur independently, providing evidence that they are separate entities.
Speech involves producing sounds in words with the correct breath support, voicing, resonance, articulation, prosody, and accuracy. Language involves meaning, i.e., the understanding and expression of words (vocabulary) and sentences (grammar).
Speech disorders and language disorders can each be further classified clinically.
Children with
Due to the childhood apraxia of speech, some children remain minimally verbal for years and augment their speech and language with sign language, gestures, or augmentative and assistive communication devices [
Speech Disorders: Definitions
Inconsistent error production on consonants & vowels across repeated production of syllables or words
Lengthened & impaired coarticulatory transitions between sounds & syllables
Inappropriate prosody
Children are typically sociable with a strong desire to communicate, yet social language is poorer than for typically developing peers.
Language Disorders: Definitions
The spectrum of intellectual disability (noted in 80% of individuals) ranges from mild to severe.
Children with
Most commonly reported are attention/concentration deficits and hyperactivity, and impulsivity, leading in many instances to a diagnosis of ADHD. Other behavioral problems include anxiety, autism spectrum disorder (ASD), sleep disturbances, self-injury, and other aggressive behaviors. Some children have autism or autistic features and social communication disorders. While many children with
Epilepsy was reported in three individuals, all of whom had generalized seizures [
The following were normal:
Growth parameters in general (e.g., weight, height, head circumference)
MRI findings in 19 of 22 individuals (for whom data were available). Of the remaining three, two had delayed myelination and one had a thin corpus callosum and a rotated hippocampal tail [
The possible relationship of the following findings to
Recurrent ear infections (~25% of infants)
Dry skin and/or eczema (20% of individuals)
Different types of hearing impairment (3 individuals)
Based on current data, life span is not shortened in
• Inconsistent error production on consonants & vowels across repeated production of syllables or words
• Lengthened & impaired coarticulatory transitions between sounds & syllables
• Inappropriate prosody
• Growth parameters in general (e.g., weight, height, head circumference)
• MRI findings in 19 of 22 individuals (for whom data were available). Of the remaining three, two had delayed myelination and one had a thin corpus callosum and a rotated hippocampal tail [
• Recurrent ear infections (~25% of infants)
• Dry skin and/or eczema (20% of individuals)
• Different types of hearing impairment (3 individuals)
## Delayed Motor Milestones
Gross motor abilities are generally better than fine motor abilities [
Sitting, crawling, and walking are delayed. Average age of sitting unsupported is six to 15 months, crawling nine to 19 months, and walking 13 to 36 months.
Fine motor development is delayed in about 70% of affected children. In particular, some children have difficulty with handwriting, which can further affect development of written language and/or exacerbate literacy difficulties [
## Speech and Language Disorder
The terms speech disorder and language disorder are often used interchangeably. Although they often co-occur, each can occur independently, providing evidence that they are separate entities.
Speech involves producing sounds in words with the correct breath support, voicing, resonance, articulation, prosody, and accuracy. Language involves meaning, i.e., the understanding and expression of words (vocabulary) and sentences (grammar).
Speech disorders and language disorders can each be further classified clinically.
Children with
Due to the childhood apraxia of speech, some children remain minimally verbal for years and augment their speech and language with sign language, gestures, or augmentative and assistive communication devices [
Speech Disorders: Definitions
Inconsistent error production on consonants & vowels across repeated production of syllables or words
Lengthened & impaired coarticulatory transitions between sounds & syllables
Inappropriate prosody
Children are typically sociable with a strong desire to communicate, yet social language is poorer than for typically developing peers.
Language Disorders: Definitions
• Inconsistent error production on consonants & vowels across repeated production of syllables or words
• Lengthened & impaired coarticulatory transitions between sounds & syllables
• Inappropriate prosody
## Intellectual Disability (ID)
The spectrum of intellectual disability (noted in 80% of individuals) ranges from mild to severe.
Children with
## Behavioral Problems
Most commonly reported are attention/concentration deficits and hyperactivity, and impulsivity, leading in many instances to a diagnosis of ADHD. Other behavioral problems include anxiety, autism spectrum disorder (ASD), sleep disturbances, self-injury, and other aggressive behaviors. Some children have autism or autistic features and social communication disorders. While many children with
## Additional Findings
Epilepsy was reported in three individuals, all of whom had generalized seizures [
## Other
The following were normal:
Growth parameters in general (e.g., weight, height, head circumference)
MRI findings in 19 of 22 individuals (for whom data were available). Of the remaining three, two had delayed myelination and one had a thin corpus callosum and a rotated hippocampal tail [
The possible relationship of the following findings to
Recurrent ear infections (~25% of infants)
Dry skin and/or eczema (20% of individuals)
Different types of hearing impairment (3 individuals)
• Growth parameters in general (e.g., weight, height, head circumference)
• MRI findings in 19 of 22 individuals (for whom data were available). Of the remaining three, two had delayed myelination and one had a thin corpus callosum and a rotated hippocampal tail [
• Recurrent ear infections (~25% of infants)
• Dry skin and/or eczema (20% of individuals)
• Different types of hearing impairment (3 individuals)
## Prognosis
Based on current data, life span is not shortened in
## Genotype-Phenotype Correlations
## Prevalence
To date, 47 individuals with
The prevalence of
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
Because the phenotypic features associated with
## 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
Evaluate speech production & receptive/expressive language in all children regardless of age.
To evaluate for specific speech diagnoses & make recommendations re appropriate treatments when warranted
To perform audiometry to exclude hearing loss (although this is not an associated feature)
Social work involvement for parental support;
Home nursing referral;
Early intervention referral;
Case management support referral.
Evaluate events suggestive of seizures; consider EEG if seizures are a concern.
Evaluate for abnormalities of tone (e.g., hypotonia).
Perform neurologic exam to evaluate for focal &/or other abnormalities that may warrant brain MRI.
Gross motor & fine motor skills;
Mobility, activities of daily living, & need for adaptive devices;
Need for ongoing PT (to improve gross motor skills) &/or ongoing OT (to improve fine motor skills, sensory processing).
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathology
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment is supportive, often including multidisciplinary specialists from pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, and medical genetics.
Treatment of Manifestations in Individuals with
Speech & language therapy tailored to child’s individual profile & developmental age
Consider early reading & spelling support as age appropriate.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Low threshold for clinical feeding eval
VFSS recommended if aspiration is suspected
Some persons may be treated w/medication (e.g., glycopyrrolate)
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; VFSS = videofluoroscopic swallowing study
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
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) are 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 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 (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a neurologist, developmental specialist, or psychiatrist.
Recommended Surveillance for Individuals with
Assessment of ongoing therapy initiated w/early interventional services
Referral to AAC specialist over time if warranted
Eval for speech disorder subtype over time if warranted
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
AAC = augmentative and alternative communication; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapist; PT = physical therapist
See
Search
• Evaluate speech production & receptive/expressive language in all children regardless of age.
• To evaluate for specific speech diagnoses & make recommendations re appropriate treatments when warranted
• To perform audiometry to exclude hearing loss (although this is not an associated feature)
• Social work involvement for parental support;
• Home nursing referral;
• Early intervention referral;
• Case management support referral.
• Evaluate events suggestive of seizures; consider EEG if seizures are a concern.
• Evaluate for abnormalities of tone (e.g., hypotonia).
• Perform neurologic exam to evaluate for focal &/or other abnormalities that may warrant brain MRI.
• Gross motor & fine motor skills;
• Mobility, activities of daily living, & need for adaptive devices;
• Need for ongoing PT (to improve gross motor skills) &/or ongoing OT (to improve fine motor skills, sensory processing).
• Speech & language therapy tailored to child’s individual profile & developmental age
• Consider early reading & spelling support as age appropriate.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Low threshold for clinical feeding eval
• VFSS recommended if aspiration is suspected
• 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 over time if warranted
• Eval for speech disorder subtype over time if warranted
• 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
Recommended Evaluations Following Initial Diagnosis in Individuals with
Evaluate speech production & receptive/expressive language in all children regardless of age.
To evaluate for specific speech diagnoses & make recommendations re appropriate treatments when warranted
To perform audiometry to exclude hearing loss (although this is not an associated feature)
Social work involvement for parental support;
Home nursing referral;
Early intervention referral;
Case management support referral.
Evaluate events suggestive of seizures; consider EEG if seizures are a concern.
Evaluate for abnormalities of tone (e.g., hypotonia).
Perform neurologic exam to evaluate for focal &/or other abnormalities that may warrant brain MRI.
Gross motor & fine motor skills;
Mobility, activities of daily living, & need for adaptive devices;
Need for ongoing PT (to improve gross motor skills) &/or ongoing OT (to improve fine motor skills, sensory processing).
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; DD = developmental delay; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; SLP = speech-language pathology
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Evaluate speech production & receptive/expressive language in all children regardless of age.
• To evaluate for specific speech diagnoses & make recommendations re appropriate treatments when warranted
• To perform audiometry to exclude hearing loss (although this is not an associated feature)
• Social work involvement for parental support;
• Home nursing referral;
• Early intervention referral;
• Case management support referral.
• Evaluate events suggestive of seizures; consider EEG if seizures are a concern.
• Evaluate for abnormalities of tone (e.g., hypotonia).
• Perform neurologic exam to evaluate for focal &/or other abnormalities that may warrant brain MRI.
• Gross motor & fine motor skills;
• Mobility, activities of daily living, & need for adaptive devices;
• Need for ongoing PT (to improve gross motor skills) &/or ongoing OT (to improve fine motor skills, sensory processing).
## Treatment of Manifestations
Treatment is supportive, often including multidisciplinary specialists from pediatrics, neurology, physiatry, occupational and physical therapy, speech-language pathology, psychiatry, ophthalmology, and medical genetics.
Treatment of Manifestations in Individuals with
Speech & language therapy tailored to child’s individual profile & developmental age
Consider early reading & spelling support as age appropriate.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Low threshold for clinical feeding eval
VFSS recommended if aspiration is suspected
Some persons may be treated w/medication (e.g., glycopyrrolate)
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; VFSS = videofluoroscopic swallowing study
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
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) are 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 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 (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a neurologist, developmental specialist, or psychiatrist.
• Speech & language therapy tailored to child’s individual profile & developmental age
• Consider early reading & spelling support as age appropriate.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Low threshold for clinical feeding eval
• VFSS recommended if aspiration is suspected
• 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.
• 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
## Motor Dysfunction
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 [
## 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 (ADHD), when necessary.
Concerns about serious aggressive or destructive behavior can be addressed by a neurologist, developmental specialist, or psychiatrist.
## Surveillance
Recommended Surveillance for Individuals with
Assessment of ongoing therapy initiated w/early interventional services
Referral to AAC specialist over time if warranted
Eval for speech disorder subtype over time if warranted
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
AAC = augmentative and alternative communication; ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapist; PT = physical therapist
• Assessment of ongoing therapy initiated w/early interventional services
• Referral to AAC specialist over time if warranted
• Eval for speech disorder subtype over time if warranted
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most 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 is unlikely to detect somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If the
If a parent of the proband is known to have 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 and to young adults who are mildly 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 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 is unlikely to detect 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 is unlikely to detect 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 is unlikely to detect somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If the
• If a parent of the proband is known to have 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 and to young adults who are mildly affected.
## Mode of Inheritance
## Risk to Family Members
Most 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 is unlikely to detect somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
If the
If a parent of the proband is known to have the
• Most 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 is unlikely to detect 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 is unlikely to detect 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 is unlikely to detect somatic mosaicism and will not detect a pathogenic variant that is present in the germ cells only.
• If the
• If a parent of the proband is known to have 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 and to young adults who are mildly 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 parents of affected individuals and to young adults who are mildly 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
P.O. Box 301584
Austin TX 78703
Speaking out for People with Intellectual and Developmental Disabilities
•
• P.O. Box 301584
• Austin TX 78703
•
•
•
•
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
•
## Molecular Genetics
SETBP1 Haploinsufficiency Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SETBP1 Haploinsufficiency Disorder (
Somatic gain-of-function
The
## Molecular Pathogenesis
## Cancer and Benign Tumors
Somatic gain-of-function
The
## Chapter Notes
The authors would like to thank all individuals with
9 May 2024 (bp) Revision:
18 November 2021 (bp) Review posted live
13 July 2021 (bvb) Original submission
• 9 May 2024 (bp) Revision:
• 18 November 2021 (bp) Review posted live
• 13 July 2021 (bvb) Original submission
## Acknowledgments
The authors would like to thank all individuals with
## Revision History
9 May 2024 (bp) Revision:
18 November 2021 (bp) Review posted live
13 July 2021 (bvb) Original submission
• 9 May 2024 (bp) Revision:
• 18 November 2021 (bp) Review posted live
• 13 July 2021 (bvb) Original submission
## References
## Published Guidelines / Consensus Statements
## Literature Cited
Clinical photographs of individuals with
Two individuals were first reported by
Reprinted from
|
[] |
18/11/2021
|
9/5/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
setd1b-ndd
|
setd1b-ndd
|
[
"Histone-lysine N-methyltransferase SETD1B",
"SETD1B",
"SETD1B-Related Neurodevelopmental Disorder"
] |
Alexandra Roston, William Gibson
|
Summary The diagnosis of
|
## Diagnosis
Developmental delay (especially speech and language delay)
Intellectual disability (ID)
Seizures that are frequently refractory to treatment
Autism spectrum disorder or autism-like behaviors
Other behavioral concerns (hyperactivity, aggression, anxiety, sleep disorders)
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 [
Because the phenotype of
Note: Single-gene testing (e.g., sequence analysis of
For an introduction to comprehensive genomic testing click
An
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.
To date, large multiexon
• Developmental delay (especially speech and language delay)
• Intellectual disability (ID)
• Seizures that are frequently refractory to treatment
• Autism spectrum disorder or autism-like behaviors
• Other behavioral concerns (hyperactivity, aggression, anxiety, sleep disorders)
• For an introduction to comprehensive genomic testing click
• An
• For an introduction to multigene panels click
## Suggestive Findings
Developmental delay (especially speech and language delay)
Intellectual disability (ID)
Seizures that are frequently refractory to treatment
Autism spectrum disorder or autism-like behaviors
Other behavioral concerns (hyperactivity, aggression, anxiety, sleep disorders)
• Developmental delay (especially speech and language delay)
• Intellectual disability (ID)
• Seizures that are frequently refractory to treatment
• Autism spectrum disorder or autism-like behaviors
• Other behavioral concerns (hyperactivity, aggression, anxiety, sleep disorders)
## 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 [
Because the phenotype of
Note: Single-gene testing (e.g., sequence analysis of
For an introduction to comprehensive genomic testing click
An
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.
To date, large multiexon
• For an introduction to comprehensive genomic testing click
• An
• For an introduction to multigene panels click
## Clinical Characteristics
Denominator reflects the number of persons assessed for the feature.
Delay in gross motor skills is frequent. When reported specifically, age at first walking ranged from 12 months to 4.5 years. One individual was reported as having normal motor development at age seven years [
Developmental regression was observed in six of 38 individuals with
The two individuals with reported normal development were evaluated at ages one and two years, and additional information for these individuals is not available.
Note: Patients reported as "intellectually disabled" at age younger than three years are included in
Seizure types were heterogeneous, and often included multiple seizure types or evolving seizure patterns. Seizure types included absence (18 individuals), myoclonic (13 individuals), generalized tonic-clonic (12 individuals), focal (4 individuals), and atonic (2 individuals). Of note, at least four individuals demonstrated eyelid myoclonia [
Seizures occurred daily in most individuals and were reported to worsen with age. Seizures were intractable in at least four individuals [
* Includes patients reported as "autistic" at age younger than three years
Dysplastic kidneys requiring transplant, an anteriorly placed anus, clubfeet, tethered cord, and contractures [
Cryptorchidism requiring surgery [
Hearing impairment [
Hypoplastic left heart [
Patent ductus arteriosus [
No clinically relevant genotype-phenotype correlations have been identified.
The penetrance of
• Dysplastic kidneys requiring transplant, an anteriorly placed anus, clubfeet, tethered cord, and contractures [
• Cryptorchidism requiring surgery [
• Hearing impairment [
• Hypoplastic left heart [
• Patent ductus arteriosus [
## Clinical Description
Denominator reflects the number of persons assessed for the feature.
Delay in gross motor skills is frequent. When reported specifically, age at first walking ranged from 12 months to 4.5 years. One individual was reported as having normal motor development at age seven years [
Developmental regression was observed in six of 38 individuals with
The two individuals with reported normal development were evaluated at ages one and two years, and additional information for these individuals is not available.
Note: Patients reported as "intellectually disabled" at age younger than three years are included in
Seizure types were heterogeneous, and often included multiple seizure types or evolving seizure patterns. Seizure types included absence (18 individuals), myoclonic (13 individuals), generalized tonic-clonic (12 individuals), focal (4 individuals), and atonic (2 individuals). Of note, at least four individuals demonstrated eyelid myoclonia [
Seizures occurred daily in most individuals and were reported to worsen with age. Seizures were intractable in at least four individuals [
* Includes patients reported as "autistic" at age younger than three years
Dysplastic kidneys requiring transplant, an anteriorly placed anus, clubfeet, tethered cord, and contractures [
Cryptorchidism requiring surgery [
Hearing impairment [
Hypoplastic left heart [
Patent ductus arteriosus [
• Dysplastic kidneys requiring transplant, an anteriorly placed anus, clubfeet, tethered cord, and contractures [
• Cryptorchidism requiring surgery [
• Hearing impairment [
• Hypoplastic left heart [
• Patent ductus arteriosus [
## Genotype-Phenotype Correlations
No clinically relevant genotype-phenotype correlations have been identified.
## Penetrance
The penetrance of
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because the phenotypic features associated with
## 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 motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Neurologic eval
EEG
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 eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those 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;
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Treatment of Manifestations in Individuals with
Education of parents/caregivers
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Seizures are frequently refractory to multiple ASMs & may require frequent follow up.
To date, there are no published trials or data re implementation of ketogenic diet & effects on seizure control.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
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 home nursing
Consider involvement in adaptive sports or
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
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. Individuals with
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, 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
At each visit
Persons w/
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & mvmt disorders.
OT = occupational therapy; PT = physical therapy
See
In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [
See
Search
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• Neurologic eval
• EEG
• 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 eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Education of parents/caregivers
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Seizures are frequently refractory to multiple ASMs & may require frequent follow up.
• To date, there are no published trials or data re implementation of ketogenic diet & effects on seizure control.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• 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 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
• At each visit
• Persons w/
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as 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 motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
Neurologic eval
EEG
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 eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those 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;
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
• Neurologic eval
• EEG
• 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 eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with
Education of parents/caregivers
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Seizures are frequently refractory to multiple ASMs & may require frequent follow up.
To date, there are no published trials or data re implementation of ketogenic diet & effects on seizure control.
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
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 home nursing
Consider involvement in adaptive sports or
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
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. Individuals with
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, 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.
• Education of parents/caregivers
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Seizures are frequently refractory to multiple ASMs & may require frequent follow up.
• To date, there are no published trials or data re implementation of ketogenic diet & effects on seizure control.
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• 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 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. Individuals with
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 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
At each visit
Persons w/
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & mvmt disorders.
OT = occupational therapy; PT = physical therapy
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• At each visit
• Persons w/
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & mvmt disorders.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASM may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASM to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [
See
## Therapies Under Investigation
Search
## Genetic Counseling
Most individuals diagnosed with
Vertical transmission of a
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, 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 an
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
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 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
• Vertical transmission of a
• 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, 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 an
• 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 an
• 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.
• * A parent with somatic and germline mosaicism for an
• 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.
## Mode of Inheritance
## Risk to Family Members
Most individuals diagnosed with
Vertical transmission of a
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, 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 an
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
• Most individuals diagnosed with
• Vertical transmission of a
• 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, 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 an
• 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 an
• 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.
• * A parent with somatic and germline mosaicism for an
• 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
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 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
Canada
•
•
•
• Canada
•
•
• Canada
•
•
•
•
•
•
•
•
## Molecular Genetics
SETD1B-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SETD1B-Related Neurodevelopmental Disorder (
Histone methyltransferases (HMTs) are a group of proteins that modify chromatin, thus regulating gene expression, through the addition of methyl groups to histones. A specific class of HMTs is the H3K4 family (histone-3-methyl-4), which methylate the fourth lysine residue on the tail of histone 3. This epigenetic modification allows for the packaging of DNA into heterochromatin.
Studies have shown a strong effect of SETD1B function on DNA methylation. Specifically, it has been suggested that loss of SETD1B function may lead to the insufficient production of H3K4me3 and DNA hypermethylation in specific loci. This specific epigenetic methylation signature associated with
Somatic variants affecting H3K4 methyltransferases, including SETD1B, have been identified in various tumors. Functional studies have suggested a role for both gain-of-function and loss-of-function variants in hematologic malignancies [
## Molecular Pathogenesis
Histone methyltransferases (HMTs) are a group of proteins that modify chromatin, thus regulating gene expression, through the addition of methyl groups to histones. A specific class of HMTs is the H3K4 family (histone-3-methyl-4), which methylate the fourth lysine residue on the tail of histone 3. This epigenetic modification allows for the packaging of DNA into heterochromatin.
Studies have shown a strong effect of SETD1B function on DNA methylation. Specifically, it has been suggested that loss of SETD1B function may lead to the insufficient production of H3K4me3 and DNA hypermethylation in specific loci. This specific epigenetic methylation signature associated with
## Cancer and Benign Tumors
Somatic variants affecting H3K4 methyltransferases, including SETD1B, have been identified in various tumors. Functional studies have suggested a role for both gain-of-function and loss-of-function variants in hematologic malignancies [
## Chapter Notes
Contact Dr William T Gibson (
The authors would like to thank the many individuals with
27 February 2025 (sw) Revision: author Dr William T Gibson available to contact regarding variants of uncertain significance
29 September 2022 (sw) Review posted live
10 June 2022 (wg) Original submission
• 27 February 2025 (sw) Revision: author Dr William T Gibson available to contact regarding variants of uncertain significance
• 29 September 2022 (sw) Review posted live
• 10 June 2022 (wg) Original submission
## Author Notes
Contact Dr William T Gibson (
## Acknowledgments
The authors would like to thank the many individuals with
## Revision History
27 February 2025 (sw) Revision: author Dr William T Gibson available to contact regarding variants of uncertain significance
29 September 2022 (sw) Review posted live
10 June 2022 (wg) Original submission
• 27 February 2025 (sw) Revision: author Dr William T Gibson available to contact regarding variants of uncertain significance
• 29 September 2022 (sw) Review posted live
• 10 June 2022 (wg) Original submission
## References
## Literature Cited
|
[] |
29/9/2022
|
27/2/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
setd2-ndd
|
setd2-ndd
|
[
"SETD2 Neurodevelopmental Disorder with or without Macrocephaly/Overgrowth",
"SETD2 Neurodevelopmental Disorder with Multiple Congenital Anomalies",
"Histone-lysine N-methyltransferase SETD2",
"SETD2",
"SETD2 Neurodevelopmental Disorders"
] |
John Pappas, Rachel Rabin
|
Summary The diagnosis of a
|
For other genetic causes of these phenotypes, see
## Diagnosis
No consensus clinical diagnostic criteria for
Congenital heart defects
Urogenital anomalies
Ophthalmologic findings including
Low anterior hairline
Biparietal narrowing
Flat face with maxillary hypoplasia
Arched eyebrows
Widely spaced eyes
Short palpebral fissures
Wide nasal bridge
Short nose with anteverted nares
Broad nasal tip with low-hanging columella
Micrognathia with mandibular hypoplasia
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 of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Several additional individuals with contiguous gene deletions in the 3p21.31 region (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 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. 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
No data on detection rate of gene-targeted deletion/duplication analysis are available.
A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with
•
• Congenital heart defects
• Urogenital anomalies
• Ophthalmologic findings including
• Congenital heart defects
• Urogenital anomalies
• Ophthalmologic findings including
• Low anterior hairline
• Biparietal narrowing
• Flat face with maxillary hypoplasia
• Arched eyebrows
• Widely spaced eyes
• Short palpebral fissures
• Wide nasal bridge
• Short nose with anteverted nares
• Broad nasal tip with low-hanging columella
• Micrognathia with mandibular hypoplasia
• Low anterior hairline
• Biparietal narrowing
• Flat face with maxillary hypoplasia
• Arched eyebrows
• Widely spaced eyes
• Short palpebral fissures
• Wide nasal bridge
• Short nose with anteverted nares
• Broad nasal tip with low-hanging columella
• Micrognathia with mandibular hypoplasia
• Congenital heart defects
• Urogenital anomalies
• Ophthalmologic findings including
• Low anterior hairline
• Biparietal narrowing
• Flat face with maxillary hypoplasia
• Arched eyebrows
• Widely spaced eyes
• Short palpebral fissures
• Wide nasal bridge
• Short nose with anteverted nares
• Broad nasal tip with low-hanging columella
• Micrognathia with mandibular hypoplasia
## Suggestive Findings
Congenital heart defects
Urogenital anomalies
Ophthalmologic findings including
Low anterior hairline
Biparietal narrowing
Flat face with maxillary hypoplasia
Arched eyebrows
Widely spaced eyes
Short palpebral fissures
Wide nasal bridge
Short nose with anteverted nares
Broad nasal tip with low-hanging columella
Micrognathia with mandibular hypoplasia
•
• Congenital heart defects
• Urogenital anomalies
• Ophthalmologic findings including
• Congenital heart defects
• Urogenital anomalies
• Ophthalmologic findings including
• Low anterior hairline
• Biparietal narrowing
• Flat face with maxillary hypoplasia
• Arched eyebrows
• Widely spaced eyes
• Short palpebral fissures
• Wide nasal bridge
• Short nose with anteverted nares
• Broad nasal tip with low-hanging columella
• Micrognathia with mandibular hypoplasia
• Low anterior hairline
• Biparietal narrowing
• Flat face with maxillary hypoplasia
• Arched eyebrows
• Widely spaced eyes
• Short palpebral fissures
• Wide nasal bridge
• Short nose with anteverted nares
• Broad nasal tip with low-hanging columella
• Micrognathia with mandibular hypoplasia
• Congenital heart defects
• Urogenital anomalies
• Ophthalmologic findings including
• Low anterior hairline
• Biparietal narrowing
• Flat face with maxillary hypoplasia
• Arched eyebrows
• Widely spaced eyes
• Short palpebral fissures
• Wide nasal bridge
• Short nose with anteverted nares
• Broad nasal tip with low-hanging columella
• Micrognathia with mandibular hypoplasia
## 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 of
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Several additional individuals with contiguous gene deletions in the 3p21.31 region (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 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. 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
No data on detection rate of gene-targeted deletion/duplication analysis are available.
A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with
## Option 1
## Option 2
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in
See
See
Several additional individuals with contiguous gene deletions in the 3p21.31 region (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 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. 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
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Epigenetic Signature Analysis / Methylation Array
A distinctive epigenetic signature (disorder-specific genome-wide changes in DNA methylation profiles) in peripheral blood leukocytes has been identified in individuals with
## Clinical Characteristics
To date, 30 individuals have been reported with a
Data from
MCA = multiple congenital anomalies; NDD = neurodevelopmental disorder
This column also includes those individuals with a heterozygous c.5219G>A (p.Arg1740Gln) pathogenic variant in
Two individuals had prenatal-onset microcephaly, but all eventually developed microcephaly.
Typically accompanied by respiratory and feeding difficulties
Hypotonia may be present. This typically does not require feeding therapy or supplemental tube feeds, as seen with
Epilepsy has been rarely described.
Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
Precocious puberty
Polycystic ovarian syndrome
Hypothyroidism
Growth hormone deficiency
Hearing loss is uncommon but has been observed. It is more commonly seen in those with the
Strabismus has been observed; cortical visual impairment and optic nerve hypoplasia have been described but are uncommon.
Recurrent infections, including recurrent otitis media, sinus infections, and/or respiratory infections
Gastroesophageal reflux disease
Constipation
Congenital heart defects
Sleep apnea (type not well described in the literature)
Hirsutism
Scoliosis
Large- and small-joint hypermobility
Cryptorchidism
Nevi
All affected individuals had normal weight and length at birth.
Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
Cleft palate with Pierre Robin sequence is common, observed in 10/12 individuals, and may contribute to both feeding and breathing issues.
One individual had medically intractable seizures until treatment with phenobarbital and a ketogenic/modified Atkin's diet. Another had better seizure control while taking cannabidiol (CBD) oil.
A triad of findings include hypoplasia of the corpus callosum, pons, and cerebellum.
Shallow sulci, ventriculomegaly, and mega cisterna magna can also be observed.
One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
Hyponatremia is common in infancy, observed in 8/12 affected individuals.
The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
Hip dysplasia
Contractures of digits, knees, and/or elbows
Thoracic dysplasia
Craniosynostosis involving sagittal and metopic sutures
Neuromuscular scoliosis
Abnormalities of the hands and feet
Brachydactyly
Camptodactyly
Syndactyly
Proximally implanted triphalangeal thumbs
Broad proximally implanted halluces
Hypoplastic distal phalanges and nails
Rocker bottom feet
Small hands and feet
Persistent fetal fingertip pads
Strabismus
Myopia
Laryngomalacia
Constipation
• Hypotonia may be present. This typically does not require feeding therapy or supplemental tube feeds, as seen with
• Epilepsy has been rarely described.
• Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
• Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
• Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
• Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
• Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
• Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
• Precocious puberty
• Polycystic ovarian syndrome
• Hypothyroidism
• Growth hormone deficiency
• Hearing loss is uncommon but has been observed. It is more commonly seen in those with the
• Strabismus has been observed; cortical visual impairment and optic nerve hypoplasia have been described but are uncommon.
• Recurrent infections, including recurrent otitis media, sinus infections, and/or respiratory infections
• Gastroesophageal reflux disease
• Constipation
• Congenital heart defects
• Sleep apnea (type not well described in the literature)
• Hirsutism
• Scoliosis
• Large- and small-joint hypermobility
• Cryptorchidism
• Nevi
• All affected individuals had normal weight and length at birth.
• Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
• All affected individuals had normal weight and length at birth.
• Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
• All affected individuals had normal weight and length at birth.
• Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
• A triad of findings include hypoplasia of the corpus callosum, pons, and cerebellum.
• Shallow sulci, ventriculomegaly, and mega cisterna magna can also be observed.
• One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
• All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
• Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
• One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
• All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
• Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
•
• Hyponatremia is common in infancy, observed in 8/12 affected individuals.
• The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
• Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
• Hyponatremia is common in infancy, observed in 8/12 affected individuals.
• The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
• Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
• Hip dysplasia
• Contractures of digits, knees, and/or elbows
• Thoracic dysplasia
• Craniosynostosis involving sagittal and metopic sutures
• Neuromuscular scoliosis
• Abnormalities of the hands and feet
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Hip dysplasia
• Contractures of digits, knees, and/or elbows
• Thoracic dysplasia
• Craniosynostosis involving sagittal and metopic sutures
• Neuromuscular scoliosis
• Abnormalities of the hands and feet
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
• All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
• Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
• Hyponatremia is common in infancy, observed in 8/12 affected individuals.
• The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
• Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
• Hip dysplasia
• Contractures of digits, knees, and/or elbows
• Thoracic dysplasia
• Craniosynostosis involving sagittal and metopic sutures
• Neuromuscular scoliosis
• Abnormalities of the hands and feet
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Strabismus
• Myopia
• Laryngomalacia
• Constipation
• Strabismus
• Myopia
• Laryngomalacia
• Constipation
• Strabismus
• Myopia
• Laryngomalacia
• Constipation
## Clinical Description
To date, 30 individuals have been reported with a
Data from
MCA = multiple congenital anomalies; NDD = neurodevelopmental disorder
This column also includes those individuals with a heterozygous c.5219G>A (p.Arg1740Gln) pathogenic variant in
Two individuals had prenatal-onset microcephaly, but all eventually developed microcephaly.
Typically accompanied by respiratory and feeding difficulties
Hypotonia may be present. This typically does not require feeding therapy or supplemental tube feeds, as seen with
Epilepsy has been rarely described.
Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
Precocious puberty
Polycystic ovarian syndrome
Hypothyroidism
Growth hormone deficiency
Hearing loss is uncommon but has been observed. It is more commonly seen in those with the
Strabismus has been observed; cortical visual impairment and optic nerve hypoplasia have been described but are uncommon.
Recurrent infections, including recurrent otitis media, sinus infections, and/or respiratory infections
Gastroesophageal reflux disease
Constipation
Congenital heart defects
Sleep apnea (type not well described in the literature)
Hirsutism
Scoliosis
Large- and small-joint hypermobility
Cryptorchidism
Nevi
All affected individuals had normal weight and length at birth.
Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
Cleft palate with Pierre Robin sequence is common, observed in 10/12 individuals, and may contribute to both feeding and breathing issues.
One individual had medically intractable seizures until treatment with phenobarbital and a ketogenic/modified Atkin's diet. Another had better seizure control while taking cannabidiol (CBD) oil.
A triad of findings include hypoplasia of the corpus callosum, pons, and cerebellum.
Shallow sulci, ventriculomegaly, and mega cisterna magna can also be observed.
One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
Hyponatremia is common in infancy, observed in 8/12 affected individuals.
The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
Hip dysplasia
Contractures of digits, knees, and/or elbows
Thoracic dysplasia
Craniosynostosis involving sagittal and metopic sutures
Neuromuscular scoliosis
Abnormalities of the hands and feet
Brachydactyly
Camptodactyly
Syndactyly
Proximally implanted triphalangeal thumbs
Broad proximally implanted halluces
Hypoplastic distal phalanges and nails
Rocker bottom feet
Small hands and feet
Persistent fetal fingertip pads
• Hypotonia may be present. This typically does not require feeding therapy or supplemental tube feeds, as seen with
• Epilepsy has been rarely described.
• Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
• Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
• Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
• Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
• Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
• Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
• Precocious puberty
• Polycystic ovarian syndrome
• Hypothyroidism
• Growth hormone deficiency
• Hearing loss is uncommon but has been observed. It is more commonly seen in those with the
• Strabismus has been observed; cortical visual impairment and optic nerve hypoplasia have been described but are uncommon.
• Recurrent infections, including recurrent otitis media, sinus infections, and/or respiratory infections
• Gastroesophageal reflux disease
• Constipation
• Congenital heart defects
• Sleep apnea (type not well described in the literature)
• Hirsutism
• Scoliosis
• Large- and small-joint hypermobility
• Cryptorchidism
• Nevi
• All affected individuals had normal weight and length at birth.
• Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
• All affected individuals had normal weight and length at birth.
• Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
• All affected individuals had normal weight and length at birth.
• Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
• A triad of findings include hypoplasia of the corpus callosum, pons, and cerebellum.
• Shallow sulci, ventriculomegaly, and mega cisterna magna can also be observed.
• One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
• All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
• Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
• One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
• All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
• Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
•
• Hyponatremia is common in infancy, observed in 8/12 affected individuals.
• The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
• Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
• Hyponatremia is common in infancy, observed in 8/12 affected individuals.
• The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
• Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
• Hip dysplasia
• Contractures of digits, knees, and/or elbows
• Thoracic dysplasia
• Craniosynostosis involving sagittal and metopic sutures
• Neuromuscular scoliosis
• Abnormalities of the hands and feet
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Hip dysplasia
• Contractures of digits, knees, and/or elbows
• Thoracic dysplasia
• Craniosynostosis involving sagittal and metopic sutures
• Neuromuscular scoliosis
• Abnormalities of the hands and feet
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
• All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
• Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
• Hyponatremia is common in infancy, observed in 8/12 affected individuals.
• The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
• Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
• Hip dysplasia
• Contractures of digits, knees, and/or elbows
• Thoracic dysplasia
• Craniosynostosis involving sagittal and metopic sutures
• Neuromuscular scoliosis
• Abnormalities of the hands and feet
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
Hypotonia may be present. This typically does not require feeding therapy or supplemental tube feeds, as seen with
Epilepsy has been rarely described.
Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
Precocious puberty
Polycystic ovarian syndrome
Hypothyroidism
Growth hormone deficiency
Hearing loss is uncommon but has been observed. It is more commonly seen in those with the
Strabismus has been observed; cortical visual impairment and optic nerve hypoplasia have been described but are uncommon.
Recurrent infections, including recurrent otitis media, sinus infections, and/or respiratory infections
Gastroesophageal reflux disease
Constipation
Congenital heart defects
Sleep apnea (type not well described in the literature)
Hirsutism
Scoliosis
Large- and small-joint hypermobility
Cryptorchidism
Nevi
• Hypotonia may be present. This typically does not require feeding therapy or supplemental tube feeds, as seen with
• Epilepsy has been rarely described.
• Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
• Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
• Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
• Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
• Generalized tonic-clonic seizures occurred in one individual at age ten years, but the affected individual remained seizure free on lamotrigine monotherapy for at least three years [
• Another individual experienced one seizure at age three years, and a third individual experienced several seizures that did not recur after ventriculoperitoneal shunt placement [
• Precocious puberty
• Polycystic ovarian syndrome
• Hypothyroidism
• Growth hormone deficiency
• Hearing loss is uncommon but has been observed. It is more commonly seen in those with the
• Strabismus has been observed; cortical visual impairment and optic nerve hypoplasia have been described but are uncommon.
• Recurrent infections, including recurrent otitis media, sinus infections, and/or respiratory infections
• Gastroesophageal reflux disease
• Constipation
• Congenital heart defects
• Sleep apnea (type not well described in the literature)
• Hirsutism
• Scoliosis
• Large- and small-joint hypermobility
• Cryptorchidism
• Nevi
All affected individuals had normal weight and length at birth.
Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
Cleft palate with Pierre Robin sequence is common, observed in 10/12 individuals, and may contribute to both feeding and breathing issues.
One individual had medically intractable seizures until treatment with phenobarbital and a ketogenic/modified Atkin's diet. Another had better seizure control while taking cannabidiol (CBD) oil.
A triad of findings include hypoplasia of the corpus callosum, pons, and cerebellum.
Shallow sulci, ventriculomegaly, and mega cisterna magna can also be observed.
One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
Hyponatremia is common in infancy, observed in 8/12 affected individuals.
The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
Hip dysplasia
Contractures of digits, knees, and/or elbows
Thoracic dysplasia
Craniosynostosis involving sagittal and metopic sutures
Neuromuscular scoliosis
Abnormalities of the hands and feet
Brachydactyly
Camptodactyly
Syndactyly
Proximally implanted triphalangeal thumbs
Broad proximally implanted halluces
Hypoplastic distal phalanges and nails
Rocker bottom feet
Small hands and feet
Persistent fetal fingertip pads
• All affected individuals had normal weight and length at birth.
• Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
• All affected individuals had normal weight and length at birth.
• Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
• All affected individuals had normal weight and length at birth.
• Weight usually remains below the 50th centile in infancy and childhood, whereas height is more variable.
• A triad of findings include hypoplasia of the corpus callosum, pons, and cerebellum.
• Shallow sulci, ventriculomegaly, and mega cisterna magna can also be observed.
• One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
• All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
• Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
• One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
• All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
• Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
•
• Hyponatremia is common in infancy, observed in 8/12 affected individuals.
• The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
• Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
• Hyponatremia is common in infancy, observed in 8/12 affected individuals.
• The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
• Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
• Hip dysplasia
• Contractures of digits, knees, and/or elbows
• Thoracic dysplasia
• Craniosynostosis involving sagittal and metopic sutures
• Neuromuscular scoliosis
• Abnormalities of the hands and feet
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Hip dysplasia
• Contractures of digits, knees, and/or elbows
• Thoracic dysplasia
• Craniosynostosis involving sagittal and metopic sutures
• Neuromuscular scoliosis
• Abnormalities of the hands and feet
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• One affected individual with multicystic dysplastic kidneys developed end-stage kidney disease.
• All males reported have cryptorchidism; micropenis and shawl scrotum have also been reported in some.
• Two females have anteriorly placed anus, and one also has a short vagina, absent cervix, and absent midline müllerian structures.
• Hyponatremia is common in infancy, observed in 8/12 affected individuals.
• The hyponatremia was initially concerning for the syndrome of inappropriate antidiuretic hormone (SIADH) secretion, but hyponatremia ultimately resolved with sodium supplementation.
• Additional endocrine abnormalities have been observed including acquired hypothyroidism and hypothalamic hamartoma in one affected individual each.
• Hip dysplasia
• Contractures of digits, knees, and/or elbows
• Thoracic dysplasia
• Craniosynostosis involving sagittal and metopic sutures
• Neuromuscular scoliosis
• Abnormalities of the hands and feet
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
• Brachydactyly
• Camptodactyly
• Syndactyly
• Proximally implanted triphalangeal thumbs
• Broad proximally implanted halluces
• Hypoplastic distal phalanges and nails
• Rocker bottom feet
• Small hands and feet
• Persistent fetal fingertip pads
## Genotype-Phenotype Correlations
Strabismus
Myopia
Laryngomalacia
Constipation
• Strabismus
• Myopia
• Laryngomalacia
• Constipation
• Strabismus
• Myopia
• Laryngomalacia
• Constipation
• Strabismus
• Myopia
• Laryngomalacia
• Constipation
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Because the phenotypic features associated with
Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MDFPMR = macrocephaly, dysmorphic facies, and psychomotor retardation; NDD = neurodevelopmental disorder; XL = X-linked
Most instances of Beckwith-Wiedemann syndrome are due to methylation abnormalities that are not heritable. A subset of affected persons have a pathogenic variant that is heritable, most commonly in an autosomal dominant manner.
Differential Diagnosis of
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; FTT = failure to thrive; ID = intellectual disability; MCA = multiple congenital anomalies; MOI = mode of inheritance; NDD = neurodevelopmental disorder
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis:
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Incl brain MRI
Consider EEG if seizures are a concern.
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.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TSH = thyroid stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis:
Incl eval of aspiration risk & nutritional status.
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Incl brain MRI
Consider EEG if seizures are a concern.
To assess for hyponatremia
If present, consider eval for SIADH.
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)
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; FTT= failure to thrive; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TSH = thyroid stimulating hormone; SIADH = syndrome of inappropriate antidiuretic hormone
To include sodium, potassium, chloride, and bicarbonate at a minimum
To date, SIADH has not been found in those with hyponatremia who have undergone evaluation.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations:
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
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
Treatment of Manifestations:
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
In refractory cases, a ketogenic diet may be trialed.
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
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; SIADH = syndrome of inappropriate antidiuretic 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
To date, SIADH has not been found in those with hyponatremia who have undergone evaluation.
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.
Recommended Surveillance for Individuals with
Monitor those w/seizures as clinically indicated.
Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
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, movement disorders.
OT = occupational therapy; PT = physical therapy
See
Search
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Incl brain MRI
• Consider EEG if seizures are a concern.
• 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.
• Incl eval of aspiration risk & nutritional status.
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Incl brain MRI
• Consider EEG if seizures are a concern.
• To assess for hyponatremia
• If present, consider eval for SIADH.
• 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)
• 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
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• In refractory cases, a ketogenic diet may be trialed.
• 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
• 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 incl seizures, changes in tone, mvmt disorders.
• 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, movement disorders.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis:
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Incl brain MRI
Consider EEG if seizures are a concern.
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.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TSH = thyroid stimulating hormone
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Recommended Evaluations Following Initial Diagnosis:
Incl eval of aspiration risk & nutritional status.
Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
Incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Incl brain MRI
Consider EEG if seizures are a concern.
To assess for hyponatremia
If present, consider eval for SIADH.
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)
Community or
Social work involvement for parental support;
Home nursing referral.
ADL = activities of daily living; FTT= failure to thrive; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy; TSH = thyroid stimulating hormone; SIADH = syndrome of inappropriate antidiuretic hormone
To include sodium, potassium, chloride, and bicarbonate at a minimum
To date, SIADH has not been found in those with hyponatremia who have undergone evaluation.
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Incl brain MRI
• Consider EEG if seizures are a concern.
• 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.
• Incl eval of aspiration risk & nutritional status.
• Consider eval for gastrostomy tube placement in those w/dysphagia &/or aspiration risk.
• Incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Incl brain MRI
• Consider EEG if seizures are a concern.
• To assess for hyponatremia
• If present, consider eval for SIADH.
• 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)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations:
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
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
Treatment of Manifestations:
Feeding therapy
Gastrostomy tube placement may be required for persistent feeding issues.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
In refractory cases, a ketogenic diet may be trialed.
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
ASM = anti-seizure medication; OT = occupational therapy; PT = physical therapy; SIADH = syndrome of inappropriate antidiuretic 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
To date, SIADH has not been found in those with hyponatremia who have undergone evaluation.
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.
• 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
• Feeding therapy
• Gastrostomy tube placement may be required for persistent feeding issues.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• In refractory cases, a ketogenic diet may be trialed.
• 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
• 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.
## 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, mvmt disorders.
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, movement disorders.
OT = occupational therapy; PT = physical therapy
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations incl seizures, changes in tone, mvmt disorders.
• 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, movement disorders.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
An individual diagnosed with a
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
The proband has a
The proband inherited a
* A parent with somatic and germline mosaicism for a
The family history of some individuals diagnosed with
If a parent of the proband is affected is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The penetrance of
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.
Once the
Differences in perspective may exist among medical professionals and within families regarding the use of prenatal 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.
• An individual diagnosed with a
• 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
• The proband has a
• The proband inherited a
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a
• * A parent with somatic and germline mosaicism for a
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a
• * A parent with somatic and germline mosaicism for a
• If a parent of the proband is affected is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The penetrance of
• 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.
## Mode of Inheritance
## Risk to Family Members
An individual diagnosed with a
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
The proband has a
The proband inherited a
* A parent with somatic and germline mosaicism for a
The family history of some individuals diagnosed with
If a parent of the proband is affected is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The penetrance of
If the proband has a known
If the parents have not been tested for the
• An individual diagnosed with a
• 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
• The proband has a
• The proband inherited a
• * A parent with somatic and germline mosaicism for a
• The proband has a
• The proband inherited a
• * A parent with somatic and germline mosaicism for a
• The family history of some individuals diagnosed with
• The proband has a
• The proband inherited a
• * A parent with somatic and germline mosaicism for a
• If a parent of the proband is affected is known to have the pathogenic variant identified in the proband, the risk to the sibs of inheriting the pathogenic variant is 50%. The penetrance of
• If the proband has a known
• 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.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 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
SETD2 Neurodevelopmental Disorders: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SETD2 Neurodevelopmental Disorders (
Loss-of-function variants in
Notable
Variants listed in the table have been provided by the authors.
MCA = multiple congenital anomalies
## Molecular Pathogenesis
Loss-of-function variants in
Notable
Variants listed in the table have been provided by the authors.
MCA = multiple congenital anomalies
## Cancer and Benign Tumors
## Chapter Notes
Dr John Pappas:
22 September 2022 (sw) Revision: epigenetic signature analysis (
30 December 2021 (ma) Review posted live
4 January 2021 (jp) Original submission
• 22 September 2022 (sw) Revision: epigenetic signature analysis (
• 30 December 2021 (ma) Review posted live
• 4 January 2021 (jp) Original submission
## Author Notes
Dr John Pappas:
## Revision History
22 September 2022 (sw) Revision: epigenetic signature analysis (
30 December 2021 (ma) Review posted live
4 January 2021 (jp) Original submission
• 22 September 2022 (sw) Revision: epigenetic signature analysis (
• 30 December 2021 (ma) Review posted live
• 4 January 2021 (jp) Original submission
## References
## Literature Cited
Clinical features of individuals with
a & b. Lateral and frontal views of an affected individual; note the prominent forehead with high frontal hairline, frontal bossing, and low-set ears
c & d. Frontal and lateral views of an unrelated affected individual showing relative macrocephaly, long face, tall forehead and pointed chin, posteriorly rotated ears, and malar flattening
Reprinted with permission from
Magnetic resonance images of six individuals who are heterozygous for a recurrent p.Arg1740Trp pathogenic variant in
Patient 1 (A-C); male age six weeks
Patient 2 (D-F): male age four days
Patient 3 (G-I): newborn female
Patient 5 (J-L): female age six years
Patient 6 (M-O): male age four years
Patient 7 (P): male age two months
All affected individuals have low craniofacial ratios (corresponding to clinical microcephaly), as well as a foreshortened and thin corpus callosum (A, D, G, J, M, P). Thinning of the corpus callosum in A, D, G, and P could be due to a combination of callosal hypogenesis and unmyelinated state of white matter during the first few weeks of life. There is subtle overhanging appearance of the terminal portions of the frontal horns of the lateral ventricles relative to the striatum (best seen on coronal B and E). Gyri are somewhat simplified and sulci are shallow (C, F, I, and L). All affected individuals have cystic enlargement of the posterior fossa (mega cisterna magna) and prominent supracerebellar cisterns (A, D, G, and M). Slightly upturned hippocampi can be appreciated on coronal images (particularly in B, H, K, and N). Patient 1 has prominent convexity extra-axial spaces with left more than right subdural hemorrhage, which may be related to birth trauma. A cleft palate can be seen in D and G (small arrows). Patient 5 has white matter volume loss (K, L), with enlargement of the third and lateral ventricles. Patients 5, 6, and 7 have probable persistent Blake pouch cyst (J, N, P). Patients 3, 5, and 6 (G, J, M) demonstrate abnormality of anteroposterior midbrain-hindbrain patterning.
Reprinted from
Facial appearance of individuals with
Patient 2 at age seven years (A); at age ten years (B-C)
Patient 4 in infancy (D-E)
Patient 5 in infancy (F-G); as a toddler (H-I)
Patient 6 as a toddler (J)
Patient 7 at age two weeks (K)
Patient 8 at age two years (L); at age 12 years (M)
Patient 10 at age five weeks (N-O)
Common facial features include widely spaced eyes, micrognathia, small upturned nose, biparietal narrowing, small forehead, microcephaly, flat face, short palpebral fissures, arched eyebrows, strabismus, broad nasal bridge and tip of the nose with low hanging columella, maxillary and mandibular hypoplasia, and slightly forward facing ears.
Reprinted from
Craniofacial characteristics in an individual with a 3p21.31 deletion. A long face, downslanted palpebral fissures, broad nasal tip, deep philtrum, and low-set, dysmorphic ears are shown.
Reprinted with permission from
|
[] |
30/12/2021
|
22/9/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sft
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sft
|
[
"Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase",
"GNE",
"Sialuria"
] |
Sialuria – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Jules G Leroy
|
Summary Sialuria is characterized by variable and transient signs and symptoms, especially in infancy. These include slightly flat and coarse facies, prolonged neonatal jaundice, equivocal or mild hepatomegaly, microcytic anemia, frequent upper respiratory infections, and episodes of gastroenteritis, dehydration, and transient failure to thrive. Mild developmental delay and hypotonia have been neither consistent nor permanent. Learning difficulty and seizures have been observed later in childhood. Sialuria has been detected retrospectively in an adult without subjective signs or complaints of disease. The long-term outcome of the disorder is unknown to date. The diagnosis of sialuria is suggested by highly elevated urinary excretion of free sialic acid using the spectrophotometric or fluorimetric thiobarbituric acid assay or thin-layer chromatography. The diagnosis is formally established by demonstration of significantly raised free sialic acid within the cytoplasm of parenchymal cells or cultured fibroblasts. Sialuria is inherited in an autosomal dominant manner. If a parent of a proband is affected or has a sialuria-causing variant in
|
## Diagnosis
The diagnosis of sialuria may be suspected in infants or young children with the following:
Mild facial coarsening
Hypotonia
Equivocal developmental delay
Frequent upper respiratory infections
Note: The likelihood of sialuria is increased after exclusion of more prevalent disorders that share laboratory results rather than clinical features. See
Constitutive overproduction of free sialic acid is the metabolic defect of sialuria [
Provided that the
Note: (1) In the spectrophotometric method, other substances may either decrease or increase the absorbance and thus lead to spurious results. (2) High-performance liquid chromatography and proton nuclear magnetic resonance spectroscopy (1H-NMR) may be helpful in sorting out relevant differential diagnoses [
The combination of one- and two-dimensional correlation spectroscopy (COSY):
Identifies a specific
Distinguishes bound sialic acid from free sialic acid and hence distinguishes sialidosis from sialuria.
Molecular Genetic Testing Used in Sialuria
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
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
Total number of persons known to have been tested to date
Six of the seven known persons with sialuria have been tested; all six had identifiable pathogenic variants in
Exons sequenced may vary by laboratory.
Including the allosteric domain (see
Testing that identifies exon or whole-gene deletions/duplications not readily 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, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosome microarray (CMA) that includes this gene/chromosome segment.
No deletions or duplications in
Assay of free sialic acid in urine
Sequence analysis of
Deletion/duplication analysis likely has limited clinical value: such testing is relevant only if no nucleotide change is detectable in or around the allosteric site in a person who fulfills all clinical and biochemical criteria of the diagnosis of sialuria.
• Mild facial coarsening
• Hypotonia
• Equivocal developmental delay
• Frequent upper respiratory infections
• Identifies a specific
• Distinguishes bound sialic acid from free sialic acid and hence distinguishes sialidosis from sialuria.
• Assay of free sialic acid in urine
• Sequence analysis of
• Deletion/duplication analysis likely has limited clinical value: such testing is relevant only if no nucleotide change is detectable in or around the allosteric site in a person who fulfills all clinical and biochemical criteria of the diagnosis of sialuria.
## Clinical Diagnosis
The diagnosis of sialuria may be suspected in infants or young children with the following:
Mild facial coarsening
Hypotonia
Equivocal developmental delay
Frequent upper respiratory infections
Note: The likelihood of sialuria is increased after exclusion of more prevalent disorders that share laboratory results rather than clinical features. See
• Mild facial coarsening
• Hypotonia
• Equivocal developmental delay
• Frequent upper respiratory infections
## Testing
Constitutive overproduction of free sialic acid is the metabolic defect of sialuria [
Provided that the
Note: (1) In the spectrophotometric method, other substances may either decrease or increase the absorbance and thus lead to spurious results. (2) High-performance liquid chromatography and proton nuclear magnetic resonance spectroscopy (1H-NMR) may be helpful in sorting out relevant differential diagnoses [
The combination of one- and two-dimensional correlation spectroscopy (COSY):
Identifies a specific
Distinguishes bound sialic acid from free sialic acid and hence distinguishes sialidosis from sialuria.
Molecular Genetic Testing Used in Sialuria
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
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
Total number of persons known to have been tested to date
Six of the seven known persons with sialuria have been tested; all six had identifiable pathogenic variants in
Exons sequenced may vary by laboratory.
Including the allosteric domain (see
Testing that identifies exon or whole-gene deletions/duplications not readily 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, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosome microarray (CMA) that includes this gene/chromosome segment.
No deletions or duplications in
• Identifies a specific
• Distinguishes bound sialic acid from free sialic acid and hence distinguishes sialidosis from sialuria.
## Molecular Genetic Testing
Molecular Genetic Testing Used in Sialuria
See
See
The ability of the test method used to detect a variant that is present in the indicated gene
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
Total number of persons known to have been tested to date
Six of the seven known persons with sialuria have been tested; all six had identifiable pathogenic variants in
Exons sequenced may vary by laboratory.
Including the allosteric domain (see
Testing that identifies exon or whole-gene deletions/duplications not readily 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, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosome microarray (CMA) that includes this gene/chromosome segment.
No deletions or duplications in
## Testing Strategy
Assay of free sialic acid in urine
Sequence analysis of
Deletion/duplication analysis likely has limited clinical value: such testing is relevant only if no nucleotide change is detectable in or around the allosteric site in a person who fulfills all clinical and biochemical criteria of the diagnosis of sialuria.
• Assay of free sialic acid in urine
• Sequence analysis of
• Deletion/duplication analysis likely has limited clinical value: such testing is relevant only if no nucleotide change is detectable in or around the allosteric site in a person who fulfills all clinical and biochemical criteria of the diagnosis of sialuria.
## Clinical Characteristics
A phenotypic definition or natural history of sialuria must remain preliminary as only seven affected persons have been reported [
Pregnancy is usually normal. Affected infants are rather small for gestational age. At birth, the OFC is normal; the facies appear rather flat and slightly coarse. Mild hepatomegaly occurs in the majority of children and prolonged neonatal jaundice can be observed. In early infancy, developmental delay is reported in most children and generalized hypotonia in some. Microcytic anemia in two infants was severe enough to require transfusion. Upper respiratory infections occur frequently into the second year of life, sometimes associated with gastroenteritis, dehydration, and transient failure to thrive. Signs of dysostosis multiplex appear to be transient, but skeletal development is delayed at least in early childhood. There are no signs of any progression of the disorder. Instead clinical expression appears to be limited to infancy or to early childhood at most.
Developmental age or IQ is borderline low. Later in childhood, physical development is normal and intellectual development can be nearly normal. One child had febrile convulsions. In about half of the children who had seizures in childhood, the seizures were controlled with phenobarbital [
The phenotypic spectrum of sialuria is insufficiently known. Moreover, it may be either equivocally abnormal or indistinguishable from the normal variation in childhood development. It is likely that children with sialuria who have no significant medical problems in infancy and/or early childhood do not come to medical attention at all. The retrospective diagnosis of sialuria in the mother of a proband supports this contention [
The direct correlation of genotype and phenotype is significant:
Penetrance cannot be estimated clinically as the findings in this disorder are nonspecific and variable between affected persons, as well as transient and limited to early childhood. Moreover, the intellectual disability inconsistently associated with sialuria is neither progressive nor significant.
In contrast, "biochemical" penetrance of the excessive urinary excretion of free sialic acid is probably complete in childhood. Excessive excretion of free sialic acid was also found in the mother of one proband, the only adult reported to have been tested so far. Hence any conclusion about "biochemical" penetrance in adults remains premature.
Anticipation has not been observed. However, no information on possible infantile signs or symptoms is available for the single affected adult known to date.
Before the simple term "sialuria" was adopted, the disorder was known as French type sialuria, because the first person described with sialuria and those who reported him were French. This descriptive nomenclature was considered useful for differentiation from Finnish type sialuria, the initial designation of the clinically severe
Sialuria has been reported in only seven persons.
The prevalence of sialuria may be underestimated. Assay of urinary levels of free sialic acid is not a routine laboratory procedure. As a rule, it is performed only in infants or young children with progressive CNS disease for confirmation or exclusion of the
The prevalence of sialuria remains unknown and is probably higher than that estimated from the existing reports of symptomatic persons.
## Clinical Description
A phenotypic definition or natural history of sialuria must remain preliminary as only seven affected persons have been reported [
Pregnancy is usually normal. Affected infants are rather small for gestational age. At birth, the OFC is normal; the facies appear rather flat and slightly coarse. Mild hepatomegaly occurs in the majority of children and prolonged neonatal jaundice can be observed. In early infancy, developmental delay is reported in most children and generalized hypotonia in some. Microcytic anemia in two infants was severe enough to require transfusion. Upper respiratory infections occur frequently into the second year of life, sometimes associated with gastroenteritis, dehydration, and transient failure to thrive. Signs of dysostosis multiplex appear to be transient, but skeletal development is delayed at least in early childhood. There are no signs of any progression of the disorder. Instead clinical expression appears to be limited to infancy or to early childhood at most.
Developmental age or IQ is borderline low. Later in childhood, physical development is normal and intellectual development can be nearly normal. One child had febrile convulsions. In about half of the children who had seizures in childhood, the seizures were controlled with phenobarbital [
The phenotypic spectrum of sialuria is insufficiently known. Moreover, it may be either equivocally abnormal or indistinguishable from the normal variation in childhood development. It is likely that children with sialuria who have no significant medical problems in infancy and/or early childhood do not come to medical attention at all. The retrospective diagnosis of sialuria in the mother of a proband supports this contention [
## Genotype-Phenotype Correlations
The direct correlation of genotype and phenotype is significant:
## Penetrance
Penetrance cannot be estimated clinically as the findings in this disorder are nonspecific and variable between affected persons, as well as transient and limited to early childhood. Moreover, the intellectual disability inconsistently associated with sialuria is neither progressive nor significant.
In contrast, "biochemical" penetrance of the excessive urinary excretion of free sialic acid is probably complete in childhood. Excessive excretion of free sialic acid was also found in the mother of one proband, the only adult reported to have been tested so far. Hence any conclusion about "biochemical" penetrance in adults remains premature.
## Anticipation
Anticipation has not been observed. However, no information on possible infantile signs or symptoms is available for the single affected adult known to date.
## Nomenclature
Before the simple term "sialuria" was adopted, the disorder was known as French type sialuria, because the first person described with sialuria and those who reported him were French. This descriptive nomenclature was considered useful for differentiation from Finnish type sialuria, the initial designation of the clinically severe
## Prevalence
Sialuria has been reported in only seven persons.
The prevalence of sialuria may be underestimated. Assay of urinary levels of free sialic acid is not a routine laboratory procedure. As a rule, it is performed only in infants or young children with progressive CNS disease for confirmation or exclusion of the
The prevalence of sialuria remains unknown and is probably higher than that estimated from the existing reports of symptomatic persons.
## Genetically Related (Allelic) Disorders
In contrast to the dominant gain-of-function effect of heterozygous pathogenic variants in the allosteric site observed in sialuria, homozygous or compound heterozygous
The
Hereditary inclusion body myopathy (hIBM) begins in the young adult with gait difficulties resulting from compromised foot dorsiflexion. Muscle weakness, first apparent in the distal limb muscles, progresses in severity. In the early stages of the disorder the proximal limb muscles (quadriceps in the legs and deltoids, biceps, and triceps in the arms) appear to be spared. Weakness in these muscles appears in the later stages of the disorder. There is gradual reduction of muscle bulk in the limbs. Affected persons become wheelchair bound. Intellectual functioning, sensation, and coordination remain intact even when the myopathy becomes more widespread and severe.
Diagnosis is based on the histopathologic findings of red rimmed vacuolar degeneration of muscle fibers; specific MRI T
## Differential Diagnosis
The
Free sialic acid storage disorders result from defective transport of free sialic acid out of lysosomes as a consequence of pathogenic variants in
Free sialic acid storage disease caused by homozygosity of the p.Lys136Glu mutated allele in
Although mild, inconsistent, and transient, the initial clinical features make the differential diagnosis in infants and young children an interesting challenge.
The diagnosis of MPS I relies on the demonstration of deficient activity of the lysosomal enzyme α-L-iduronidase in peripheral blood leukocytes or cultured fibroblasts. Glycosaminoglycan (GAG) (heparan and dermatan sulphate) urinary excretion is a useful preliminary test.
Mucolipidosis III alpha/beta is caused by homozygous or compound heterozygous pathogenic variants in
• Mucolipidosis III alpha/beta is caused by homozygous or compound heterozygous pathogenic variants in
## Increased Urinary and Intracellular Free Sialic Acid
The
Free sialic acid storage disorders result from defective transport of free sialic acid out of lysosomes as a consequence of pathogenic variants in
Free sialic acid storage disease caused by homozygosity of the p.Lys136Glu mutated allele in
## Initial Clinical Features (Coarse Facies, Hypotonia, Hepatomegaly)
Although mild, inconsistent, and transient, the initial clinical features make the differential diagnosis in infants and young children an interesting challenge.
The diagnosis of MPS I relies on the demonstration of deficient activity of the lysosomal enzyme α-L-iduronidase in peripheral blood leukocytes or cultured fibroblasts. Glycosaminoglycan (GAG) (heparan and dermatan sulphate) urinary excretion is a useful preliminary test.
Mucolipidosis III alpha/beta is caused by homozygous or compound heterozygous pathogenic variants in
• Mucolipidosis III alpha/beta is caused by homozygous or compound heterozygous pathogenic variants in
## Management
To establish the extent of disease in a person diagnosed with sialuria, the following evaluations are recommended, if they have not already been completed. Note: The priority of these recommendations depends on the signs observed in the patient and/or noted by the parents:
CBC with differential to evaluate for microcytic anemia
Measurement of serum bilirubin concentration to evaluate for jaundice
Skeletal survey to evaluate for dysostosis multiplex
Developmental and neurologic assessment
EEG when relevant
Neuroimaging with the purpose of differentiating sialuria from neurodegenerative lysosomal storage disorders
Persons with sialuria need symptomatic and supportive management, including treatment of anemia, prolonged but mild jaundice, and convulsions. Barbiturates have been more effective in treating the occasional convulsion in early childhood than other antiepileptic drugs (AEDs).
Affected individuals benefit from early developmental intervention and appropriate educational programs.
Appropriate antibiotics to prevent secondary bacterial super-infection in the upper/lower airways are indicated.
The following are appropriate:
Clinical follow up during and after infancy to confirm that CNS disease is not progressive (in contrast to
Follow-up evaluations three to four times in infancy, twice in the second year of life, and once every subsequent year
See
Search
Click
• CBC with differential to evaluate for microcytic anemia
• Measurement of serum bilirubin concentration to evaluate for jaundice
• Skeletal survey to evaluate for dysostosis multiplex
• Developmental and neurologic assessment
• EEG when relevant
• Neuroimaging with the purpose of differentiating sialuria from neurodegenerative lysosomal storage disorders
• Clinical follow up during and after infancy to confirm that CNS disease is not progressive (in contrast to
• Follow-up evaluations three to four times in infancy, twice in the second year of life, and once every subsequent year
## Evaluations Following Initial Diagnosis
To establish the extent of disease in a person diagnosed with sialuria, the following evaluations are recommended, if they have not already been completed. Note: The priority of these recommendations depends on the signs observed in the patient and/or noted by the parents:
CBC with differential to evaluate for microcytic anemia
Measurement of serum bilirubin concentration to evaluate for jaundice
Skeletal survey to evaluate for dysostosis multiplex
Developmental and neurologic assessment
EEG when relevant
Neuroimaging with the purpose of differentiating sialuria from neurodegenerative lysosomal storage disorders
• CBC with differential to evaluate for microcytic anemia
• Measurement of serum bilirubin concentration to evaluate for jaundice
• Skeletal survey to evaluate for dysostosis multiplex
• Developmental and neurologic assessment
• EEG when relevant
• Neuroimaging with the purpose of differentiating sialuria from neurodegenerative lysosomal storage disorders
## Treatment of Manifestations
Persons with sialuria need symptomatic and supportive management, including treatment of anemia, prolonged but mild jaundice, and convulsions. Barbiturates have been more effective in treating the occasional convulsion in early childhood than other antiepileptic drugs (AEDs).
Affected individuals benefit from early developmental intervention and appropriate educational programs.
## Prevention of Secondary Complications
Appropriate antibiotics to prevent secondary bacterial super-infection in the upper/lower airways are indicated.
## Surveillance
The following are appropriate:
Clinical follow up during and after infancy to confirm that CNS disease is not progressive (in contrast to
Follow-up evaluations three to four times in infancy, twice in the second year of life, and once every subsequent year
• Clinical follow up during and after infancy to confirm that CNS disease is not progressive (in contrast to
• Follow-up evaluations three to four times in infancy, twice in the second year of life, and once every subsequent year
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
Click
## Genetic Counseling
Sialuria is inherited in an autosomal dominant manner.
Most persons diagnosed with sialuria do not have a parent known to be affected. However, molecular genetic testing has usually not been performed on both parents; thus, the actual percentage of persons who have inherited the pathogenic variant from a parent is unknown.
A proband with sialuria most likely has the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
If a parent of the proband is affected or has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
If the pathogenic variant found in the proband cannot be detected in the DNA of the either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has not been reported.
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.
Interpretation of prenatal diagnosis testing is complicated by the current lack of information about the phenotype, particularly its long-term outcome. Results of prenatal testing cannot predict the age of onset, clinical course, or degree of disability.
• Most persons diagnosed with sialuria do not have a parent known to be affected. However, molecular genetic testing has usually not been performed on both parents; thus, the actual percentage of persons who have inherited the pathogenic variant from a parent is unknown.
• A proband with sialuria most likely has the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• If a parent of the proband is affected or has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the pathogenic variant found in the proband cannot be detected in the DNA of the either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has not been reported.
• 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
Sialuria is inherited in an autosomal dominant manner.
## Risk to Family Members
Most persons diagnosed with sialuria do not have a parent known to be affected. However, molecular genetic testing has usually not been performed on both parents; thus, the actual percentage of persons who have inherited the pathogenic variant from a parent is unknown.
A proband with sialuria most likely has the disorder as the result of a
Recommendations for the evaluation of parents of a proband with an apparent
If a parent of the proband is affected or has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
If the pathogenic variant found in the proband cannot be detected in the DNA of the either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has not been reported.
• Most persons diagnosed with sialuria do not have a parent known to be affected. However, molecular genetic testing has usually not been performed on both parents; thus, the actual percentage of persons who have inherited the pathogenic variant from a parent is unknown.
• A proband with sialuria most likely has the disorder as the result of a
• Recommendations for the evaluation of parents of a proband with an apparent
• If a parent of the proband is affected or has a pathogenic variant, the risk to the sibs of inheriting the variant is 50%.
• If the pathogenic variant found in the proband cannot be detected in the DNA of the either parent, the risk to sibs is low, but greater than that of the general population because of the possibility of germline mosaicism. Germline mosaicism has not been reported.
## 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 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
Interpretation of prenatal diagnosis testing is complicated by the current lack of information about the phenotype, particularly its long-term outcome. Results of prenatal testing cannot predict the age of onset, clinical course, or degree of disability.
## Resources
United Kingdom
•
• United Kingdom
•
## Molecular Genetics
Sialuria: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Sialuria (
In each person with sialuria, the
The lack of feedback inhibition results in highly excessive production of free sialic acid and in its very elevated concentrations in the cellular cytoplasm, interstitial tissues, and body fluids, such as urine.
Defective allosteric inhibition is not an exceptional cause of human metabolic disease. It has been shown recently also for the glutamate dehydrogenase gene in infants with hyperinsulinism and hyperammonemia (see
Note: Homozygous or compound heterozygous pathogenic variants in either the epimerase domain or the kinase domain are associated with adult-onset autosomal recessive hereditary inclusion body myopathy (hIBM). See
Selected
Note on variant classification: Variants listed in the table have been provided by the author.
Note on nomenclature:
The codon numbers correspond to reference sequence
Human GNE (GNE/MNK) exists in three different isoforms – hGNE1, hGNE2, and hGNE3 – the latter two possessing extended or deleted N-terminal regions, respectively. The isoform hGNE1 is ubiquitously expressed, most intensively in liver and placenta. Lower concentrations are detectable in muscle, brain, kidney, and pancreas [
It is of interest that as a monomer GNE/MNK has no catalytic activity. It requires di- and even multimerization of the nascent polypeptides in order to become fully active as a bifunctional enzyme [
The activity of the bifunctional and rate-limiting GNE enzyme is normal in sialuria fibroblasts, but no longer subject to retro-inhibition by the end-product CMP-sialic acid, when one and only one of the two
The apparently rare individuals with sialuria have a clinically mild disorder. Nevertheless, a pathogenic variant resulting in an allosteric autosomal dominant metabolic defect is of considerable importance in the study of the various physiologic roles of free sialic acid and of sialylation in tissues. Moreover, the metabolic trait has been shown to be important in the production of biologic molecules with therapeutic potential and in testing the feasibility of silencing mutation effects by RNA interference. Click
## Molecular Genetic Pathogenesis
In each person with sialuria, the
The lack of feedback inhibition results in highly excessive production of free sialic acid and in its very elevated concentrations in the cellular cytoplasm, interstitial tissues, and body fluids, such as urine.
Defective allosteric inhibition is not an exceptional cause of human metabolic disease. It has been shown recently also for the glutamate dehydrogenase gene in infants with hyperinsulinism and hyperammonemia (see
Note: Homozygous or compound heterozygous pathogenic variants in either the epimerase domain or the kinase domain are associated with adult-onset autosomal recessive hereditary inclusion body myopathy (hIBM). See
Selected
Note on variant classification: Variants listed in the table have been provided by the author.
Note on nomenclature:
The codon numbers correspond to reference sequence
Human GNE (GNE/MNK) exists in three different isoforms – hGNE1, hGNE2, and hGNE3 – the latter two possessing extended or deleted N-terminal regions, respectively. The isoform hGNE1 is ubiquitously expressed, most intensively in liver and placenta. Lower concentrations are detectable in muscle, brain, kidney, and pancreas [
It is of interest that as a monomer GNE/MNK has no catalytic activity. It requires di- and even multimerization of the nascent polypeptides in order to become fully active as a bifunctional enzyme [
The activity of the bifunctional and rate-limiting GNE enzyme is normal in sialuria fibroblasts, but no longer subject to retro-inhibition by the end-product CMP-sialic acid, when one and only one of the two
The apparently rare individuals with sialuria have a clinically mild disorder. Nevertheless, a pathogenic variant resulting in an allosteric autosomal dominant metabolic defect is of considerable importance in the study of the various physiologic roles of free sialic acid and of sialylation in tissues. Moreover, the metabolic trait has been shown to be important in the production of biologic molecules with therapeutic potential and in testing the feasibility of silencing mutation effects by RNA interference. Click
## References
## Literature Cited
## Suggested Reading
## Chapter Notes
The help and advice regarding recent progress in hIBM, provided by Dr Marjan Huizing and Dr Donna M Krasnewich, NIH, Bethesda, MD, is gratefully acknowledged.
7 March 2019 (ma) Chapter retired: extremely rare
18 October 2012 (me) Comprehensive update posted live
2 March 2010 (me) Comprehensive update posted live
27 February 2007 (jgl) Revision: clinical testing and prenatal diagnosis no longer available
10 March 2006 (me) Comprehensive update posted live
14 January 2004 (me) Review posted live
26 September 2003 (jgl) Original submission
• 7 March 2019 (ma) Chapter retired: extremely rare
• 18 October 2012 (me) Comprehensive update posted live
• 2 March 2010 (me) Comprehensive update posted live
• 27 February 2007 (jgl) Revision: clinical testing and prenatal diagnosis no longer available
• 10 March 2006 (me) Comprehensive update posted live
• 14 January 2004 (me) Review posted live
• 26 September 2003 (jgl) Original submission
## Acknowledgments
The help and advice regarding recent progress in hIBM, provided by Dr Marjan Huizing and Dr Donna M Krasnewich, NIH, Bethesda, MD, is gratefully acknowledged.
## Revision History
7 March 2019 (ma) Chapter retired: extremely rare
18 October 2012 (me) Comprehensive update posted live
2 March 2010 (me) Comprehensive update posted live
27 February 2007 (jgl) Revision: clinical testing and prenatal diagnosis no longer available
10 March 2006 (me) Comprehensive update posted live
14 January 2004 (me) Review posted live
26 September 2003 (jgl) Original submission
• 7 March 2019 (ma) Chapter retired: extremely rare
• 18 October 2012 (me) Comprehensive update posted live
• 2 March 2010 (me) Comprehensive update posted live
• 27 February 2007 (jgl) Revision: clinical testing and prenatal diagnosis no longer available
• 10 March 2006 (me) Comprehensive update posted live
• 14 January 2004 (me) Review posted live
• 26 September 2003 (jgl) Original submission
|
[
"Z Argov, I Eisenberg, G Grabov-Nardini, M Sadeh, I Wirguin, D Soffer, S Mitrani-Rosenbaum. Hereditary inclusion body myopathy: the Middle Eastern genetic cluster.. Neurology. 2003;60:1519-23",
"Z Argov, S Mitrani-Rosenbaum. The hereditary inclusion body myopathy enigma and its future therapy.. Neurotherapeutics. 2008;5:633-7",
"N Aula, A Jalanko, P Aula, L Peltonen. Unraveling the molecular pathogenesis of free sialic acid storage disorders: altered targeting of mutant sialin.. Mol Genet Metab. 2002;77:99-107",
"N Aula, P Salomäki, R Timonen, F Verheijen, G Mancini, JE Månsson, P Aula, L Peltonen. The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation.. Am J Hum Genet. 2000;67:832-40",
"C Bellini, RC Hennekam, E Fulcheri, M Rutigliani, G Morcaldi, F Boccardo, E Bonioli. Etiology of nonimmune hydrops fetalis: a systematic review.. Am J Med Genet A. 2009;149A:844-51",
"R Biancheri, E Verbeek, A Rossi, R Gaggero, L Roccatagliata, R Gatti, O van Diggelen, FW Verheyen, GM Mancini. An Italian severe Salla disease variant associated with a SLC17A5 mutation earlier described in infantile sialic acid storage disease.. Clin Genet. 2002;61:443-7",
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"PP Cardo, C Lombardo, R Gatti. A simple detection of sialic acid storage disorders by urinary 'free' and 'total' sialic acid determinations.. Clin Chim Acta. 1985;150:129-35",
"SS Cathey, M Kudo, S Tiede, A Raas-Rothschild, T Braulke, M Beck, HA Taylor, WM Canfield, JG Leroy, EF Neufeld, VA McKusick. Molecular order in mucolipidosis II and III nomenclature.. Am J Med Genet A. 2008;146A:512-3",
"SS Cathey, JG Leroy, T Wood, K Eaves, RJ Simensen, M Kudo, RE Stevenson, MJ Friez. Phenotype and genotype in mucolipidoses II and III alpha/beta: a study of 61 probands.. J Med Genet. 2010;47:38-48",
"UF Engelke, ML Liebrand-van Sambeek, JG de Jong, JG Leroy, E Morava, JA Smeitink, RA Wevers. N-acetylated metabolites in urine: proton nuclear magnetic resonance spectroscopic study on patients with inborn errors of metabolism.. Clin Chem. 2004;50:58-66",
"GM Enns, R Seppala, TJ Musci, K Weisiger, LD Ferrell, DA Wenger, WA Gahl, S Packman. Clinical course and biochemistry of sialuria.. J Inherit Metab Dis. 2001;24:328-36",
"H Ferreira, R Seppala, R Pinto, M Huizing, E Martins, AC Braga, L Gomes, DM Krasnewich, MC Sa Miranda, WA Gahl. Sialuria in a Portuguese girl: clinical, biochemical, and molecular characteristics.. Mol Genet Metab. 1999;67:131-7",
"KP Gopaul, MA Crook. The inborn errors of sialic acid metabolism and their laboratory investigation.. Clin Lab. 2006;52:155-69",
"M Huizing. Disease mechanisms associated with mutations of the GNE gene.. Drug Discov today. 2005;2:519-27",
"M Huizing, DM Krasnewich. Hereditary inclusion body myopathy: a decade of progress.. Biochim Biophys Acta 2009;1792:881-7",
"M Huizing, G Rakocevic, SE Sparks, I Mamali, A Shatunov, L Goldfarb, D Krasnewich, WA Gahl, MC Dalakas. Hypoglycosylation of alpha-dystroglycan in patients with hereditary IBM due to GNE mutations.. Mol Genet Metab 2004;81:196-202",
"T Kayashima, H Matsuo, A Satoh, T Ohta, K Yoshiura, N Matsumoto, Y Nakane, N Niikawa, T Kishino. Nonaka myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase gene (GNE).. J Hum Genet. 2002;47:77-9",
"S Krause, S Hinderlich, S Amsili, R Horstkorte, H Wiendl, Z Argov, S Mitrani-Rosenbaum, H Lochmüller. Localization of UDP-GlcNAc 2-epimerase/ManAc kinase (GNE) in the Golgi complex and the nucleus of mammalian cells.. Exp Cell Res. 2005;304:365-79",
"E Lemyre, P Russo, SB Melançon, R Gagné, M Potier, M Lambert. Clinical spectrum of infantile free sialic acid storage disease.. Am J Med Genet. 1999;82:385-91",
"JG Leroy, R Seppala, M Huizing, G Dacremont, H De Simpel, RN Van Coster, E Orvisky, DM Krasnewich, WA Gahl. Dominant inheritance of sialuria, an inborn error of feedback inhibition.. Am J Hum Genet. 2001;68:1419-27",
"F Mochel, B Yang, J Barritault, JN Thompson, UF Engelke, NH McNeill, WS Benko, CR Kaneski, DR Adams, M Tsokos, M Abu-Asab, M Huizing, F Seguin, RA Wevers, J Ding, FW Verheijen, R Schiffmann. Free sialic acid storage disease without sialuria.. Ann Neurol. 2009;65:753-7",
"RP Morse, R Kleta, J Alroy, WA Gahl. Novel form of intermediate salla disease: clinical and neuroimaging features.. J Child Neurol. 2005;20:814-6",
"I Nishino, S Noguchi, K Murayama, A Driss, K Sugie, Y Oya, T Nagata, K Chida, T Takahashi, Y Takusa, T Ohi, J Nishimiya, N Sunohara, E Ciafaloni, M Kawai, M Aoki, I Nonaka. Distal myopathy with rimmed vacuoles is allelic to hereditary inclusion body myopathy.. Neurology. 2002;59:1689-93",
"SO Reinke, G Lehmer, S Hinderlich, W Reutter. Regulation and pathophysiological implications of UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE) as the key enzyme of sialic acid biosynthesis.. Biol Chem. 2009;390:591-9",
"R Seppala, VP Lehto, WA Gahl. Mutations in the human UDP-N-acetylglucosamine 2-epimerase gene define the disease sialuria and the allosteric site of the enzyme.. Am J Hum Genet. 1999;64:1563-9",
"DL Stone, E Sidransky. Hydrops fetalis: lysosomal storage disorders in extremis.. Adv Pediatr. 1999;46:409-40",
"H Tomimitsu, J Shimizu, K Ishikawa, N Ohkoshi, I Kanazawa, H Mizusawa. Distal myopathy with rimmed vacuoles (DMRV): new GNE mutations and splice variant.. Neurology. 2004;62:1607-10",
"F Valianpour, NG Abeling, M Duran, JG Huijmans, W Kulik. Quantification of free sialic acid in urine by HPLC-electrospray tandem mass spectrometry: a tool for the diagnosis of sialic acid storage disease.. Clin Chem. 2004;50:403-9",
"T Varho, S Jääskeläinen, U Tolonen, P Sonninen, L Vainionpää, P Aula, M Sillanpää. Central and peripheral nervous system dysfunction in the clinical variation of Salla disease.. Neurology. 2000;55:99-104",
"TT Varho, LE Alajoki, KM Posti, TT Korhonen, MG Renlund, SR Nyman, ML Sillanpää, PP Aula. Phenotypic spectrum of Salla disease, a free sialic acid storage disorder.. Pediatr Neurol. 2002;26:267-73",
"OM Vasconcelos, R Raju, MC Dalakas. GNE mutations in an American family with quadriceps-sparing IBM and lack of mutations in s-IBM.. Neurology. 2002;59:1776-9",
"FW Verheijen, E Verbeek, N Aula, CE Beerens, AC Havelaar, M Joosse, L Peltonen, P Aula, H Galjaard, PJ van der Spek, GM Mancini. A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases.. Nat Genet. 1999;23:462-5"
] |
14/1/2004
|
18/10/2012
|
27/2/2007
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sgbs
|
sgbs
|
[
"Glypican-3",
"GPC3",
"Simpson-Golabi-Behmel Syndrome Type 1"
] |
Simpson-Golabi-Behmel Syndrome Type 1
|
Alex F Nisbet, Evan R Hathaway, Jennifer M Kalish
|
Summary Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is characterized by pre- and postnatal macrosomia; distinctive craniofacial features (including macrocephaly, coarse facial features, macrostomia, macroglossia, and palate abnormalities); and, commonly, mild-to-severe intellectual disability with or without structural brain anomalies. Other variable findings include supernumerary nipples, diastasis recti / umbilical hernia, congenital heart defects, diaphragmatic hernia, genitourinary defects, and gastrointestinal issues. Skeletal anomalies can include vertebral fusion, scoliosis, rib anomalies, and congenital hip dislocation. Hand anomalies can include large hands and postaxial polydactyly. Affected individuals are at increased risk for embryonal tumors including Wilms tumor, hepatoblastoma, adrenal neuroblastoma, gonadoblastoma, hepatocellular carcinoma, and medulloblastoma. The diagnosis of SGBS1 is established in a male proband with suggestive findings and/or a hemizygous pathogenic variant in SGBS1 is inherited in an X-linked manner. If the mother of the proband has a pathogenic variant, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Males who inherit the pathogenic variant will be affected. Females who inherit the pathogenic variant will be carriers, although due to X-chromosome inactivation, carrier females may have manifestations of SGBS1. Males with SGBS1 will pass the pathogenic variant to all their daughters and none of their sons. Carrier testing for at-risk relatives and prenatal testing for a pregnancy at increased risk are possible for families in which the pathogenic variant has been identified.
|
## Diagnosis
For the purposes of this
Consensus clinical diagnostic criteria for Simpson-Golabi-Behmel syndrome type 1 (SGBS1) have not been established.
SGBS1
Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
Redundant, furrowed skin over the glabella
Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
Prominent forehead
Macrostomia
Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
Micrognathia in neonates; macrognathia in older individuals
Other features
Supernumerary nipples
Diastasis recti / umbilical hernia
Diaphragmatic hernia
Hand and foot anomalies (brachydactyly, cutaneous syndactyly, polydactyly, shortened distal phalanges, fingernail dysplasia)
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 SGBS1, molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to CMA click
When the diagnosis of SGBS1 has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Simpson-Golabi-Behmel Syndrome Type 1
SGBS1 = Simpson-Golabi-Behmel syndrome type 1
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.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Contiguous deletions of
•
•
•
• Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
• Prominent forehead
• Macrostomia
• Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
• Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
• Micrognathia in neonates; macrognathia in older individuals
• Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
• Prominent forehead
• Macrostomia
• Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
• Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
• Micrognathia in neonates; macrognathia in older individuals
• Other features
• Supernumerary nipples
• Diastasis recti / umbilical hernia
• Diaphragmatic hernia
• Hand and foot anomalies (brachydactyly, cutaneous syndactyly, polydactyly, shortened distal phalanges, fingernail dysplasia)
• Supernumerary nipples
• Diastasis recti / umbilical hernia
• Diaphragmatic hernia
• Hand and foot anomalies (brachydactyly, cutaneous syndactyly, polydactyly, shortened distal phalanges, fingernail dysplasia)
• Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
• Prominent forehead
• Macrostomia
• Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
• Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
• Micrognathia in neonates; macrognathia in older individuals
• Supernumerary nipples
• Diastasis recti / umbilical hernia
• Diaphragmatic hernia
• Hand and foot anomalies (brachydactyly, cutaneous syndactyly, polydactyly, shortened distal phalanges, fingernail dysplasia)
• For an introduction to multigene panels click
• For an introduction to CMA click
## Suggestive Findings
SGBS1
Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
Redundant, furrowed skin over the glabella
Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
Prominent forehead
Macrostomia
Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
Micrognathia in neonates; macrognathia in older individuals
Other features
Supernumerary nipples
Diastasis recti / umbilical hernia
Diaphragmatic hernia
Hand and foot anomalies (brachydactyly, cutaneous syndactyly, polydactyly, shortened distal phalanges, fingernail dysplasia)
•
•
•
• Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
• Prominent forehead
• Macrostomia
• Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
• Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
• Micrognathia in neonates; macrognathia in older individuals
• Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
• Prominent forehead
• Macrostomia
• Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
• Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
• Micrognathia in neonates; macrognathia in older individuals
• Other features
• Supernumerary nipples
• Diastasis recti / umbilical hernia
• Diaphragmatic hernia
• Hand and foot anomalies (brachydactyly, cutaneous syndactyly, polydactyly, shortened distal phalanges, fingernail dysplasia)
• Supernumerary nipples
• Diastasis recti / umbilical hernia
• Diaphragmatic hernia
• Hand and foot anomalies (brachydactyly, cutaneous syndactyly, polydactyly, shortened distal phalanges, fingernail dysplasia)
• Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
• Prominent forehead
• Macrostomia
• Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
• Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
• Micrognathia in neonates; macrognathia in older individuals
• Supernumerary nipples
• Diastasis recti / umbilical hernia
• Diaphragmatic hernia
• Hand and foot anomalies (brachydactyly, cutaneous syndactyly, polydactyly, shortened distal phalanges, fingernail dysplasia)
## 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 genetic testing approaches can include a combination of
When the phenotypic and laboratory findings suggest the diagnosis of SGBS1, molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to CMA click
When the diagnosis of SGBS1 has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Simpson-Golabi-Behmel Syndrome Type 1
SGBS1 = Simpson-Golabi-Behmel syndrome type 1
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.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Contiguous deletions of
• For an introduction to multigene panels click
• For an introduction to CMA click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of SGBS1, molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to CMA click
• For an introduction to multigene panels click
• For an introduction to CMA click
## Option 2
When the diagnosis of SGBS1 has not been considered because an individual has atypical phenotypic features,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Simpson-Golabi-Behmel Syndrome Type 1
SGBS1 = Simpson-Golabi-Behmel syndrome type 1
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.
Chromosomal microarray analysis (CMA) uses oligonucleotide or SNP arrays to detect genome-wide large deletions/duplications (including
Data derived from the subscription-based professional view of Human Gene Mutation Database [
Contiguous deletions of
## Clinical Characteristics
Males and females can present similarly with Simpson-Golabi-Behmel syndrome type 1 (SGBS1). However, there is skewing of males to females in a 9:1 ratio. Individuals of both sexes present with overgrowth, characteristic facial features, skeletal abnormalities, and genitourinary dysfunction. Males often present with cryptorchidism. Females are less likely to present with significant manifestations of SGBS1, potentially due to skewed X-chromosome inactivation. There have not been extensive studies of sex differences in SGBS1 due to the small number of females reported to date and mildly affected or unaffected female carriers who do not present until they have an affected son.
SGBS1 is characterized by pre- and postnatal overgrowth, distinctive facies, and variable visceral, skeletal, and neurodevelopmental abnormalities. To date, more than 180 individuals have been identified with a pathogenic variant in
Simpson-Golabi-Behmel Syndrome Type 1: Frequency of Select Features
Based on
SD = standard deviations
As with other overgrowth syndromes, hypoglycemia may be present in the neonatal period; however, hypoglycemia is rare in SGBS1 and is not considered to be a cardinal feature.
Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
Redundant, furrowed skin over the glabella
Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
Prominent forehead
Macrostomia
Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
Micrognathia in neonates; large mandible (macrognathia) in older individuals
Congenital heart defects are variable; septal defects are common. Pulmonic stenosis, aortic coarctation, transposition of the great vessels, and patent ductus arteriosus or patent foramen ovale have been reported.
Conduction defects and arrhythmias have also been described [
Other genitourinary anomalies include hypospadias, penile hypoplasia, ambiguous genitalia, anal atresia, bifid scrotum, cryptorchidism, hydrocele, and inguinal hernia [
Hand anomalies such as large hands, broad thumbs, and brachydactyly are common. Other findings include syndactyly, clinodactyly, and postaxial polydactyly. Striking index finger hypoplasia with congenital abnormalities of the proximal phalanx have been reported [
Advanced bone age, including presence of ossified carpal bones in a newborn, has been described [
Normal intelligence has been described, but mild-to-severe intellectual disability is common, with language delay being the most characteristic finding.
Hydrocephalus, epilepsy, and attention-deficit/hyperactivity disorder may also be present [
Brain abnormalities have been reported, including agenesis of the corpus callosum, Chiari malformation, hydrocephalus, and hypoplasia of the cerebellar vermis [
Additionally, several tumors have been reported in single individuals, but it is unknown if they are related to the pathogenesis of SGBS1 or reflect the underlying population-level neoplastic risk. Each of the following has been reported in single individuals:
Acute lymphoblastic leukemia [
Ameloblastoma [
Diffuse neonatal hemangiomatosis [
Hepatocellular carcinoma [
Medulloblastoma [
Pancreatic carcinoma [
Renal neuroblastoma [
Due to skewed X-chromosome inactivation, heterozygous females can have variable manifestations of SBGS1 ranging from completely unaffected to fully recapitulating the severe phenotype, including overgrowth, widely spaced eyes, broad and upturned nasal tip with prominent columella, macrostomia, prominent chin, hypoplastic fingernails, coccygeal skin tag and bony appendage, extra lumbar and thoracic vertebrae, and accessory nipples [
To date, nine heterozygous females with clinical expression of SGBS1 have been reported [
There are no known clinically relevant genotype-phenotype correlations for SGBS1 to date.
All males reported with a
SGBS1 was initially described by
Terms no longer in use for SGBS1:
Gigantism-dysplasia syndrome
Encephalo-tropho-schisis syndrome
Golabi-Rosen syndrome
Simpson dysmorphia syndrome
The prevalence of SGBS1 is unknown; however, it is believed to be underdiagnosed due to the wide spectrum of clinical severity.
• As with other overgrowth syndromes, hypoglycemia may be present in the neonatal period; however, hypoglycemia is rare in SGBS1 and is not considered to be a cardinal feature.
• Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
• Prominent forehead
• Macrostomia
• Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
• Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
• Micrognathia in neonates; large mandible (macrognathia) in older individuals
• Congenital heart defects are variable; septal defects are common. Pulmonic stenosis, aortic coarctation, transposition of the great vessels, and patent ductus arteriosus or patent foramen ovale have been reported.
• Conduction defects and arrhythmias have also been described [
• Acute lymphoblastic leukemia [
• Ameloblastoma [
• Diffuse neonatal hemangiomatosis [
• Hepatocellular carcinoma [
• Medulloblastoma [
• Pancreatic carcinoma [
• Renal neuroblastoma [
• Gigantism-dysplasia syndrome
• Encephalo-tropho-schisis syndrome
• Golabi-Rosen syndrome
• Simpson dysmorphia syndrome
## Clinical Description
Males and females can present similarly with Simpson-Golabi-Behmel syndrome type 1 (SGBS1). However, there is skewing of males to females in a 9:1 ratio. Individuals of both sexes present with overgrowth, characteristic facial features, skeletal abnormalities, and genitourinary dysfunction. Males often present with cryptorchidism. Females are less likely to present with significant manifestations of SGBS1, potentially due to skewed X-chromosome inactivation. There have not been extensive studies of sex differences in SGBS1 due to the small number of females reported to date and mildly affected or unaffected female carriers who do not present until they have an affected son.
SGBS1 is characterized by pre- and postnatal overgrowth, distinctive facies, and variable visceral, skeletal, and neurodevelopmental abnormalities. To date, more than 180 individuals have been identified with a pathogenic variant in
Simpson-Golabi-Behmel Syndrome Type 1: Frequency of Select Features
Based on
SD = standard deviations
As with other overgrowth syndromes, hypoglycemia may be present in the neonatal period; however, hypoglycemia is rare in SGBS1 and is not considered to be a cardinal feature.
Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
Redundant, furrowed skin over the glabella
Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
Prominent forehead
Macrostomia
Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
Micrognathia in neonates; large mandible (macrognathia) in older individuals
Congenital heart defects are variable; septal defects are common. Pulmonic stenosis, aortic coarctation, transposition of the great vessels, and patent ductus arteriosus or patent foramen ovale have been reported.
Conduction defects and arrhythmias have also been described [
Other genitourinary anomalies include hypospadias, penile hypoplasia, ambiguous genitalia, anal atresia, bifid scrotum, cryptorchidism, hydrocele, and inguinal hernia [
Hand anomalies such as large hands, broad thumbs, and brachydactyly are common. Other findings include syndactyly, clinodactyly, and postaxial polydactyly. Striking index finger hypoplasia with congenital abnormalities of the proximal phalanx have been reported [
Advanced bone age, including presence of ossified carpal bones in a newborn, has been described [
Normal intelligence has been described, but mild-to-severe intellectual disability is common, with language delay being the most characteristic finding.
Hydrocephalus, epilepsy, and attention-deficit/hyperactivity disorder may also be present [
Brain abnormalities have been reported, including agenesis of the corpus callosum, Chiari malformation, hydrocephalus, and hypoplasia of the cerebellar vermis [
Additionally, several tumors have been reported in single individuals, but it is unknown if they are related to the pathogenesis of SGBS1 or reflect the underlying population-level neoplastic risk. Each of the following has been reported in single individuals:
Acute lymphoblastic leukemia [
Ameloblastoma [
Diffuse neonatal hemangiomatosis [
Hepatocellular carcinoma [
Medulloblastoma [
Pancreatic carcinoma [
Renal neuroblastoma [
Due to skewed X-chromosome inactivation, heterozygous females can have variable manifestations of SBGS1 ranging from completely unaffected to fully recapitulating the severe phenotype, including overgrowth, widely spaced eyes, broad and upturned nasal tip with prominent columella, macrostomia, prominent chin, hypoplastic fingernails, coccygeal skin tag and bony appendage, extra lumbar and thoracic vertebrae, and accessory nipples [
To date, nine heterozygous females with clinical expression of SGBS1 have been reported [
• As with other overgrowth syndromes, hypoglycemia may be present in the neonatal period; however, hypoglycemia is rare in SGBS1 and is not considered to be a cardinal feature.
• Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
• Prominent forehead
• Macrostomia
• Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
• Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
• Micrognathia in neonates; large mandible (macrognathia) in older individuals
• Congenital heart defects are variable; septal defects are common. Pulmonic stenosis, aortic coarctation, transposition of the great vessels, and patent ductus arteriosus or patent foramen ovale have been reported.
• Conduction defects and arrhythmias have also been described [
• Acute lymphoblastic leukemia [
• Ameloblastoma [
• Diffuse neonatal hemangiomatosis [
• Hepatocellular carcinoma [
• Medulloblastoma [
• Pancreatic carcinoma [
• Renal neuroblastoma [
## Affected Males
SGBS1 is characterized by pre- and postnatal overgrowth, distinctive facies, and variable visceral, skeletal, and neurodevelopmental abnormalities. To date, more than 180 individuals have been identified with a pathogenic variant in
Simpson-Golabi-Behmel Syndrome Type 1: Frequency of Select Features
Based on
SD = standard deviations
As with other overgrowth syndromes, hypoglycemia may be present in the neonatal period; however, hypoglycemia is rare in SGBS1 and is not considered to be a cardinal feature.
Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
Redundant, furrowed skin over the glabella
Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
Prominent forehead
Macrostomia
Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
Micrognathia in neonates; large mandible (macrognathia) in older individuals
Congenital heart defects are variable; septal defects are common. Pulmonic stenosis, aortic coarctation, transposition of the great vessels, and patent ductus arteriosus or patent foramen ovale have been reported.
Conduction defects and arrhythmias have also been described [
Other genitourinary anomalies include hypospadias, penile hypoplasia, ambiguous genitalia, anal atresia, bifid scrotum, cryptorchidism, hydrocele, and inguinal hernia [
Hand anomalies such as large hands, broad thumbs, and brachydactyly are common. Other findings include syndactyly, clinodactyly, and postaxial polydactyly. Striking index finger hypoplasia with congenital abnormalities of the proximal phalanx have been reported [
Advanced bone age, including presence of ossified carpal bones in a newborn, has been described [
Normal intelligence has been described, but mild-to-severe intellectual disability is common, with language delay being the most characteristic finding.
Hydrocephalus, epilepsy, and attention-deficit/hyperactivity disorder may also be present [
Brain abnormalities have been reported, including agenesis of the corpus callosum, Chiari malformation, hydrocephalus, and hypoplasia of the cerebellar vermis [
Additionally, several tumors have been reported in single individuals, but it is unknown if they are related to the pathogenesis of SGBS1 or reflect the underlying population-level neoplastic risk. Each of the following has been reported in single individuals:
Acute lymphoblastic leukemia [
Ameloblastoma [
Diffuse neonatal hemangiomatosis [
Hepatocellular carcinoma [
Medulloblastoma [
Pancreatic carcinoma [
Renal neuroblastoma [
• As with other overgrowth syndromes, hypoglycemia may be present in the neonatal period; however, hypoglycemia is rare in SGBS1 and is not considered to be a cardinal feature.
• Widely spaced eyes, epicanthal folds, and downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge and anteverted nares in infants; broad nose and coarsening of the facial features in older individuals
• Prominent forehead
• Macrostomia
• Macroglossia with or without a midline groove in the lower lip and/or deep furrow in the middle of the tongue
• Cleft lip and/or submucous cleft palate (with a bifid uvula); high and narrow palate
• Micrognathia in neonates; large mandible (macrognathia) in older individuals
• Congenital heart defects are variable; septal defects are common. Pulmonic stenosis, aortic coarctation, transposition of the great vessels, and patent ductus arteriosus or patent foramen ovale have been reported.
• Conduction defects and arrhythmias have also been described [
• Acute lymphoblastic leukemia [
• Ameloblastoma [
• Diffuse neonatal hemangiomatosis [
• Hepatocellular carcinoma [
• Medulloblastoma [
• Pancreatic carcinoma [
• Renal neuroblastoma [
## Heterozygous Females
Due to skewed X-chromosome inactivation, heterozygous females can have variable manifestations of SBGS1 ranging from completely unaffected to fully recapitulating the severe phenotype, including overgrowth, widely spaced eyes, broad and upturned nasal tip with prominent columella, macrostomia, prominent chin, hypoplastic fingernails, coccygeal skin tag and bony appendage, extra lumbar and thoracic vertebrae, and accessory nipples [
To date, nine heterozygous females with clinical expression of SGBS1 have been reported [
## Genotype-Phenotype Correlations
There are no known clinically relevant genotype-phenotype correlations for SGBS1 to date.
## Penetrance
All males reported with a
## Nomenclature
SGBS1 was initially described by
Terms no longer in use for SGBS1:
Gigantism-dysplasia syndrome
Encephalo-tropho-schisis syndrome
Golabi-Rosen syndrome
Simpson dysmorphia syndrome
• Gigantism-dysplasia syndrome
• Encephalo-tropho-schisis syndrome
• Golabi-Rosen syndrome
• Simpson dysmorphia syndrome
## Prevalence
The prevalence of SGBS1 is unknown; however, it is believed to be underdiagnosed due to the wide spectrum of clinical severity.
## Genetically Related (Allelic) Disorders
No other phenotypes are known to be associated with germline pathogenic variants in
Germline pathogenic variants in
## Differential Diagnosis
Disorders to Consider in the Differential Diagnosis of Simpson-Golabi-Behmel Syndrome Type 1
Macrosomia
Macroglossia
Ear anomalies
Diastasis recti
Hypoglycemia
Genitourinary malformations
↑ incidence of tumors
Appreciably different facial features (midface flattening in BWS; broader forehead in SGBS1)
Absence of relative macrocephaly
Absence of skeletal abnormalities
Omphalocele
Phenotype often less pronounced w/age (In SGBS1, characteristic features may not be present in infancy.)
Hemihypertrophy/lateralized overgrowth more common
Persons w/BWS are less tall & less dysmorphic, w/fewer visceral & skeletal malformations.
Macrosomia
High incidence of Wilms tumor
Distinctive facial features
Neonatal mortality is high.
Overgrowth
macrocephaly
Intellectual disability
Cryptorchidism
Behavioral/psychiatric issues
Seizures
Distinctive facial features
Acute myeloid leukemia predisposition
Joint hypermobility
Hypotonia
Overgrowth
Umbilical hernia
Ear anomalies
Hypotonia
Advanced bone age
Vertebral defects
Hypertelorism
Flat occiput
Deep horizontal chin crease, large ears
Absence of downslanting palpebral fissures, dental malocclusion, & central groove of lower lip (all characteristic of SGBS1
Psychomotor delay typically more prominent
Postnatal overgrowth
Advanced bone age
Macrocephaly
Downslanting palpebral fissures
Marfanoid habitus w/long & slender body, low body mass, long & narrow face, arachnodactyly, long tapered fingers
Aggressive, self-injurious behavior
Normal birth weight
Advanced bone age
Intellectual disability
Distinctive facial features
Predisposition to fractures
Hypertelorism
Broad forehead
Downslanting palpebral fissures
Hypoglycemia
Macrosomia
Widely spaced eyes, epicanthal folds, downslanted palpebral fissures
Redundant, furrowed skin over the glabella
Wide nasal bridge & anteverted nares in infants; broad nose & coarse facial appearance in older persons
Macrocephaly
Macrostomia
Macroglossia
Cleft lip &/or submucous cleft palate (w/bifid uvula); high & narrow palate
Small mandible (micrognathia) in neonates; macrognathia in older persons
Multiple congenital anomalies
Coarse facies
Diaphragmatic hernia w/lung hypoplasia
Cleft lip/palate
Congenital heart defects
Ear anomalies
Macrostomia
Hydrocephalus
Micro- & retrognathia
Overgrowth
Vertebral anomalies
Ear malformations
Cryptorchidism
Intellectual disability
Accelerated osseous maturation
Large extremities
Hypotonia
Macrocephaly
Coarse facial features
Bifid ribs
Multiple jaw keratocysts frequently beginning in 2nd decade of life
Basal cell carcinomas usually from 3rd decade onward
Intellectual Disability
Macrocephaly
Overgrowth
Advanced bone age
Frontal bossing
Low-set ears
Behavioral findings
Eye findings
Hypotonia
Hyponatremia
Respiratory issues
Epilepsy
Arched eyebrows
Micrognathia w/mandibular hypoplasia
Pre- and postnatal overgrowth
Macrocephaly
Frontal bossing
Hypertelorism
Downslanting palpebral fissures
Low & broad nasal bridge
Musculoskeletal abnormalities
Genitourinary abnormalities (umbilical hernia, cryptorchidism)
Structural brain abnormalities
Respiratory issues, scoliosis
Widened distal ulnas
Widened distal femurs
Coxa valga
Flat feet
Pronation of feet
↓ muscle bulk
Phimosis
Recurrent respiratory infections
Aspiration of thin liquids
AD = autosomal dominant; AR = autosomal recessive; MOI = mode of inheritance; XL = X-linked
BWS is associated with abnormal regulation of gene transcription in two imprinted domains on chromosome 11p15.5 (also known as the BWS critical region). Regulation may be disrupted by any one of numerous mechanisms. 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.
• Macrosomia
• Macroglossia
• Ear anomalies
• Diastasis recti
• Hypoglycemia
• Genitourinary malformations
• ↑ incidence of tumors
• Appreciably different facial features (midface flattening in BWS; broader forehead in SGBS1)
• Absence of relative macrocephaly
• Absence of skeletal abnormalities
• Omphalocele
• Phenotype often less pronounced w/age (In SGBS1, characteristic features may not be present in infancy.)
• Hemihypertrophy/lateralized overgrowth more common
• Persons w/BWS are less tall & less dysmorphic, w/fewer visceral & skeletal malformations.
• Macrosomia
• High incidence of Wilms tumor
• Distinctive facial features
• Neonatal mortality is high.
• Overgrowth
• macrocephaly
• Intellectual disability
• Cryptorchidism
• Behavioral/psychiatric issues
• Seizures
• Distinctive facial features
• Acute myeloid leukemia predisposition
• Joint hypermobility
• Hypotonia
• Overgrowth
• Umbilical hernia
• Ear anomalies
• Hypotonia
• Advanced bone age
• Vertebral defects
• Hypertelorism
• Flat occiput
• Deep horizontal chin crease, large ears
• Absence of downslanting palpebral fissures, dental malocclusion, & central groove of lower lip (all characteristic of SGBS1
• Psychomotor delay typically more prominent
• Postnatal overgrowth
• Advanced bone age
• Macrocephaly
• Downslanting palpebral fissures
• Marfanoid habitus w/long & slender body, low body mass, long & narrow face, arachnodactyly, long tapered fingers
• Aggressive, self-injurious behavior
• Normal birth weight
• Advanced bone age
• Intellectual disability
• Distinctive facial features
• Predisposition to fractures
• Hypertelorism
• Broad forehead
• Downslanting palpebral fissures
• Hypoglycemia
• Macrosomia
• Widely spaced eyes, epicanthal folds, downslanted palpebral fissures
• Redundant, furrowed skin over the glabella
• Wide nasal bridge & anteverted nares in infants; broad nose & coarse facial appearance in older persons
• Macrocephaly
• Macrostomia
• Macroglossia
• Cleft lip &/or submucous cleft palate (w/bifid uvula); high & narrow palate
• Small mandible (micrognathia) in neonates; macrognathia in older persons
• Multiple congenital anomalies
• Coarse facies
• Diaphragmatic hernia w/lung hypoplasia
• Cleft lip/palate
• Congenital heart defects
• Ear anomalies
• Macrostomia
• Hydrocephalus
• Micro- & retrognathia
• Overgrowth
• Vertebral anomalies
• Ear malformations
• Cryptorchidism
• Intellectual disability
• Accelerated osseous maturation
• Large extremities
• Hypotonia
• Macrocephaly
• Coarse facial features
• Bifid ribs
• Multiple jaw keratocysts frequently beginning in 2nd decade of life
• Basal cell carcinomas usually from 3rd decade onward
• Intellectual Disability
• Macrocephaly
• Overgrowth
• Advanced bone age
• Frontal bossing
• Low-set ears
• Behavioral findings
• Eye findings
• Hypotonia
• Hyponatremia
• Respiratory issues
• Epilepsy
• Arched eyebrows
• Micrognathia w/mandibular hypoplasia
• Pre- and postnatal overgrowth
• Macrocephaly
• Frontal bossing
• Hypertelorism
• Downslanting palpebral fissures
• Low & broad nasal bridge
• Musculoskeletal abnormalities
• Genitourinary abnormalities (umbilical hernia, cryptorchidism)
• Structural brain abnormalities
• Respiratory issues, scoliosis
• Widened distal ulnas
• Widened distal femurs
• Coxa valga
• Flat feet
• Pronation of feet
• ↓ muscle bulk
• Phimosis
• Recurrent respiratory infections
• Aspiration of thin liquids
## Management
No clinical practice guidelines for Simpson-Golabi-Behmel syndrome type 1 (SGBS1) 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 and needs in an individual diagnosed with SGBS1, the evaluations summarized in
Simpson-Golabi-Behmel Syndrome Type 1: Recommended Evaluations Following Initial Diagnosis
Community or
Social work involvement for parental support
Home nursing referral
AFP = alpha-fetoprotein; MOI = mode of inheritance; SGBS1 = Simpson-Golabi-Behmel syndrome type 1
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for SGBS1. 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
Simpson-Golabi-Behmel Syndrome Type 1: Treatment of Manifestations
If due to macroglossia, consider mgmt similar to
Sleep study & potential CPAP or hemiglossectomy if indicated
Milder feeding issues may be managed w/special nipples or nasogastric feeding in consultation w/specialist.
Consider gastrostomy tube in those w/severe feeding issues.
CPAP = continuous positive airway pressure; OT = occupational therapy; OSA = obstructive sleep apnea; PT = physical therapy; SGBS1 = Simpson-Golabi-Behmel syndrome type 1
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.
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Simpson-Golabi-Behmel Syndrome Type 1: Recommended Surveillance for Males
Abdominal ultrasound & serum AFP level every 3 mos from time of diagnosis until age 3 yrs
Renal ultrasound every 3 mos until age 7 yrs
AFP = alpha-fetoprotein; SGBS1 = Simpson-Golabi-Behmel syndrome type 1
Little information on tumor risk in heterozygous females is available; there are currently only a few reports of tumors in females with SGBS1 (see Clinical Description,
It is appropriate to clarify the genetic status of older and younger at-risk male and female relatives of an affected individual by molecular genetic testing for the familial SGBS1-related genetic alteration in order to identify as early as possible those who would benefit from preventive measures such as tumor surveillance in males. Specific recommendations depend on the sex of the paternal source of the pathogenic variant and are family specific.
See
A number of gestational complications have been described in case reports of pregnancies of fetuses with SGBS1. Gestational hypertension, diabetes, preeclampsia, fetal distress, and preterm labor have been reported in the birthing parents of persons with SGBS1. It is not known whether there is increased risk of these gestational complications in SGBS1 pregnancies. Of note, polyhydramnios has been sufficiently evaluated and reported in 68% of SGBS1 pregnancies. Fetal macrocephaly and overgrowth may necessitate cesarean delivery or early induction of labor [
Search
• Community or
• Social work involvement for parental support
• Home nursing referral
• If due to macroglossia, consider mgmt similar to
• Sleep study & potential CPAP or hemiglossectomy if indicated
• Milder feeding issues may be managed w/special nipples or nasogastric feeding in consultation w/specialist.
• Consider gastrostomy tube in those w/severe feeding issues.
• 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.
• Abdominal ultrasound & serum AFP level every 3 mos from time of diagnosis until age 3 yrs
• Renal ultrasound every 3 mos until age 7 yrs
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SGBS1, the evaluations summarized in
Simpson-Golabi-Behmel Syndrome Type 1: Recommended Evaluations Following Initial Diagnosis
Community or
Social work involvement for parental support
Home nursing referral
AFP = alpha-fetoprotein; MOI = mode of inheritance; SGBS1 = Simpson-Golabi-Behmel syndrome type 1
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Community or
• Social work involvement for parental support
• Home nursing referral
## Treatment of Manifestations
There is no cure for SGBS1. 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
Simpson-Golabi-Behmel Syndrome Type 1: Treatment of Manifestations
If due to macroglossia, consider mgmt similar to
Sleep study & potential CPAP or hemiglossectomy if indicated
Milder feeding issues may be managed w/special nipples or nasogastric feeding in consultation w/specialist.
Consider gastrostomy tube in those w/severe feeding issues.
CPAP = continuous positive airway pressure; OT = occupational therapy; OSA = obstructive sleep apnea; PT = physical therapy; SGBS1 = Simpson-Golabi-Behmel syndrome type 1
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.
• If due to macroglossia, consider mgmt similar to
• Sleep study & potential CPAP or hemiglossectomy if indicated
• Milder feeding issues may be managed w/special nipples or nasogastric feeding in consultation w/specialist.
• Consider gastrostomy tube in those w/severe feeding issues.
• 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.
## 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
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Simpson-Golabi-Behmel Syndrome Type 1: Recommended Surveillance for Males
Abdominal ultrasound & serum AFP level every 3 mos from time of diagnosis until age 3 yrs
Renal ultrasound every 3 mos until age 7 yrs
AFP = alpha-fetoprotein; SGBS1 = Simpson-Golabi-Behmel syndrome type 1
Little information on tumor risk in heterozygous females is available; there are currently only a few reports of tumors in females with SGBS1 (see Clinical Description,
• Abdominal ultrasound & serum AFP level every 3 mos from time of diagnosis until age 3 yrs
• Renal ultrasound every 3 mos until age 7 yrs
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of older and younger at-risk male and female relatives of an affected individual by molecular genetic testing for the familial SGBS1-related genetic alteration in order to identify as early as possible those who would benefit from preventive measures such as tumor surveillance in males. Specific recommendations depend on the sex of the paternal source of the pathogenic variant and are family specific.
See
## Pregnancy Management
A number of gestational complications have been described in case reports of pregnancies of fetuses with SGBS1. Gestational hypertension, diabetes, preeclampsia, fetal distress, and preterm labor have been reported in the birthing parents of persons with SGBS1. It is not known whether there is increased risk of these gestational complications in SGBS1 pregnancies. Of note, polyhydramnios has been sufficiently evaluated and reported in 68% of SGBS1 pregnancies. Fetal macrocephaly and overgrowth may necessitate cesarean delivery or early induction of labor [
## Therapies Under Investigation
Search
## Genetic Counseling
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) 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 SBGS1-causing genetic alteration; therefore, he does not require further testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may demonstrate some features of the condition. Note: If a woman has more than one affected child and no other affected relatives, and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
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
The mother may have somatic/germline mosaicism [
Molecular genetic testing capable of detecting the SBGS1-causing genetic alteration identified in the proband is recommended for the mother to confirm her genetic status and to allow reliable recurrence risk assessment.
A female proband may have inherited the SBGS1-causing genetic alteration from either her mother (who may or may not have manifestations of SBGS1) or her father or the genetic alteration may be
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 SBGS1-causing genetic alteration, the chance of transmitting the genetic alteration in each pregnancy is 50%.
Males who inherit the genetic alteration will be affected.
Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
If the proband represents a simplex case and if the SBGS1-causing genetic alteration cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism. Maternal germline mosaicism has been reported [
If the mother of the proband has an SGBS1-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%.
Males who inherit the genetic alteration will be affected.
Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
If the father of the proband has an SGBS1-causing genetic alteration, he will transmit it to all of his daughters and none of his sons. Transmission from an affected father to his affected daughter has been reported in one family to date [Støve el al 2017].
If the proband represents a simplex case and if the SGBS1-causing genetic alteration cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (both maternal and paternal germline mosaicism have been reported in SGBS1 [
Affected males transmit the SGBS1-causing genetic alteration to all of their daughters and none of their sons.
To date, only one affected male has been reported to reproduce; the affected male was only diagnosed after the fetal demise of the affected child [
Note: Molecular genetic testing may be able to identify the family member in whom a
Identification of apparently asymptomatic female heterozygotes requires prior identification of the SGBS1-causing genetic alteration in the family.
Note: Females who are heterozygous for this X-linked disorder may be affected; heterozygous females with features of SGBS1 have been reported (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 or who are at risk of having an SGBS1-causing genetic alteration.
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 SBGS1-causing genetic alteration; therefore, he does not require further testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may demonstrate some features of the condition. Note: If a woman has more than one affected child and no other affected relatives, and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• 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
• The mother may have somatic/germline mosaicism [
• The mother may be a heterozygote.
• The affected male may have a
• The mother may have somatic/germline mosaicism [
• Molecular genetic testing capable of detecting the SBGS1-causing genetic alteration identified in the proband is recommended for the mother to confirm her genetic status and to allow reliable recurrence risk assessment.
• The mother may be a heterozygote.
• The affected male may have a
• The mother may have somatic/germline mosaicism [
• A female proband may have inherited the SBGS1-causing genetic alteration from either her mother (who may or may not have manifestations of SBGS1) or her father or the genetic alteration may be
• 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 SBGS1-causing genetic alteration, the chance of transmitting the genetic alteration in each pregnancy is 50%.
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• If the proband represents a simplex case and if the SBGS1-causing genetic alteration cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism. Maternal germline mosaicism has been reported [
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• If the mother of the proband has an SGBS1-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%.
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• If the father of the proband has an SGBS1-causing genetic alteration, he will transmit it to all of his daughters and none of his sons. Transmission from an affected father to his affected daughter has been reported in one family to date [Støve el al 2017].
• If the proband represents a simplex case and if the SGBS1-causing genetic alteration cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (both maternal and paternal germline mosaicism have been reported in SGBS1 [
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• Affected males transmit the SGBS1-causing genetic alteration to all of their daughters and none of their sons.
• To date, only one affected male has been reported to reproduce; the affected male was only diagnosed after the fetal demise of the affected child [
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 who are at risk of having an SGBS1-causing genetic alteration.
## Mode of Inheritance
Simpson-Golabi-Behmel syndrome type 1 (SGBS1) 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 SBGS1-causing genetic alteration; therefore, he does not require further testing.
In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may demonstrate some features of the condition. Note: If a woman has more than one affected child and no other affected relatives, and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
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
The mother may have somatic/germline mosaicism [
Molecular genetic testing capable of detecting the SBGS1-causing genetic alteration identified in the proband is recommended for the mother to confirm her genetic status and to allow reliable recurrence risk assessment.
A female proband may have inherited the SBGS1-causing genetic alteration from either her mother (who may or may not have manifestations of SBGS1) or her father or the genetic alteration may be
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 SBGS1-causing genetic alteration, the chance of transmitting the genetic alteration in each pregnancy is 50%.
Males who inherit the genetic alteration will be affected.
Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
If the proband represents a simplex case and if the SBGS1-causing genetic alteration cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism. Maternal germline mosaicism has been reported [
If the mother of the proband has an SGBS1-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%.
Males who inherit the genetic alteration will be affected.
Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
If the father of the proband has an SGBS1-causing genetic alteration, he will transmit it to all of his daughters and none of his sons. Transmission from an affected father to his affected daughter has been reported in one family to date [Støve el al 2017].
If the proband represents a simplex case and if the SGBS1-causing genetic alteration cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (both maternal and paternal germline mosaicism have been reported in SGBS1 [
Affected males transmit the SGBS1-causing genetic alteration to all of their daughters and none of their sons.
To date, only one affected male has been reported to reproduce; the affected male was only diagnosed after the fetal demise of the affected child [
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 SBGS1-causing genetic alteration; therefore, he does not require further testing.
• In a family with more than one affected individual, the mother of an affected male is an obligate heterozygote and may demonstrate some features of the condition. Note: If a woman has more than one affected child and no other affected relatives, and if the pathogenic variant cannot be detected in her leukocyte DNA, she most likely has germline mosaicism.
• 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
• The mother may have somatic/germline mosaicism [
• The mother may be a heterozygote.
• The affected male may have a
• The mother may have somatic/germline mosaicism [
• Molecular genetic testing capable of detecting the SBGS1-causing genetic alteration identified in the proband is recommended for the mother to confirm her genetic status and to allow reliable recurrence risk assessment.
• The mother may be a heterozygote.
• The affected male may have a
• The mother may have somatic/germline mosaicism [
• A female proband may have inherited the SBGS1-causing genetic alteration from either her mother (who may or may not have manifestations of SBGS1) or her father or the genetic alteration may be
• 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 SBGS1-causing genetic alteration, the chance of transmitting the genetic alteration in each pregnancy is 50%.
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• If the proband represents a simplex case and if the SBGS1-causing genetic alteration cannot be detected in the leukocyte DNA of the mother, the risk to sibs is slightly greater than that of the general population because of the possibility of maternal germline mosaicism. Maternal germline mosaicism has been reported [
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• If the mother of the proband has an SGBS1-causing genetic alteration, the chance of transmitting it in each pregnancy is 50%.
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• If the father of the proband has an SGBS1-causing genetic alteration, he will transmit it to all of his daughters and none of his sons. Transmission from an affected father to his affected daughter has been reported in one family to date [Støve el al 2017].
• If the proband represents a simplex case and if the SGBS1-causing genetic alteration cannot be detected in the leukocyte DNA of either parent, the risk to sibs is slightly greater than that of the general population because of the possibility of parental germline mosaicism (both maternal and paternal germline mosaicism have been reported in SGBS1 [
• Males who inherit the genetic alteration will be affected.
• Females who inherit the genetic alteration will be heterozygotes. Due to skewed X-chromosome inactivation, heterozygous females may have manifestations of SBGS1 (see Clinical Description,
• Affected males transmit the SGBS1-causing genetic alteration to all of their daughters and none of their sons.
• To date, only one affected male has been reported to reproduce; the affected male was only diagnosed after the fetal demise of the affected child [
## Heterozygote Detection
Identification of apparently asymptomatic female heterozygotes requires prior identification of the SGBS1-causing genetic alteration in the family.
Note: Females who are heterozygous for this X-linked disorder may be affected; heterozygous females with features of SGBS1 have been reported (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 or who are at risk of having an SGBS1-causing genetic alteration.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 who are at risk of having an SGBS1-causing genetic alteration.
## 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
Simpson-Golabi-Behmel Syndrome Type 1: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Simpson-Golabi-Behmel Syndrome Type 1 (
Most individuals with Simpson-Golabi-Behmel syndrome type 1 (SGBS1) have pathogenic variants in
## Molecular Pathogenesis
Most individuals with Simpson-Golabi-Behmel syndrome type 1 (SGBS1) have pathogenic variants in
## Chapter Notes
Mr Hathaway is a licensed genetic counselor.
Dr Kalish is board certified in pediatrics and clinical genetics and is an Assistant Professor of Pediatrics and Genetics.
Dr Kalish (
We thank the patients who have engaged with our research and the colleagues who have referred patients to the clinic and the research.
Kathy Culver, MS; California Pacific Medical Center (2006-2011)Mahin Golabi, MD, MPH; California Pacific Medical Center (2006-2018)Christina X Gonzalez-Gandolfi, BA; Children's Hospital of Philadelphia (2018-2023)Evan R Hathaway, MS, LCGC (2018-present)Aaron James; University of California San Francisco (2006-2011)Jennifer M Kalish, MD, PhD (2018-present) Stephen D Klein, MD, PhD (2023-2024)Alva Leung, BS; California Pacific Medical Center (2011-2018)Christina Lopez, BS; California Pacific Medical Center (2011-2018) Alex F Nisbet, BS (2023-present)Brian J Sajorda, BA; Children's Hospital of Philadelphia (2018-2023)
14 November 2024 (jk) Revision: references added [
7 December 2023 (gm) Comprehensive update posted live
29 November 2018 (ma) Comprehensive update posted live
23 June 2011 (me) Comprehensive update posted live
19 December 2006 (me) Review posted live
6 July 2006 (kc) Original submission
• 14 November 2024 (jk) Revision: references added [
• 7 December 2023 (gm) Comprehensive update posted live
• 29 November 2018 (ma) Comprehensive update posted live
• 23 June 2011 (me) Comprehensive update posted live
• 19 December 2006 (me) Review posted live
• 6 July 2006 (kc) Original submission
## Author Notes
Mr Hathaway is a licensed genetic counselor.
Dr Kalish is board certified in pediatrics and clinical genetics and is an Assistant Professor of Pediatrics and Genetics.
Dr Kalish (
## Acknowledgements
We thank the patients who have engaged with our research and the colleagues who have referred patients to the clinic and the research.
## Author History
Kathy Culver, MS; California Pacific Medical Center (2006-2011)Mahin Golabi, MD, MPH; California Pacific Medical Center (2006-2018)Christina X Gonzalez-Gandolfi, BA; Children's Hospital of Philadelphia (2018-2023)Evan R Hathaway, MS, LCGC (2018-present)Aaron James; University of California San Francisco (2006-2011)Jennifer M Kalish, MD, PhD (2018-present) Stephen D Klein, MD, PhD (2023-2024)Alva Leung, BS; California Pacific Medical Center (2011-2018)Christina Lopez, BS; California Pacific Medical Center (2011-2018) Alex F Nisbet, BS (2023-present)Brian J Sajorda, BA; Children's Hospital of Philadelphia (2018-2023)
## Revision History
14 November 2024 (jk) Revision: references added [
7 December 2023 (gm) Comprehensive update posted live
29 November 2018 (ma) Comprehensive update posted live
23 June 2011 (me) Comprehensive update posted live
19 December 2006 (me) Review posted live
6 July 2006 (kc) Original submission
• 14 November 2024 (jk) Revision: references added [
• 7 December 2023 (gm) Comprehensive update posted live
• 29 November 2018 (ma) Comprehensive update posted live
• 23 June 2011 (me) Comprehensive update posted live
• 19 December 2006 (me) Review posted live
• 6 July 2006 (kc) Original submission
## References
## Literature Cited
|
[] |
19/12/2006
|
7/12/2023
|
14/11/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sgpl1
|
sgpl1
|
[
"SGPL1 Deficiency",
"Steroid-Resistant Nephrotic Syndrome Type 14",
"SGPL1 Deficiency",
"Steroid-Resistant Nephrotic Syndrome Type 14",
"Sphingosine-1-phosphate lyase 1",
"SGPL1",
"Sphingosine Phosphate Lyase Insufficiency Syndrome"
] |
Sphingosine Phosphate Lyase Insufficiency Syndrome
|
Kathryn Nicole Weaver, Bonnie Sullivan, Friedhelm Hildebrandt, Jonathan Strober, Megan Cooper, Rathi Prasad, Julie Saba
|
Summary Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome (ranging from nonimmune fetal hydrops to adolescent onset), primary adrenal insufficiency (with or without mineralocorticoid deficiency), testicular insufficiency, hypothyroidism, ichthyosis, lymphopenia/immunodeficiency, and neurologic abnormalities that can include developmental delay, regression / progressive neurologic involvement, cranial nerve deficits, and peripheral motor and sensory neuropathy. The diagnosis of SPLIS is established in a proband with at least one suggestive finding and biallelic pathogenic variants in SPLIS is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
Sphingosine phosphate lyase insufficiency syndrome (SPLIS)
Primary adrenal insufficiency (low cortisol with normal or high ACTH). Typically, glucocorticoid deficiency; some individuals also have mineralocorticoid deficiency.
Testicular insufficiency (increased gonadotropins, poor response to LH stimulation); typically manifest in newborns as micropenis and cryptorchidism or microorchidism
Primary hypothyroidism (low-to-normal free thyroxine levels with increased thyroid stimulating hormone)
T-cell lymphopenia or pan lymphopenia. Low absolute lymphocyte counts; low CD3, CD4, CD8 T-cell subsets with or without low absolute B- and NK-cell counts
Low-to-normal immunoglobulins
Abnormal TREC (T-cell receptor excision circle) newborn screening test (on occasion)
Normal or impaired T-cell functional assays, proliferation, and response to vaccinations
Cranial nerve deficits
Sensorineural hearing loss
Developmental delay
Regression / progressive neurologic involvement
Upper motor neuron involvement presenting as weakness and/or spasticity
Lower motor neuron involvement including motor and sensory neuropathy
Seizures (generalized or complex partial)
The diagnosis of sphingosine phosphate lyase insufficiency syndrome (SPLIS)
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
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sphingosine Phosphate Lyase Insufficiency 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
•
• Primary adrenal insufficiency (low cortisol with normal or high ACTH). Typically, glucocorticoid deficiency; some individuals also have mineralocorticoid deficiency.
• Testicular insufficiency (increased gonadotropins, poor response to LH stimulation); typically manifest in newborns as micropenis and cryptorchidism or microorchidism
• Primary hypothyroidism (low-to-normal free thyroxine levels with increased thyroid stimulating hormone)
• Primary adrenal insufficiency (low cortisol with normal or high ACTH). Typically, glucocorticoid deficiency; some individuals also have mineralocorticoid deficiency.
• Testicular insufficiency (increased gonadotropins, poor response to LH stimulation); typically manifest in newborns as micropenis and cryptorchidism or microorchidism
• Primary hypothyroidism (low-to-normal free thyroxine levels with increased thyroid stimulating hormone)
•
• T-cell lymphopenia or pan lymphopenia. Low absolute lymphocyte counts; low CD3, CD4, CD8 T-cell subsets with or without low absolute B- and NK-cell counts
• Low-to-normal immunoglobulins
• Abnormal TREC (T-cell receptor excision circle) newborn screening test (on occasion)
• Normal or impaired T-cell functional assays, proliferation, and response to vaccinations
• T-cell lymphopenia or pan lymphopenia. Low absolute lymphocyte counts; low CD3, CD4, CD8 T-cell subsets with or without low absolute B- and NK-cell counts
• Low-to-normal immunoglobulins
• Abnormal TREC (T-cell receptor excision circle) newborn screening test (on occasion)
• Normal or impaired T-cell functional assays, proliferation, and response to vaccinations
• Cranial nerve deficits
• Sensorineural hearing loss
• Developmental delay
• Regression / progressive neurologic involvement
• Upper motor neuron involvement presenting as weakness and/or spasticity
• Lower motor neuron involvement including motor and sensory neuropathy
• Seizures (generalized or complex partial)
• Cranial nerve deficits
• Sensorineural hearing loss
• Developmental delay
• Regression / progressive neurologic involvement
• Upper motor neuron involvement presenting as weakness and/or spasticity
• Lower motor neuron involvement including motor and sensory neuropathy
• Seizures (generalized or complex partial)
• Primary adrenal insufficiency (low cortisol with normal or high ACTH). Typically, glucocorticoid deficiency; some individuals also have mineralocorticoid deficiency.
• Testicular insufficiency (increased gonadotropins, poor response to LH stimulation); typically manifest in newborns as micropenis and cryptorchidism or microorchidism
• Primary hypothyroidism (low-to-normal free thyroxine levels with increased thyroid stimulating hormone)
• T-cell lymphopenia or pan lymphopenia. Low absolute lymphocyte counts; low CD3, CD4, CD8 T-cell subsets with or without low absolute B- and NK-cell counts
• Low-to-normal immunoglobulins
• Abnormal TREC (T-cell receptor excision circle) newborn screening test (on occasion)
• Normal or impaired T-cell functional assays, proliferation, and response to vaccinations
• Cranial nerve deficits
• Sensorineural hearing loss
• Developmental delay
• Regression / progressive neurologic involvement
• Upper motor neuron involvement presenting as weakness and/or spasticity
• Lower motor neuron involvement including motor and sensory neuropathy
• Seizures (generalized or complex partial)
## Suggestive Findings
Sphingosine phosphate lyase insufficiency syndrome (SPLIS)
Primary adrenal insufficiency (low cortisol with normal or high ACTH). Typically, glucocorticoid deficiency; some individuals also have mineralocorticoid deficiency.
Testicular insufficiency (increased gonadotropins, poor response to LH stimulation); typically manifest in newborns as micropenis and cryptorchidism or microorchidism
Primary hypothyroidism (low-to-normal free thyroxine levels with increased thyroid stimulating hormone)
T-cell lymphopenia or pan lymphopenia. Low absolute lymphocyte counts; low CD3, CD4, CD8 T-cell subsets with or without low absolute B- and NK-cell counts
Low-to-normal immunoglobulins
Abnormal TREC (T-cell receptor excision circle) newborn screening test (on occasion)
Normal or impaired T-cell functional assays, proliferation, and response to vaccinations
Cranial nerve deficits
Sensorineural hearing loss
Developmental delay
Regression / progressive neurologic involvement
Upper motor neuron involvement presenting as weakness and/or spasticity
Lower motor neuron involvement including motor and sensory neuropathy
Seizures (generalized or complex partial)
•
• Primary adrenal insufficiency (low cortisol with normal or high ACTH). Typically, glucocorticoid deficiency; some individuals also have mineralocorticoid deficiency.
• Testicular insufficiency (increased gonadotropins, poor response to LH stimulation); typically manifest in newborns as micropenis and cryptorchidism or microorchidism
• Primary hypothyroidism (low-to-normal free thyroxine levels with increased thyroid stimulating hormone)
• Primary adrenal insufficiency (low cortisol with normal or high ACTH). Typically, glucocorticoid deficiency; some individuals also have mineralocorticoid deficiency.
• Testicular insufficiency (increased gonadotropins, poor response to LH stimulation); typically manifest in newborns as micropenis and cryptorchidism or microorchidism
• Primary hypothyroidism (low-to-normal free thyroxine levels with increased thyroid stimulating hormone)
•
• T-cell lymphopenia or pan lymphopenia. Low absolute lymphocyte counts; low CD3, CD4, CD8 T-cell subsets with or without low absolute B- and NK-cell counts
• Low-to-normal immunoglobulins
• Abnormal TREC (T-cell receptor excision circle) newborn screening test (on occasion)
• Normal or impaired T-cell functional assays, proliferation, and response to vaccinations
• T-cell lymphopenia or pan lymphopenia. Low absolute lymphocyte counts; low CD3, CD4, CD8 T-cell subsets with or without low absolute B- and NK-cell counts
• Low-to-normal immunoglobulins
• Abnormal TREC (T-cell receptor excision circle) newborn screening test (on occasion)
• Normal or impaired T-cell functional assays, proliferation, and response to vaccinations
• Cranial nerve deficits
• Sensorineural hearing loss
• Developmental delay
• Regression / progressive neurologic involvement
• Upper motor neuron involvement presenting as weakness and/or spasticity
• Lower motor neuron involvement including motor and sensory neuropathy
• Seizures (generalized or complex partial)
• Cranial nerve deficits
• Sensorineural hearing loss
• Developmental delay
• Regression / progressive neurologic involvement
• Upper motor neuron involvement presenting as weakness and/or spasticity
• Lower motor neuron involvement including motor and sensory neuropathy
• Seizures (generalized or complex partial)
• Primary adrenal insufficiency (low cortisol with normal or high ACTH). Typically, glucocorticoid deficiency; some individuals also have mineralocorticoid deficiency.
• Testicular insufficiency (increased gonadotropins, poor response to LH stimulation); typically manifest in newborns as micropenis and cryptorchidism or microorchidism
• Primary hypothyroidism (low-to-normal free thyroxine levels with increased thyroid stimulating hormone)
• T-cell lymphopenia or pan lymphopenia. Low absolute lymphocyte counts; low CD3, CD4, CD8 T-cell subsets with or without low absolute B- and NK-cell counts
• Low-to-normal immunoglobulins
• Abnormal TREC (T-cell receptor excision circle) newborn screening test (on occasion)
• Normal or impaired T-cell functional assays, proliferation, and response to vaccinations
• Cranial nerve deficits
• Sensorineural hearing loss
• Developmental delay
• Regression / progressive neurologic involvement
• Upper motor neuron involvement presenting as weakness and/or spasticity
• Lower motor neuron involvement including motor and sensory neuropathy
• Seizures (generalized or complex partial)
## Establishing the Diagnosis
The diagnosis of sphingosine phosphate lyase insufficiency syndrome (SPLIS)
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
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sphingosine Phosphate Lyase Insufficiency 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Option 1
For an introduction to multigene panels click
## Option 2
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Sphingosine Phosphate Lyase Insufficiency 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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
## Clinical Characteristics
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome, primary adrenal insufficiency (with or without mineralocorticoid deficiency), testicular insufficiency, immunodeficiency, and neurologic abnormalities, and may also include primary hypothyroidism and ichthyosis (
To date, 46 individuals with sphingosine phosphate lyase insufficiency syndrome (SPLIS) have been reported [
Features of Sphingosine Phosphate Lyase Insufficiency Syndrome
Cranial nerve deficits (11/46)
Strabismus (6/46)
Ptosis (2/46)
Developmental delay (9/46)
Regression/progressive neurologic involvement (6/46)
Peripheral motor & sensory neuropathy (5/46)
Spasticity
The range of renal involvement extends from nonimmune fetal hydrops at the severe end to delayed evidence of nephrosis for many years after diagnosis or no renal involvement after years of follow up, as observed in two sibs in their twenties and thirties [
Six affected individuals underwent kidney transplantation: two at age five years; one at age five years and again at age 12 years; and one at age eight years. Age at transplant of the other two individuals was not provided; however, at time of last update one was age 8.4 years and the other 17.5 years.
Pathology of renal biopsies is usually consistent with glomerulosclerosis, especially with focal segmental glomerulosclerosis (FSGS) and ultrastructural finding of podocyte foot-process effacement. Three affected individuals had collapsing variant FSGS, a subclassification associated with rapid disease progression [
Most individuals with adrenal insufficiency have become symptomatic in the first decade of life. The oldest reported age of onset was 11 years [
Adrenal calcifications or enlargement, which may be seen prenatally, are likely a risk factor for adrenal insufficiency [
Multiple individuals with SPLIS have experienced frequent infections including several whose cause of death was related to infection [
To date, two individuals with SPLIS have had abnormal TREC (T-cell receptor excision circle) on newborn screening. In one, absolute lymphocyte count was low with distorted distribution of naive to memory cells and low B and NK cell counts; IgG levels were not determined; immune response to vaccinations was protective. In the other, absolute lymphocyte count was low with low absolute CD3 T cells and normal B and NK cell counts; IgG levels were low; immune response to vaccinations was not determined [
Cranial nerve VIII involvement manifests as sensorineural hearing loss. The loss may be congenital or diagnosed later in the first decade; it can be progressive and severe, and unilateral or bilateral (e.g., bilateral, upward sloping with air-bone gap at 500 Hz).
Age of onset of deterioration and type of first manifestation are variable, in some cases as young as 12 months (case 4 in
Acute or subacute onset
Mononeuropathy or polyneuropathy involving upper or lower limbs, often distal
Median or ulnar paralysis
Absent reflexes
Sensory neuropathy, transient pain, loss of vibration sense
Spontaneous resolution that is complete or with residual deficits
Progression leading to muscle wasting, contractures, scoliosis, hemiparesis
In two sisters who had no other manifestations of SPLIS, the following were observed [
Nerve conduction studies showed undetectable compound muscle and sensory nerve action potentials;
EMG showed spontaneous activity and a neuropathy pattern;
Axonal neuropathy was demonstrated by axonal disintegration on sural nerve biopsy in one sib.
One individual was hospitalized on numerous occasions due to gastrointestinal symptoms with no identified infectious etiology.
In some instances, affected infants were below normal weight, often in association with severe illness requiring hospitalization. Failure to thrive may be the presenting complaint, and may be associated with adrenal insufficiency, nephrotic syndrome, or poor feeding.
Rare skeletal abnormalities have been observed (craniotabes, short stature, rachitic rosary sign, scoliosis, asymmetric skull). Scoliosis may be secondary to neurologic defects.
Rarely: intestinal malrotation; pericardial effusion, dilated cardiomyopathy, dysmorphic features (hypertelorism, down-slanting palpebral fissures).
Genotype-phenotype correlations are not fully defined for SPLIS.
Intrafamilial variability is observed as the clinical manifestations and age of onset can vary within the same family in which affected individuals have the same
The prevalence of SPLIS is unknown. To date, approximately 46 individuals with SPLIS have been reported. The total number of reported individuals depends on whether or not sibs of index cases whose presentations are consistent with the diagnosis of SPLIS (but without molecular genetic confirmation) were counted.
• Cranial nerve deficits (11/46)
• Strabismus (6/46)
• Ptosis (2/46)
• Developmental delay (9/46)
• Regression/progressive neurologic involvement (6/46)
• Peripheral motor & sensory neuropathy (5/46)
• Spasticity
• Acute or subacute onset
• Mononeuropathy or polyneuropathy involving upper or lower limbs, often distal
• Median or ulnar paralysis
• Absent reflexes
• Sensory neuropathy, transient pain, loss of vibration sense
• Spontaneous resolution that is complete or with residual deficits
• Progression leading to muscle wasting, contractures, scoliosis, hemiparesis
• Nerve conduction studies showed undetectable compound muscle and sensory nerve action potentials;
• EMG showed spontaneous activity and a neuropathy pattern;
• Axonal neuropathy was demonstrated by axonal disintegration on sural nerve biopsy in one sib.
• One individual was hospitalized on numerous occasions due to gastrointestinal symptoms with no identified infectious etiology.
• In some instances, affected infants were below normal weight, often in association with severe illness requiring hospitalization. Failure to thrive may be the presenting complaint, and may be associated with adrenal insufficiency, nephrotic syndrome, or poor feeding.
• Rare skeletal abnormalities have been observed (craniotabes, short stature, rachitic rosary sign, scoliosis, asymmetric skull). Scoliosis may be secondary to neurologic defects.
• Rarely: intestinal malrotation; pericardial effusion, dilated cardiomyopathy, dysmorphic features (hypertelorism, down-slanting palpebral fissures).
## Clinical Description
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is characterized by varying combinations of steroid-resistant nephrotic syndrome, primary adrenal insufficiency (with or without mineralocorticoid deficiency), testicular insufficiency, immunodeficiency, and neurologic abnormalities, and may also include primary hypothyroidism and ichthyosis (
To date, 46 individuals with sphingosine phosphate lyase insufficiency syndrome (SPLIS) have been reported [
Features of Sphingosine Phosphate Lyase Insufficiency Syndrome
Cranial nerve deficits (11/46)
Strabismus (6/46)
Ptosis (2/46)
Developmental delay (9/46)
Regression/progressive neurologic involvement (6/46)
Peripheral motor & sensory neuropathy (5/46)
Spasticity
The range of renal involvement extends from nonimmune fetal hydrops at the severe end to delayed evidence of nephrosis for many years after diagnosis or no renal involvement after years of follow up, as observed in two sibs in their twenties and thirties [
Six affected individuals underwent kidney transplantation: two at age five years; one at age five years and again at age 12 years; and one at age eight years. Age at transplant of the other two individuals was not provided; however, at time of last update one was age 8.4 years and the other 17.5 years.
Pathology of renal biopsies is usually consistent with glomerulosclerosis, especially with focal segmental glomerulosclerosis (FSGS) and ultrastructural finding of podocyte foot-process effacement. Three affected individuals had collapsing variant FSGS, a subclassification associated with rapid disease progression [
Most individuals with adrenal insufficiency have become symptomatic in the first decade of life. The oldest reported age of onset was 11 years [
Adrenal calcifications or enlargement, which may be seen prenatally, are likely a risk factor for adrenal insufficiency [
Multiple individuals with SPLIS have experienced frequent infections including several whose cause of death was related to infection [
To date, two individuals with SPLIS have had abnormal TREC (T-cell receptor excision circle) on newborn screening. In one, absolute lymphocyte count was low with distorted distribution of naive to memory cells and low B and NK cell counts; IgG levels were not determined; immune response to vaccinations was protective. In the other, absolute lymphocyte count was low with low absolute CD3 T cells and normal B and NK cell counts; IgG levels were low; immune response to vaccinations was not determined [
Cranial nerve VIII involvement manifests as sensorineural hearing loss. The loss may be congenital or diagnosed later in the first decade; it can be progressive and severe, and unilateral or bilateral (e.g., bilateral, upward sloping with air-bone gap at 500 Hz).
Age of onset of deterioration and type of first manifestation are variable, in some cases as young as 12 months (case 4 in
Acute or subacute onset
Mononeuropathy or polyneuropathy involving upper or lower limbs, often distal
Median or ulnar paralysis
Absent reflexes
Sensory neuropathy, transient pain, loss of vibration sense
Spontaneous resolution that is complete or with residual deficits
Progression leading to muscle wasting, contractures, scoliosis, hemiparesis
In two sisters who had no other manifestations of SPLIS, the following were observed [
Nerve conduction studies showed undetectable compound muscle and sensory nerve action potentials;
EMG showed spontaneous activity and a neuropathy pattern;
Axonal neuropathy was demonstrated by axonal disintegration on sural nerve biopsy in one sib.
One individual was hospitalized on numerous occasions due to gastrointestinal symptoms with no identified infectious etiology.
In some instances, affected infants were below normal weight, often in association with severe illness requiring hospitalization. Failure to thrive may be the presenting complaint, and may be associated with adrenal insufficiency, nephrotic syndrome, or poor feeding.
Rare skeletal abnormalities have been observed (craniotabes, short stature, rachitic rosary sign, scoliosis, asymmetric skull). Scoliosis may be secondary to neurologic defects.
Rarely: intestinal malrotation; pericardial effusion, dilated cardiomyopathy, dysmorphic features (hypertelorism, down-slanting palpebral fissures).
• Cranial nerve deficits (11/46)
• Strabismus (6/46)
• Ptosis (2/46)
• Developmental delay (9/46)
• Regression/progressive neurologic involvement (6/46)
• Peripheral motor & sensory neuropathy (5/46)
• Spasticity
• Acute or subacute onset
• Mononeuropathy or polyneuropathy involving upper or lower limbs, often distal
• Median or ulnar paralysis
• Absent reflexes
• Sensory neuropathy, transient pain, loss of vibration sense
• Spontaneous resolution that is complete or with residual deficits
• Progression leading to muscle wasting, contractures, scoliosis, hemiparesis
• Nerve conduction studies showed undetectable compound muscle and sensory nerve action potentials;
• EMG showed spontaneous activity and a neuropathy pattern;
• Axonal neuropathy was demonstrated by axonal disintegration on sural nerve biopsy in one sib.
• One individual was hospitalized on numerous occasions due to gastrointestinal symptoms with no identified infectious etiology.
• In some instances, affected infants were below normal weight, often in association with severe illness requiring hospitalization. Failure to thrive may be the presenting complaint, and may be associated with adrenal insufficiency, nephrotic syndrome, or poor feeding.
• Rare skeletal abnormalities have been observed (craniotabes, short stature, rachitic rosary sign, scoliosis, asymmetric skull). Scoliosis may be secondary to neurologic defects.
• Rarely: intestinal malrotation; pericardial effusion, dilated cardiomyopathy, dysmorphic features (hypertelorism, down-slanting palpebral fissures).
## Nephrotic Syndrome
The range of renal involvement extends from nonimmune fetal hydrops at the severe end to delayed evidence of nephrosis for many years after diagnosis or no renal involvement after years of follow up, as observed in two sibs in their twenties and thirties [
Six affected individuals underwent kidney transplantation: two at age five years; one at age five years and again at age 12 years; and one at age eight years. Age at transplant of the other two individuals was not provided; however, at time of last update one was age 8.4 years and the other 17.5 years.
Pathology of renal biopsies is usually consistent with glomerulosclerosis, especially with focal segmental glomerulosclerosis (FSGS) and ultrastructural finding of podocyte foot-process effacement. Three affected individuals had collapsing variant FSGS, a subclassification associated with rapid disease progression [
## Endocrine Involvement
Most individuals with adrenal insufficiency have become symptomatic in the first decade of life. The oldest reported age of onset was 11 years [
Adrenal calcifications or enlargement, which may be seen prenatally, are likely a risk factor for adrenal insufficiency [
Multiple individuals with SPLIS have experienced frequent infections including several whose cause of death was related to infection [
To date, two individuals with SPLIS have had abnormal TREC (T-cell receptor excision circle) on newborn screening. In one, absolute lymphocyte count was low with distorted distribution of naive to memory cells and low B and NK cell counts; IgG levels were not determined; immune response to vaccinations was protective. In the other, absolute lymphocyte count was low with low absolute CD3 T cells and normal B and NK cell counts; IgG levels were low; immune response to vaccinations was not determined [
## Neurologic Abnormalities
Cranial nerve VIII involvement manifests as sensorineural hearing loss. The loss may be congenital or diagnosed later in the first decade; it can be progressive and severe, and unilateral or bilateral (e.g., bilateral, upward sloping with air-bone gap at 500 Hz).
Age of onset of deterioration and type of first manifestation are variable, in some cases as young as 12 months (case 4 in
Acute or subacute onset
Mononeuropathy or polyneuropathy involving upper or lower limbs, often distal
Median or ulnar paralysis
Absent reflexes
Sensory neuropathy, transient pain, loss of vibration sense
Spontaneous resolution that is complete or with residual deficits
Progression leading to muscle wasting, contractures, scoliosis, hemiparesis
In two sisters who had no other manifestations of SPLIS, the following were observed [
Nerve conduction studies showed undetectable compound muscle and sensory nerve action potentials;
EMG showed spontaneous activity and a neuropathy pattern;
Axonal neuropathy was demonstrated by axonal disintegration on sural nerve biopsy in one sib.
• Acute or subacute onset
• Mononeuropathy or polyneuropathy involving upper or lower limbs, often distal
• Median or ulnar paralysis
• Absent reflexes
• Sensory neuropathy, transient pain, loss of vibration sense
• Spontaneous resolution that is complete or with residual deficits
• Progression leading to muscle wasting, contractures, scoliosis, hemiparesis
• Nerve conduction studies showed undetectable compound muscle and sensory nerve action potentials;
• EMG showed spontaneous activity and a neuropathy pattern;
• Axonal neuropathy was demonstrated by axonal disintegration on sural nerve biopsy in one sib.
## Other
One individual was hospitalized on numerous occasions due to gastrointestinal symptoms with no identified infectious etiology.
In some instances, affected infants were below normal weight, often in association with severe illness requiring hospitalization. Failure to thrive may be the presenting complaint, and may be associated with adrenal insufficiency, nephrotic syndrome, or poor feeding.
Rare skeletal abnormalities have been observed (craniotabes, short stature, rachitic rosary sign, scoliosis, asymmetric skull). Scoliosis may be secondary to neurologic defects.
Rarely: intestinal malrotation; pericardial effusion, dilated cardiomyopathy, dysmorphic features (hypertelorism, down-slanting palpebral fissures).
• One individual was hospitalized on numerous occasions due to gastrointestinal symptoms with no identified infectious etiology.
• In some instances, affected infants were below normal weight, often in association with severe illness requiring hospitalization. Failure to thrive may be the presenting complaint, and may be associated with adrenal insufficiency, nephrotic syndrome, or poor feeding.
• Rare skeletal abnormalities have been observed (craniotabes, short stature, rachitic rosary sign, scoliosis, asymmetric skull). Scoliosis may be secondary to neurologic defects.
• Rarely: intestinal malrotation; pericardial effusion, dilated cardiomyopathy, dysmorphic features (hypertelorism, down-slanting palpebral fissures).
## Genotype-Phenotype Correlations
Genotype-phenotype correlations are not fully defined for SPLIS.
Intrafamilial variability is observed as the clinical manifestations and age of onset can vary within the same family in which affected individuals have the same
## Prevalence
The prevalence of SPLIS is unknown. To date, approximately 46 individuals with SPLIS have been reported. The total number of reported individuals depends on whether or not sibs of index cases whose presentations are consistent with the diagnosis of SPLIS (but without molecular genetic confirmation) were counted.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Sphingosine Phosphate Lyase Insufficiency Syndrome
AD = autosomal dominant; AR = autosomal recessive; DiffDx = differential diagnosis; MOI = mode of inheritance; SPLIS = sphingosine phosphate lyase insufficiency syndrome
Differential Diagnosis of Clinical Findings Associated with Sphingosine Phosphate Lyase Insufficiency Syndrome
Congenital ichthyosis is a feature of several genetic syndromes.
Nonsyndromic ichthyosis (e.g.,
Many disorders affect the adrenal cortex → inadequate production of adrenal steroids & features incl vomiting, hypoglycemia, poor weight gain, & fatigue.
Causes can include: disorders that affect steroid biosynthesis, cholesterol metabolism, mitochondrial function (see
Isolated T-cell deficiency may be found in many primary immune deficiencies (e.g., SCID,
Combined T-, B-, & NK-cell deficiency can be seen in primary immune deficiencies incl
FSGS = focal segmental glomerulosclerosis; PNP = purine nucleoside phosphorylase; SCID = severe combined immunodeficiency; SPLIS = sphingosine phosphate lyase insufficiency syndrome
Collapsing variant FSGS is a pathologic diagnosis given when one or more glomeruli show segmental or global obliteration of the glomerular capillary lumen due to collapse of the glomerular basement membrane associated with podocyte hypertrophy and hyperplasia. It is most often seen in association with severe nephrotic syndrome and rapid progression to end-stage kidney disease.
• Congenital ichthyosis is a feature of several genetic syndromes.
• Nonsyndromic ichthyosis (e.g.,
• Many disorders affect the adrenal cortex → inadequate production of adrenal steroids & features incl vomiting, hypoglycemia, poor weight gain, & fatigue.
• Causes can include: disorders that affect steroid biosynthesis, cholesterol metabolism, mitochondrial function (see
• Isolated T-cell deficiency may be found in many primary immune deficiencies (e.g., SCID,
• Combined T-, B-, & NK-cell deficiency can be seen in primary immune deficiencies incl
## Management
To establish the extent of disease and needs in an individual diagnosed with sphingosine phosphate lyase insufficiency syndrome (SPLIS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Sphingosine Phosphate Lyase Insufficiency Syndrome
Serum creatinine/BUN; urine protein/creatinine; renal ultrasound
May require kidney biopsy
Early morning ACTH & cortisol
Serum electrolytes
Plasma renin activity
Adrenal ultrasound; ACTH stimulation test if baseline results borderline
T-, B-, & NK-cell subset analysis
Serum immunoglobulins
T-cell proliferation assays
Antibody titers to vaccinations
Assess for UMN involvement (spasticity, ↑ DTRs) & LMN involvement (strength, sensation, DTRs); if abnormal consider EMG & NCV.
Consider EEG if seizures are a concern.
Brain MRI if not previously performed
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)
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
ACTH = adrenocorticotropic hormone; ADL = activities of daily living; DD = developmental delay; DTRs = deep tendon reflexes; EEG = electroencephalogram; EMG = electromyogram; LMN = lower motor neuron; MOI = mode of inheritance; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy; TSH = thyroid stimulating hormone; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Sphingosine Phosphate Lyase Insufficiency Syndrome
Medical mgmt of kidney failure per nephrologist
Kidney replacement therapy if refractory to medical mgmt
Glucocorticoid replacement
Mineralocorticoid replacement as required ± sodium supplementation
Appropriate counseling for sick days; emergency & perioperative mgmt
Infants w/micropenis: consider testosterone Rx to ↑ penile length & allow for urination standing up.
At puberty: consider need for testosterone Rx.
Consider counseling re potential ↓ spermatogenesis & possible sperm banking.
Rule out electrolyte disturbances & hypoglycemia.
Information is insufficient re specific antiseizure mgmt. Consider pyridoxine trial.
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; DD = developmental delay; ID = intellectual disability; 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.
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, and modified assignments.
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.
There are no published surveillance guidelines. Based on the known potential medical conditions associated with SPLIS, we propose consideration of the following (see
Recommended Surveillance for Individuals with Sphingosine Phosphate Lyase Insufficiency Syndrome
Urine protein/creatinine
Nephrology follow up
Annual urine protein/creatinine if w/o known disease
Annual blood pressure
OT = occupational therapy; PT = physical therapy
Any nephrotoxic drug should be avoided.
If renal insufficiency is present, avoid medications that require renal excretion.
Live vaccines or exposure to infectious agents may be particularly dangerous due to immunodeficiency.
Transfusion products should be irradiated.
It is appropriate to clarify the genetic 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 treatment and awareness of
See
Responsiveness to cofactor supplementation (pyridoxine HCl) has been reported in two individuals with sphingosine phosphate lyase insufficiency syndrome [
Search
• Serum creatinine/BUN; urine protein/creatinine; renal ultrasound
• May require kidney biopsy
• Early morning ACTH & cortisol
• Serum electrolytes
• Plasma renin activity
• Adrenal ultrasound; ACTH stimulation test if baseline results borderline
• T-, B-, & NK-cell subset analysis
• Serum immunoglobulins
• T-cell proliferation assays
• Antibody titers to vaccinations
• Assess for UMN involvement (spasticity, ↑ DTRs) & LMN involvement (strength, sensation, DTRs); if abnormal consider EMG & NCV.
• Consider EEG if seizures are a concern.
• Brain MRI if not previously performed
• 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)
• Motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Medical mgmt of kidney failure per nephrologist
• Kidney replacement therapy if refractory to medical mgmt
• Glucocorticoid replacement
• Mineralocorticoid replacement as required ± sodium supplementation
• Appropriate counseling for sick days; emergency & perioperative mgmt
• Infants w/micropenis: consider testosterone Rx to ↑ penile length & allow for urination standing up.
• At puberty: consider need for testosterone Rx.
• Consider counseling re potential ↓ spermatogenesis & possible sperm banking.
• Rule out electrolyte disturbances & hypoglycemia.
• Information is insufficient re specific antiseizure mgmt. Consider pyridoxine trial.
• 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.
• 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, and modified assignments.
• 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.
• Urine protein/creatinine
• Nephrology follow up
• Annual urine protein/creatinine if w/o known disease
• Annual blood pressure
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with sphingosine phosphate lyase insufficiency syndrome (SPLIS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Sphingosine Phosphate Lyase Insufficiency Syndrome
Serum creatinine/BUN; urine protein/creatinine; renal ultrasound
May require kidney biopsy
Early morning ACTH & cortisol
Serum electrolytes
Plasma renin activity
Adrenal ultrasound; ACTH stimulation test if baseline results borderline
T-, B-, & NK-cell subset analysis
Serum immunoglobulins
T-cell proliferation assays
Antibody titers to vaccinations
Assess for UMN involvement (spasticity, ↑ DTRs) & LMN involvement (strength, sensation, DTRs); if abnormal consider EMG & NCV.
Consider EEG if seizures are a concern.
Brain MRI if not previously performed
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)
Motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support;
Home nursing referral.
ACTH = adrenocorticotropic hormone; ADL = activities of daily living; DD = developmental delay; DTRs = deep tendon reflexes; EEG = electroencephalogram; EMG = electromyogram; LMN = lower motor neuron; MOI = mode of inheritance; NCV = nerve conduction velocity; OT = occupational therapy; PT = physical therapy; TSH = thyroid stimulating hormone; UMN = upper motor neuron
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Serum creatinine/BUN; urine protein/creatinine; renal ultrasound
• May require kidney biopsy
• Early morning ACTH & cortisol
• Serum electrolytes
• Plasma renin activity
• Adrenal ultrasound; ACTH stimulation test if baseline results borderline
• T-, B-, & NK-cell subset analysis
• Serum immunoglobulins
• T-cell proliferation assays
• Antibody titers to vaccinations
• Assess for UMN involvement (spasticity, ↑ DTRs) & LMN involvement (strength, sensation, DTRs); if abnormal consider EMG & NCV.
• Consider EEG if seizures are a concern.
• Brain MRI if not previously performed
• 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)
• 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 Sphingosine Phosphate Lyase Insufficiency Syndrome
Medical mgmt of kidney failure per nephrologist
Kidney replacement therapy if refractory to medical mgmt
Glucocorticoid replacement
Mineralocorticoid replacement as required ± sodium supplementation
Appropriate counseling for sick days; emergency & perioperative mgmt
Infants w/micropenis: consider testosterone Rx to ↑ penile length & allow for urination standing up.
At puberty: consider need for testosterone Rx.
Consider counseling re potential ↓ spermatogenesis & possible sperm banking.
Rule out electrolyte disturbances & hypoglycemia.
Information is insufficient re specific antiseizure mgmt. Consider pyridoxine trial.
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; DD = developmental delay; ID = intellectual disability; 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.
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, and modified assignments.
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.
• Medical mgmt of kidney failure per nephrologist
• Kidney replacement therapy if refractory to medical mgmt
• Glucocorticoid replacement
• Mineralocorticoid replacement as required ± sodium supplementation
• Appropriate counseling for sick days; emergency & perioperative mgmt
• Infants w/micropenis: consider testosterone Rx to ↑ penile length & allow for urination standing up.
• At puberty: consider need for testosterone Rx.
• Consider counseling re potential ↓ spermatogenesis & possible sperm banking.
• Rule out electrolyte disturbances & hypoglycemia.
• Information is insufficient re specific antiseizure mgmt. Consider pyridoxine trial.
• 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.
• 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, and modified assignments.
• 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.
## 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, and modified assignments.
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, and modified assignments.
• 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.
## Surveillance
There are no published surveillance guidelines. Based on the known potential medical conditions associated with SPLIS, we propose consideration of the following (see
Recommended Surveillance for Individuals with Sphingosine Phosphate Lyase Insufficiency Syndrome
Urine protein/creatinine
Nephrology follow up
Annual urine protein/creatinine if w/o known disease
Annual blood pressure
OT = occupational therapy; PT = physical therapy
• Urine protein/creatinine
• Nephrology follow up
• Annual urine protein/creatinine if w/o known disease
• Annual blood pressure
## Agents/Circumstances to Avoid
Any nephrotoxic drug should be avoided.
If renal insufficiency is present, avoid medications that require renal excretion.
Live vaccines or exposure to infectious agents may be particularly dangerous due to immunodeficiency.
Transfusion products should be irradiated.
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic 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 treatment and awareness of
See
## Therapies Under Investigation
Responsiveness to cofactor supplementation (pyridoxine HCl) has been reported in two individuals with sphingosine phosphate lyase insufficiency syndrome [
Search
## Genetic Counseling
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) 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
Intrafamilial variability is observed in SPLIS; age of onset and clinical manifestations of SPLIS may vary in sibs with 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, 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., 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
• Intrafamilial variability is observed in SPLIS; age of onset and clinical manifestations of SPLIS may vary in sibs with biallelic
• 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
Sphingosine phosphate lyase insufficiency syndrome (SPLIS) 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
Intrafamilial variability is observed in SPLIS; age of onset and clinical manifestations of SPLIS may vary in sibs with 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 an
• Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
• If both parents are known to be heterozygous for an
• Intrafamilial variability is observed in SPLIS; age of onset and clinical manifestations of SPLIS may vary in sibs with 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, 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
Canada
•
•
•
• Canada
•
•
•
## Molecular Genetics
Sphingosine Phosphate Lyase Insufficiency Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Sphingosine Phosphate Lyase Insufficiency Syndrome (
Loss of SPL activity results in the following:
Accumulation of S1P as well as other sphingolipids that can be cytotoxic and may contribute to the neurologic features of SPLIS
Failure of lymphocytes to egress from the thymus and peripheral lymphoid organs resulting in lymphopenia
Altered morphology of glomerular cells called podocytes that support the filtration function of the kidney, suggesting that disruption of sphingolipid metabolism causes glomerular damage leading to nephrosis
Reduction of specialized ceramides and long-chain aldehydes formed by the degradation of S1P that are important in the skin barrier function – which may explain the occurrence of ichthyosis in SPLIS
SPL may play a role in adrenal gland development, which may explain the primary adrenal insufficiency observed in SPLIS. Furthermore, accumulation of upstream sphingolipid intermediates may impair acute steroidogenesis [
Note: While SPLIS is considered a sphingolipidosis, it is not a lysosomal storage disease.
Notable
Pathogenic variant present in 10/46 persons reported w/SPLIS [
Variants listed in the table have been provided by the authors.
• Accumulation of S1P as well as other sphingolipids that can be cytotoxic and may contribute to the neurologic features of SPLIS
• Failure of lymphocytes to egress from the thymus and peripheral lymphoid organs resulting in lymphopenia
• Altered morphology of glomerular cells called podocytes that support the filtration function of the kidney, suggesting that disruption of sphingolipid metabolism causes glomerular damage leading to nephrosis
• Reduction of specialized ceramides and long-chain aldehydes formed by the degradation of S1P that are important in the skin barrier function – which may explain the occurrence of ichthyosis in SPLIS
## Molecular Pathogenesis
Loss of SPL activity results in the following:
Accumulation of S1P as well as other sphingolipids that can be cytotoxic and may contribute to the neurologic features of SPLIS
Failure of lymphocytes to egress from the thymus and peripheral lymphoid organs resulting in lymphopenia
Altered morphology of glomerular cells called podocytes that support the filtration function of the kidney, suggesting that disruption of sphingolipid metabolism causes glomerular damage leading to nephrosis
Reduction of specialized ceramides and long-chain aldehydes formed by the degradation of S1P that are important in the skin barrier function – which may explain the occurrence of ichthyosis in SPLIS
SPL may play a role in adrenal gland development, which may explain the primary adrenal insufficiency observed in SPLIS. Furthermore, accumulation of upstream sphingolipid intermediates may impair acute steroidogenesis [
Note: While SPLIS is considered a sphingolipidosis, it is not a lysosomal storage disease.
Notable
Pathogenic variant present in 10/46 persons reported w/SPLIS [
Variants listed in the table have been provided by the authors.
• Accumulation of S1P as well as other sphingolipids that can be cytotoxic and may contribute to the neurologic features of SPLIS
• Failure of lymphocytes to egress from the thymus and peripheral lymphoid organs resulting in lymphopenia
• Altered morphology of glomerular cells called podocytes that support the filtration function of the kidney, suggesting that disruption of sphingolipid metabolism causes glomerular damage leading to nephrosis
• Reduction of specialized ceramides and long-chain aldehydes formed by the degradation of S1P that are important in the skin barrier function – which may explain the occurrence of ichthyosis in SPLIS
## Chapter Notes
We are grateful to all those who have reported cases and cohorts of individuals with SPLIS/NPHS14, helping to reveal the range of presentations, pathogenic variants associated with the condition, and initial insights into its pathogenesis. We are also grateful to the families who have shared medical information in the interest of advancing care and treatment for individuals suffering from SPLIS.
15 October 2020 (bp) Review posted live
31 March 2020 (knw) Original submission
• 15 October 2020 (bp) Review posted live
• 31 March 2020 (knw) Original submission
## Author Notes
## Acknowledgments
We are grateful to all those who have reported cases and cohorts of individuals with SPLIS/NPHS14, helping to reveal the range of presentations, pathogenic variants associated with the condition, and initial insights into its pathogenesis. We are also grateful to the families who have shared medical information in the interest of advancing care and treatment for individuals suffering from SPLIS.
## Revision History
15 October 2020 (bp) Review posted live
31 March 2020 (knw) Original submission
• 15 October 2020 (bp) Review posted live
• 31 March 2020 (knw) Original submission
## References
## Literature Cited
|
[] |
15/10/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
sgs
|
sgs
|
[
"Ski oncogene",
"SKI",
"Shprintzen-Goldberg Syndrome"
] |
Shprintzen-Goldberg Syndrome
|
Marie T Greally
|
Summary Shprintzen-Goldberg syndrome (SGS) is characterized by: delayed motor and cognitive milestones and mild-to-moderate intellectual disability; craniosynostosis of the coronal, sagittal, or lambdoid sutures; distinctive craniofacial features; and musculoskeletal findings including olichostenomelia, arachnodactyly, camptodactyly, pectus excavatum or carinatum, scoliosis, joint hypermobility or contractures, pes planus, foot malposition, and C1-C2 spine malformation. Cardiovascular anomalies may include mitral valve prolapse, secundum atrial septal defect, and aortic root dilatation. Minimal subcutaneous fat, abdominal wall defects, and myopia are also characteristic findings. The diagnosis of SGS is established in a proband with a heterozygous pathogenic variant in SGS, caused by a heterozygous pathogenic variant in
|
## Diagnosis
Formal diagnostic criteria for Shprintzen-Goldberg syndrome (SGS) have not been established.
SGS
Dolichocephaly with or without scaphocephaly
Tall or prominent forehead
Hypertelorism
Downslanting palpebral fissures
Ocular proptosis
Malar flattening
High narrow palate with prominent palatine ridges
Micrognathia and/or retrognathia
Apparently low-set and posteriorly rotated ears
Dolichostenomelia
Arachnodactyly
Camptodactyly
Pectus excavatum or carinatum
Scoliosis
Joint hypermobility or contractures
Pes planus
Foot malposition/talipes equinovarus/club foot
C1-C2 spine malformation
The diagnosis of SGS
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 SGS is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of SGS, 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 craniosynostosis,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Shprintzen-Goldberg 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.
Contiguous deletion of
•
• Dolichocephaly with or without scaphocephaly
• Tall or prominent forehead
• Hypertelorism
• Downslanting palpebral fissures
• Ocular proptosis
• Malar flattening
• High narrow palate with prominent palatine ridges
• Micrognathia and/or retrognathia
• Apparently low-set and posteriorly rotated ears
• Dolichocephaly with or without scaphocephaly
• Tall or prominent forehead
• Hypertelorism
• Downslanting palpebral fissures
• Ocular proptosis
• Malar flattening
• High narrow palate with prominent palatine ridges
• Micrognathia and/or retrognathia
• Apparently low-set and posteriorly rotated ears
•
• Dolichostenomelia
• Arachnodactyly
• Camptodactyly
• Pectus excavatum or carinatum
• Scoliosis
• Joint hypermobility or contractures
• Pes planus
• Foot malposition/talipes equinovarus/club foot
• C1-C2 spine malformation
• Dolichostenomelia
• Arachnodactyly
• Camptodactyly
• Pectus excavatum or carinatum
• Scoliosis
• Joint hypermobility or contractures
• Pes planus
• Foot malposition/talipes equinovarus/club foot
• C1-C2 spine malformation
• Dolichocephaly with or without scaphocephaly
• Tall or prominent forehead
• Hypertelorism
• Downslanting palpebral fissures
• Ocular proptosis
• Malar flattening
• High narrow palate with prominent palatine ridges
• Micrognathia and/or retrognathia
• Apparently low-set and posteriorly rotated ears
• Dolichostenomelia
• Arachnodactyly
• Camptodactyly
• Pectus excavatum or carinatum
• Scoliosis
• Joint hypermobility or contractures
• Pes planus
• Foot malposition/talipes equinovarus/club foot
• C1-C2 spine malformation
• For an introduction to multigene panels click
## Suggestive Findings
SGS
Dolichocephaly with or without scaphocephaly
Tall or prominent forehead
Hypertelorism
Downslanting palpebral fissures
Ocular proptosis
Malar flattening
High narrow palate with prominent palatine ridges
Micrognathia and/or retrognathia
Apparently low-set and posteriorly rotated ears
Dolichostenomelia
Arachnodactyly
Camptodactyly
Pectus excavatum or carinatum
Scoliosis
Joint hypermobility or contractures
Pes planus
Foot malposition/talipes equinovarus/club foot
C1-C2 spine malformation
•
• Dolichocephaly with or without scaphocephaly
• Tall or prominent forehead
• Hypertelorism
• Downslanting palpebral fissures
• Ocular proptosis
• Malar flattening
• High narrow palate with prominent palatine ridges
• Micrognathia and/or retrognathia
• Apparently low-set and posteriorly rotated ears
• Dolichocephaly with or without scaphocephaly
• Tall or prominent forehead
• Hypertelorism
• Downslanting palpebral fissures
• Ocular proptosis
• Malar flattening
• High narrow palate with prominent palatine ridges
• Micrognathia and/or retrognathia
• Apparently low-set and posteriorly rotated ears
•
• Dolichostenomelia
• Arachnodactyly
• Camptodactyly
• Pectus excavatum or carinatum
• Scoliosis
• Joint hypermobility or contractures
• Pes planus
• Foot malposition/talipes equinovarus/club foot
• C1-C2 spine malformation
• Dolichostenomelia
• Arachnodactyly
• Camptodactyly
• Pectus excavatum or carinatum
• Scoliosis
• Joint hypermobility or contractures
• Pes planus
• Foot malposition/talipes equinovarus/club foot
• C1-C2 spine malformation
• Dolichocephaly with or without scaphocephaly
• Tall or prominent forehead
• Hypertelorism
• Downslanting palpebral fissures
• Ocular proptosis
• Malar flattening
• High narrow palate with prominent palatine ridges
• Micrognathia and/or retrognathia
• Apparently low-set and posteriorly rotated ears
• Dolichostenomelia
• Arachnodactyly
• Camptodactyly
• Pectus excavatum or carinatum
• Scoliosis
• Joint hypermobility or contractures
• Pes planus
• Foot malposition/talipes equinovarus/club foot
• C1-C2 spine malformation
## Establishing the Diagnosis
The diagnosis of SGS
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 SGS is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of SGS, 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 craniosynostosis,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Shprintzen-Goldberg 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.
Contiguous deletion of
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of SGS, 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 craniosynostosis,
If exome sequencing is not diagnostic – and particularly when evidence supports autosomal dominant inheritance –
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Shprintzen-Goldberg 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.
Contiguous deletion of
## Clinical Characteristics
To date, 44 individuals have been identified with a pathogenic variant in
Select Features of Shprintzen-Goldberg Syndrome
Typically coronal, sagittal, or lambdoid sutures
Characteristic craniofacial features include hypertelorism, downslanting palpebral fissures, ocular proptosis, high narrow palate, micrognathia, and low-set posteriorly rotated ears. Cleft palate was reported in three of 17 individuals with SGS [
Dural ectasia (5/8 individuals) [
Chiari I malformation (2/3 individuals) [
Cryptorchidism (1/1 male) [
No genotype-phenotype correlations have been identified.
Penetrance is unknown.
Goldberg-Shprintzen syndrome and Shprintzen-Goldberg omphalocele syndrome are separate syndromes, not related to SGS.
Other names that have been used to refer to SGS:
Craniosynostosis with arachnodactyly and abdominal hernias
Marfanoid-craniosynostosis syndrome
Shprintzen-Goldberg craniosynostosis syndrome
Shprintzen-Goldberg marfanoid syndrome
The term Furlong syndrome has been used to describe one individual with craniosynostosis, features of SGS, normal intelligence, and aortic enlargement.
SGS is a rare disorder and the prevalence is unknown. A
• Dural ectasia (5/8 individuals) [
• Chiari I malformation (2/3 individuals) [
• Cryptorchidism (1/1 male) [
• Craniosynostosis with arachnodactyly and abdominal hernias
• Marfanoid-craniosynostosis syndrome
• Shprintzen-Goldberg craniosynostosis syndrome
• Shprintzen-Goldberg marfanoid syndrome
## Clinical Description
To date, 44 individuals have been identified with a pathogenic variant in
Select Features of Shprintzen-Goldberg Syndrome
Typically coronal, sagittal, or lambdoid sutures
Characteristic craniofacial features include hypertelorism, downslanting palpebral fissures, ocular proptosis, high narrow palate, micrognathia, and low-set posteriorly rotated ears. Cleft palate was reported in three of 17 individuals with SGS [
Dural ectasia (5/8 individuals) [
Chiari I malformation (2/3 individuals) [
Cryptorchidism (1/1 male) [
• Dural ectasia (5/8 individuals) [
• Chiari I malformation (2/3 individuals) [
• Cryptorchidism (1/1 male) [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Penetrance
Penetrance is unknown.
## Nomenclature
Goldberg-Shprintzen syndrome and Shprintzen-Goldberg omphalocele syndrome are separate syndromes, not related to SGS.
Other names that have been used to refer to SGS:
Craniosynostosis with arachnodactyly and abdominal hernias
Marfanoid-craniosynostosis syndrome
Shprintzen-Goldberg craniosynostosis syndrome
Shprintzen-Goldberg marfanoid syndrome
The term Furlong syndrome has been used to describe one individual with craniosynostosis, features of SGS, normal intelligence, and aortic enlargement.
• Craniosynostosis with arachnodactyly and abdominal hernias
• Marfanoid-craniosynostosis syndrome
• Shprintzen-Goldberg craniosynostosis syndrome
• Shprintzen-Goldberg marfanoid syndrome
## Prevalence
SGS is a rare disorder and the prevalence is unknown. A
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Hypotonia and intellectual disability are rare findings in individuals with LDS and MFS but appear to be almost always present in those with SGS.
Some of the distinctive radiographic findings in SGS are rarely found in individuals with either LDS or MFS. These include:
C1/C2 abnormality (in 7/10 individuals with SGS) [
Thirteen pairs of ribs (1/1) [
Chiari I malformation (2/3 ) [
Aortic root dilatation is less frequent in SGS than in LDS or MFS, but when present in individuals with SGS, it can be severe [
Comparison of Clinical Features of SGS,
= feature is present; ++ = feature is more commonly present; +++ = feature is most commonly present; − = feature is absent; LDS =
Approximately 75%-85% of Loeys-Dietz syndrome is attributed to pathogenic variants in
Marfan syndrome is caused by pathogenic variants in
Disorders of Interest in the Differential Diagnosis of Shprintzen-Goldberg Syndrome
Dolichostenomelia, arachnodactyly
Kyphosis/scoliosis
Aortic dilatation (occasionally present)
Aortic dilatation
Sagittal craniosynostosis, shallow orbits, palate abnormalities, &/or bifid uvula
ID (mild to moderate)
Skeletal anomalies
Marfanoid body habitus
Arachnodactyly & camptodactyly
Congenital heart disease
Hydronephrosis
Hearing loss
Seizures
AD = autosomal dominant; AR = autosomal recessive; CCA = congenital contractural arachnodactyly; DiffDx = differential diagnosis; FMD = frontometaphyseal dysplasia; ID = intellectual disability; MNS = Melnick-Needles syndrome; MOI = mode of inheritance; SGS = Shprintzen-Goldberg syndrome; XL = X-linked
Kyphosis/scoliosis in ~50% of individuals with CCA (begins as early as infancy, is progressive, & causes the greatest morbidity in CCA)
• Hypotonia and intellectual disability are rare findings in individuals with LDS and MFS but appear to be almost always present in those with SGS.
• Some of the distinctive radiographic findings in SGS are rarely found in individuals with either LDS or MFS. These include:
• C1/C2 abnormality (in 7/10 individuals with SGS) [
• Thirteen pairs of ribs (1/1) [
• Chiari I malformation (2/3 ) [
• C1/C2 abnormality (in 7/10 individuals with SGS) [
• Thirteen pairs of ribs (1/1) [
• Chiari I malformation (2/3 ) [
• Aortic root dilatation is less frequent in SGS than in LDS or MFS, but when present in individuals with SGS, it can be severe [
• C1/C2 abnormality (in 7/10 individuals with SGS) [
• Thirteen pairs of ribs (1/1) [
• Chiari I malformation (2/3 ) [
• Dolichostenomelia, arachnodactyly
• Kyphosis/scoliosis
• Aortic dilatation (occasionally present)
• Aortic dilatation
• Sagittal craniosynostosis, shallow orbits, palate abnormalities, &/or bifid uvula
• ID (mild to moderate)
• Skeletal anomalies
• Marfanoid body habitus
• Arachnodactyly & camptodactyly
• Congenital heart disease
• Hydronephrosis
• Hearing loss
• Seizures
## Management
To establish the extent of disease and needs in an individual diagnosed with Shprintzen-Goldberg syndrome (SGS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Shprintzen-Goldberg Syndrome
Physical exam
Head CT to evaluate sutures if craniosynostosis suspected
Management of SGS is best conducted through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, cardiothoracic surgeon, and craniofacial team.
Treatment of Manifestations in Individuals with Shprintzen-Goldberg Syndrome
DD = developmental delay
For individuals with cardiac complications, subacute bacterial endocarditis prophylaxis is recommended for dental work or other procedures expected to contaminate the bloodstream with bacteria.
Recommended Surveillance for Individuals with Shprintzen-Goldberg Syndrome
Cervical spine eval
Clinical eval for scoliosis
The following should be avoided:
Contact sports, which may lead to catastrophic complications in those with cardiovascular issues or cervical spine anomalies/instability
Agents that stimulate the cardiovascular system, including routine use of decongestants
Activities that cause joint pain or injury
See
Search
• Physical exam
• Head CT to evaluate sutures if craniosynostosis suspected
• Cervical spine eval
• Clinical eval for scoliosis
• Contact sports, which may lead to catastrophic complications in those with cardiovascular issues or cervical spine anomalies/instability
• Agents that stimulate the cardiovascular system, including routine use of decongestants
• Activities that cause joint pain or injury
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Shprintzen-Goldberg syndrome (SGS), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Shprintzen-Goldberg Syndrome
Physical exam
Head CT to evaluate sutures if craniosynostosis suspected
• Physical exam
• Head CT to evaluate sutures if craniosynostosis suspected
## Treatment of Manifestations
Management of SGS is best conducted through the coordinated input of a multidisciplinary team of specialists including a clinical geneticist, cardiologist, ophthalmologist, orthopedist, cardiothoracic surgeon, and craniofacial team.
Treatment of Manifestations in Individuals with Shprintzen-Goldberg Syndrome
DD = developmental delay
## Prevention of Secondary Complications
For individuals with cardiac complications, subacute bacterial endocarditis prophylaxis is recommended for dental work or other procedures expected to contaminate the bloodstream with bacteria.
## Surveillance
Recommended Surveillance for Individuals with Shprintzen-Goldberg Syndrome
Cervical spine eval
Clinical eval for scoliosis
• Cervical spine eval
• Clinical eval for scoliosis
## Agents/Circumstances to Avoid
The following should be avoided:
Contact sports, which may lead to catastrophic complications in those with cardiovascular issues or cervical spine anomalies/instability
Agents that stimulate the cardiovascular system, including routine use of decongestants
Activities that cause joint pain or injury
• Contact sports, which may lead to catastrophic complications in those with cardiovascular issues or cervical spine anomalies/instability
• Agents that stimulate the cardiovascular system, including routine use of decongestants
• Activities that cause joint pain or injury
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
Shprintzen-Goldberg syndrome (SGS), caused by a heterozygous pathogenic variant in
To date, most probands diagnosed with SGS represent simplex cases (i.e., a single occurrence in a family) and are assumed to have the disorder as a result of a
Rarely, an individual diagnosed with SGS has the disorder as the result of an inherited pathogenic variant. Recurrence of SGS was reported in a three-generation family with SGS [
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 SGS may appear to be negative because of a milder phenotypic presentation in an affected family member. Therefore, an apparently negative family history cannot be confirmed until appropriate clinical evaluation and/or molecular genetic testing has been performed.
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 heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. Multigenerational familial recurrence of SGS is rare but has been reported [
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.
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, most probands diagnosed with SGS represent simplex cases (i.e., a single occurrence in a family) and are assumed to have the disorder as a result of a
• Rarely, an individual diagnosed with SGS has the disorder as the result of an inherited pathogenic variant. Recurrence of SGS was reported in a three-generation family with SGS [
• 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 SGS may appear to be negative because of a milder phenotypic presentation in an affected family member. Therefore, an apparently negative family history cannot be confirmed until appropriate clinical evaluation and/or molecular genetic testing has been performed.
• 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 heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. Multigenerational familial recurrence of SGS is rare but has been reported [
• 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
Shprintzen-Goldberg syndrome (SGS), caused by a heterozygous pathogenic variant in
## Risk to Family Members
To date, most probands diagnosed with SGS represent simplex cases (i.e., a single occurrence in a family) and are assumed to have the disorder as a result of a
Rarely, an individual diagnosed with SGS has the disorder as the result of an inherited pathogenic variant. Recurrence of SGS was reported in a three-generation family with SGS [
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 SGS may appear to be negative because of a milder phenotypic presentation in an affected family member. Therefore, an apparently negative family history cannot be confirmed until appropriate clinical evaluation and/or molecular genetic testing has been performed.
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 heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. Multigenerational familial recurrence of SGS is rare but has been reported [
If the proband has a known
If the parents have not been tested for the
• To date, most probands diagnosed with SGS represent simplex cases (i.e., a single occurrence in a family) and are assumed to have the disorder as a result of a
• Rarely, an individual diagnosed with SGS has the disorder as the result of an inherited pathogenic variant. Recurrence of SGS was reported in a three-generation family with SGS [
• 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 SGS may appear to be negative because of a milder phenotypic presentation in an affected family member. Therefore, an apparently negative family history cannot be confirmed until appropriate clinical evaluation and/or molecular genetic testing has been performed.
• 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 heterozygous for the pathogenic variant identified in the proband, the risk to the sibs is 50%. Multigenerational familial recurrence of SGS is rare but has been reported [
• If the proband has a known
• 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
Shprintzen-Goldberg Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Shprintzen-Goldberg Syndrome (
The SKI oncogene is present in all cells, and is commonly active during development. It has a 728 amino-acid sequence with multiple domains and is expressed both inside and outside the cell. The different domains have different functions, including interaction with SMAD proteins.
TGF-β signaling is crucial to normal development and maintenance of various organs, including the vasculature.
## Molecular Pathogenesis
The SKI oncogene is present in all cells, and is commonly active during development. It has a 728 amino-acid sequence with multiple domains and is expressed both inside and outside the cell. The different domains have different functions, including interaction with SMAD proteins.
TGF-β signaling is crucial to normal development and maintenance of various organs, including the vasculature.
## Chapter Notes
9 April 2020 (sw) Comprehensive update posted live
13 June 2013 (me) Comprehensive update posted live
16 November 2010 (me) Comprehensive update posted live
13 January 2006 (me) Review posted live
2 December 2004 (mtg) Original submission
• 9 April 2020 (sw) Comprehensive update posted live
• 13 June 2013 (me) Comprehensive update posted live
• 16 November 2010 (me) Comprehensive update posted live
• 13 January 2006 (me) Review posted live
• 2 December 2004 (mtg) Original submission
## Revision History
9 April 2020 (sw) Comprehensive update posted live
13 June 2013 (me) Comprehensive update posted live
16 November 2010 (me) Comprehensive update posted live
13 January 2006 (me) Review posted live
2 December 2004 (mtg) Original submission
• 9 April 2020 (sw) Comprehensive update posted live
• 13 June 2013 (me) Comprehensive update posted live
• 16 November 2010 (me) Comprehensive update posted live
• 13 January 2006 (me) Review posted live
• 2 December 2004 (mtg) Original submission
## References
## Literature Cited
Clinical features of Shprintzen-Goldberg syndrome. Note craniosynostosis with typical craniofacial features including dolichocephaly, proptosis, hypertelorism, low-set ears, and retrognathia. Hand and foot images show arachnodactyly and camptodactyly.
From
|
[
"LC Adès, K Sullivan, A Biggin, EA Haan, M Brett, KJ Holman, J Dixon, S Robertson, AD Holmes, J Rogers, B Bennetts. FBN1, TGFBR1, and the Marfan-craniosynostosis/mental retardation disorders revisited.. Am J Med Genet A. 2006;140:1047-58",
"PY Au, HE Racher, JM Graham, N Kramer, RB Lowry, JS Parboosingh, AM Innes. De novo exon 1 missense mutations of SKI and Shprintzen-Goldberg syndrome: two new cases and clinical review.. Am J Med Genet A. 2014;164A:676-84",
"V Carmignac, J Thevenon, L Adès, B Callewaert, S Julia, C Thauvin-Robinet, L Gueneau, JB Courcet, E Lopez, K Holman, M Renard, H Plauchu, G Plessis, J De Backer, A Child, G Arno, L Duplomb, P Callier, B Aral, P Vabres, N Gigot, E Arbustini, M Grasso, PN Robinson, C Goizet, C Baumann, M Di Rocco, J Sanchez Del Pozo, F Huet, G Jondeau, G Collod-Beroud, C Beroud, J Amiel, V Cormier-Daire, JB Rivière, C Boileau, A De Paepe, L Faivre. In-frame mutations in exon 1 of SKI cause dominant Shprintzen-Goldberg syndrome.. Am J Hum Genet. 2012;91:950-7",
"AJ Doyle, JJ Doyle, SL Bessling, S Maragh, ME Lindsay, D Schepers, E Gillis, G Mortier, T Homfray, K Sauls, RA Norris, ND Huso, D Leahy, DW Mohr, MJ Caulfield, AF Scott, A Destrée, RC Hennekam, PH Arn, CJ Curry, L Van Laer, AS McCallion, BL Loeys, HC Dietz. Mutations in the TGF-β repressor SKI cause Shprintzen-Goldberg syndrome with aortic aneurysm.. Nat Genet. 2012;44:1249-54",
"GR O'Dougherty, DH Fulkerson, M Kern, K Haldar, B Calhoun. Complications of insufficient dura and blood loss during surgical intervention in Shprintzen-Goldberg syndrome: a case report.. Am J Case Rep. 2019;20:1159-69",
"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 Saito, T Nakane, H Yagasaki, A Naito, K Sugita. Shprintzen-Goldberg syndrome associated with first cervical vertebra defects.. Pediatr Int. 2017;59:1098-100",
"D Schepers, AJ Doyle, G Oswald, E Sparks, L Myers, PJ Willems, S Mansour, MA Simpson, H Frysira, A Maat-Kievit, R Van Minkelen, JM Hoogeboom, GR Mortier, H Titheradge, L Brueton, L Starr, Z Stark, C Ockeloen, CM Lourenco, E Blair, E Hobson, J Hurst, I Maystadt, A Destrée, KM Girisha, M Miller, HC Dietz, B Loeys, L Van Laer. The SMAD-binding domain of SKI: a hotspot for de novo mutations causing Shprintzen-Goldberg syndrome.. Eur J Hum Genet. 2015;23:224-8",
"N Takeda, H Hara, T Fujiwara, T Kanaya, S Maemura, I. Komuro. TGF-β signaling-related genes and thoracic aortic aneurysms and dissections.. Int J Mol Sci. 2018;19:2125",
"AC Tecalco-Cruz, DG Ríos-López, G Vázquez-Victorio, RE Rosales-Alvarez, M Macías-Silva. Transcriptional cofactors Ski and SnoN are major regulators of the TGF-β/Smad signaling pathway in health and disease.. Signal Transduct Target Ther. 2018;3:15",
"K Yauy, F Tran Mau-Them, M Willems, C Coubes, P Blanchet, C Herlin, I Taleb Arrada, E Sanchez, JM Faure, MP Le Gac, O Prodhomme, A Boland, V Meyer, JB Rivière, Y Duffourd, JF Deleuze, T Guignard, G Captier, M Barat-Houari, D Genevieve. B3GAT3-related disorder with craniosynostosis and bone fragility due to a unique mutation.. Genet Med. 2018;20:269-74",
"L Zhang, X Xu, K Sun, J Sun, Y Wang, Y Liu, N Yang, C Tao, B Cai, G Shi, F Zhang, J. Shi. A de novo mutation in DHD domain of SKI causing spina bifida with no craniofacial malformation or intellectual disability.. Am J Med Genet A. 2019;179:936-9",
"X Zhu, Y Zhang, J Wang, JF Yang, YF Yang, ZP Tan. 576 kb deletion in 1p36.33-p36.32 containing SKI is associated with limb malformation, congenital heart disease and epilepsy.. Gene. 2013;528:352-5"
] |
13/1/2006
|
9/4/2020
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
shashi-pena
|
shashi-pena
|
[
"SHAPNS",
"SHAPNS",
"Putative Polycomb group protein ASXL2",
"ASXL2",
"Shashi-Pena Syndrome"
] |
Shashi-Pena Syndrome
|
Julie M Porter, Loren DM Pena, Rebecca C Spillmann, Amanda Johnson, Vandana Shashi
|
Summary Shashi-Pena syndrome is characterized by distinctive facial features accompanied by variable further clinical findings. Facial features may include glabellar nevus simplex, widely spaced and prominent/proptotic eyes with epicanthal folds and ptosis, arched eyebrows, broad nasal tip, and low-set/posteriorly rotated ears. Dental anomalies may include early eruption and loss of teeth as well as small and fragile teeth. Most affected individuals have infantile hypotonia that frequently resolves over time. Macrosomia and macrocephaly are also common. Affected individuals can have variable developmental delay / intellectual disability, ranging from low-average intellectual abilities to severe intellectual disability. They often demonstrate difficulties with attention and aggressive behavior. Affected individuals may have feeding difficulties that require supportive nasogastric or gastrostomy tube feeding, skin findings (capillary malformations, deep palmar creases, hypertrichosis), skeletal anomalies (scoliosis/kyphosis, hypermobility, frequent fractures), congenital heart defects, seizures, hypoglycemia (most typically in infancy, may be due to hyperinsulinism), vision abnormalities (strabismus, amblyopia), conductive hearing loss, sleep apnea, temperature dysregulation, and global volume loss on brain MRI. The diagnosis of Shashi-Pena syndrome is established in a proband with suggestive clinical findings and a heterozygous pathogenic variant in Shashi-Pena syndrome is an autosomal dominant disorder typically caused by a
|
## Diagnosis
No consensus clinical diagnostic criteria for Shashi-Pena syndrome have been published.
Shashi-Pena syndrome
Distinctive facial features (most recognizable in infancy and becoming less discernible in older individuals) (see
Nevus simplex in the glabellar region of the forehead
Widely spaced and prominent/proptotic eyes with epicanthal folds
Ptosis
Arched eyebrows
Broad nasal tip
Low-set/posteriorly rotated ears
Macrosomia, defined as weight and length/height >2 standard deviations (SD) above the mean for age and sex.
Macrocephaly, defined as a head circumference that is >2 SD above the mean for age and sex
Generalized hypotonia of infancy
Mild-to-severe developmental delay or intellectual disability
Seizures, which may be febrile and/or non-febrile; among the non-febrile seizures, focal, generalized tonic-clonic, and absence have been described.
Dental findings, including early tooth eruption, premature loss of primary dentition, and small teeth
Congenital heart defects
Hypoglycemia that typically starts in the neonatal period and can be persistent into older ages
Deep palmar/plantar creases
Skeletal manifestations, including scoliosis/kyphosis or frequent fractures
The diagnosis of Shashi-Pena 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 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 Shashi-Pena syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of Shashi-Pena syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Shashi-Pena 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.
To date, no large intragenic deletions/duplications have been reported in individuals with Shashi-Pena syndrome.
• Distinctive facial features (most recognizable in infancy and becoming less discernible in older individuals) (see
• Nevus simplex in the glabellar region of the forehead
• Widely spaced and prominent/proptotic eyes with epicanthal folds
• Ptosis
• Arched eyebrows
• Broad nasal tip
• Low-set/posteriorly rotated ears
• Nevus simplex in the glabellar region of the forehead
• Widely spaced and prominent/proptotic eyes with epicanthal folds
• Ptosis
• Arched eyebrows
• Broad nasal tip
• Low-set/posteriorly rotated ears
• Macrosomia, defined as weight and length/height >2 standard deviations (SD) above the mean for age and sex.
• Macrocephaly, defined as a head circumference that is >2 SD above the mean for age and sex
• Generalized hypotonia of infancy
• Mild-to-severe developmental delay or intellectual disability
• Seizures, which may be febrile and/or non-febrile; among the non-febrile seizures, focal, generalized tonic-clonic, and absence have been described.
• Dental findings, including early tooth eruption, premature loss of primary dentition, and small teeth
• Congenital heart defects
• Hypoglycemia that typically starts in the neonatal period and can be persistent into older ages
• Deep palmar/plantar creases
• Skeletal manifestations, including scoliosis/kyphosis or frequent fractures
• Nevus simplex in the glabellar region of the forehead
• Widely spaced and prominent/proptotic eyes with epicanthal folds
• Ptosis
• Arched eyebrows
• Broad nasal tip
• Low-set/posteriorly rotated ears
• For an introduction to multigene panels click
## Suggestive Findings
Shashi-Pena syndrome
Distinctive facial features (most recognizable in infancy and becoming less discernible in older individuals) (see
Nevus simplex in the glabellar region of the forehead
Widely spaced and prominent/proptotic eyes with epicanthal folds
Ptosis
Arched eyebrows
Broad nasal tip
Low-set/posteriorly rotated ears
Macrosomia, defined as weight and length/height >2 standard deviations (SD) above the mean for age and sex.
Macrocephaly, defined as a head circumference that is >2 SD above the mean for age and sex
Generalized hypotonia of infancy
Mild-to-severe developmental delay or intellectual disability
Seizures, which may be febrile and/or non-febrile; among the non-febrile seizures, focal, generalized tonic-clonic, and absence have been described.
Dental findings, including early tooth eruption, premature loss of primary dentition, and small teeth
Congenital heart defects
Hypoglycemia that typically starts in the neonatal period and can be persistent into older ages
Deep palmar/plantar creases
Skeletal manifestations, including scoliosis/kyphosis or frequent fractures
• Distinctive facial features (most recognizable in infancy and becoming less discernible in older individuals) (see
• Nevus simplex in the glabellar region of the forehead
• Widely spaced and prominent/proptotic eyes with epicanthal folds
• Ptosis
• Arched eyebrows
• Broad nasal tip
• Low-set/posteriorly rotated ears
• Nevus simplex in the glabellar region of the forehead
• Widely spaced and prominent/proptotic eyes with epicanthal folds
• Ptosis
• Arched eyebrows
• Broad nasal tip
• Low-set/posteriorly rotated ears
• Macrosomia, defined as weight and length/height >2 standard deviations (SD) above the mean for age and sex.
• Macrocephaly, defined as a head circumference that is >2 SD above the mean for age and sex
• Generalized hypotonia of infancy
• Mild-to-severe developmental delay or intellectual disability
• Seizures, which may be febrile and/or non-febrile; among the non-febrile seizures, focal, generalized tonic-clonic, and absence have been described.
• Dental findings, including early tooth eruption, premature loss of primary dentition, and small teeth
• Congenital heart defects
• Hypoglycemia that typically starts in the neonatal period and can be persistent into older ages
• Deep palmar/plantar creases
• Skeletal manifestations, including scoliosis/kyphosis or frequent fractures
• Nevus simplex in the glabellar region of the forehead
• Widely spaced and prominent/proptotic eyes with epicanthal folds
• Ptosis
• Arched eyebrows
• Broad nasal tip
• Low-set/posteriorly rotated ears
## Establishing the Diagnosis
The diagnosis of Shashi-Pena 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 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 Shashi-Pena syndrome is broad, individuals with the distinctive findings described in
When the phenotypic and laboratory findings suggest the diagnosis of Shashi-Pena syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Shashi-Pena 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.
To date, no large intragenic deletions/duplications have been reported in individuals with Shashi-Pena syndrome.
• For an introduction to multigene panels click
## Option 1
When the phenotypic and laboratory findings suggest the diagnosis of Shashi-Pena syndrome, molecular genetic testing approaches can include
For an introduction to multigene panels click
• For an introduction to multigene panels click
## Option 2
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Shashi-Pena 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.
To date, no large intragenic deletions/duplications have been reported in individuals with Shashi-Pena syndrome.
## Clinical Characteristics
Shashi-Pena syndrome is characterized by distinctive facial features accompanied by variable further clinical findings, which may include macrocephaly, dental anomalies, congenital heart defects, seizures, hypoglycemia, hypotonia, developmental delays / intellectual disabilities, skeletal abnormalities, and global volume loss on brain MRI.
To date, at least 23 individuals have been identified with pathogenic truncating variants in
Shashi-Pena Syndrome: Frequency of Select Features
ASD = atrial septal defect; PFO = patent foramen ovale; PDA = patent ductus arteriosus
Data is derived from 12 published individuals and 11 unpublished individuals [
Data points were missing for some individuals, so the denominator for each feature is indicated in the table.
Gingival overgrowth
Microdontia
Sialorrhea
Increased alveolar bone density
Gross motor delays have manifested as delayed walking (range: age 18 months to after age 4 years).
Verbal communication may be achieved as early as age two years, although some affected individuals continued to be nonverbal at age four years.
The range of intellectual abilities extends from low-average IQ (reported in one such person) to severe ID.
Of these, about one third have febrile seizures only, one third have non-febrile seizures only, and one third have both febrile and non-febrile seizures.
Among non-febrile seizures, generalized tonic-clonic, focal, and absence seizures have been described.
There is no specific pattern of EEG changes noted in people with Shashi-Pena syndrome, but EEG findings tend to be consistent with the reported seizure type.
Seizures are typically well controlled with standard anti-seizure medications when needed (see
About two thirds of affected individuals have scoliosis/kyphosis (11/16; 69%) and/or joint hypermobility (9/14; 64%), although without frank joint dislocations.
Scoliosis/kyphosis may require significant surgical intervention.
A predisposition to fractures (5/17; 29%) and hip dysplasia have been noted in fewer than one third of affected individuals.
Ventricular septal defects
Coarctation of the aorta
Pulmonary artery valve thickening
Pulmonary artery stenosis
The exact presentation is variable. Some affected individuals experienced hypoglycemia only in the neonatal period, others had episodic hypoglycemia, and one affected individual had severe hypoglycemia requiring continuous feeds.
Hyperinsulinism has been documented in at least two affected individuals, and one was successfully treated with octreotide [
Although no genotype-phenotype correlations have been identified, thus far all pathogenic variants associated with the classic findings of Shashi-Pena syndrome have been
The exact prevalence of Shashi-Pena syndrome is unknown; it likely is an ultra-rare condition [
• Gingival overgrowth
• Microdontia
• Sialorrhea
• Increased alveolar bone density
• Gross motor delays have manifested as delayed walking (range: age 18 months to after age 4 years).
• Verbal communication may be achieved as early as age two years, although some affected individuals continued to be nonverbal at age four years.
• The range of intellectual abilities extends from low-average IQ (reported in one such person) to severe ID.
• Of these, about one third have febrile seizures only, one third have non-febrile seizures only, and one third have both febrile and non-febrile seizures.
• Among non-febrile seizures, generalized tonic-clonic, focal, and absence seizures have been described.
• There is no specific pattern of EEG changes noted in people with Shashi-Pena syndrome, but EEG findings tend to be consistent with the reported seizure type.
• Seizures are typically well controlled with standard anti-seizure medications when needed (see
• Of these, about one third have febrile seizures only, one third have non-febrile seizures only, and one third have both febrile and non-febrile seizures.
• Among non-febrile seizures, generalized tonic-clonic, focal, and absence seizures have been described.
• There is no specific pattern of EEG changes noted in people with Shashi-Pena syndrome, but EEG findings tend to be consistent with the reported seizure type.
• Seizures are typically well controlled with standard anti-seizure medications when needed (see
• Of these, about one third have febrile seizures only, one third have non-febrile seizures only, and one third have both febrile and non-febrile seizures.
• Among non-febrile seizures, generalized tonic-clonic, focal, and absence seizures have been described.
• There is no specific pattern of EEG changes noted in people with Shashi-Pena syndrome, but EEG findings tend to be consistent with the reported seizure type.
• Seizures are typically well controlled with standard anti-seizure medications when needed (see
• About two thirds of affected individuals have scoliosis/kyphosis (11/16; 69%) and/or joint hypermobility (9/14; 64%), although without frank joint dislocations.
• Scoliosis/kyphosis may require significant surgical intervention.
• A predisposition to fractures (5/17; 29%) and hip dysplasia have been noted in fewer than one third of affected individuals.
• Ventricular septal defects
• Coarctation of the aorta
• Pulmonary artery valve thickening
• Pulmonary artery stenosis
• The exact presentation is variable. Some affected individuals experienced hypoglycemia only in the neonatal period, others had episodic hypoglycemia, and one affected individual had severe hypoglycemia requiring continuous feeds.
• Hyperinsulinism has been documented in at least two affected individuals, and one was successfully treated with octreotide [
## Clinical Description
Shashi-Pena syndrome is characterized by distinctive facial features accompanied by variable further clinical findings, which may include macrocephaly, dental anomalies, congenital heart defects, seizures, hypoglycemia, hypotonia, developmental delays / intellectual disabilities, skeletal abnormalities, and global volume loss on brain MRI.
To date, at least 23 individuals have been identified with pathogenic truncating variants in
Shashi-Pena Syndrome: Frequency of Select Features
ASD = atrial septal defect; PFO = patent foramen ovale; PDA = patent ductus arteriosus
Data is derived from 12 published individuals and 11 unpublished individuals [
Data points were missing for some individuals, so the denominator for each feature is indicated in the table.
Gingival overgrowth
Microdontia
Sialorrhea
Increased alveolar bone density
Gross motor delays have manifested as delayed walking (range: age 18 months to after age 4 years).
Verbal communication may be achieved as early as age two years, although some affected individuals continued to be nonverbal at age four years.
The range of intellectual abilities extends from low-average IQ (reported in one such person) to severe ID.
Of these, about one third have febrile seizures only, one third have non-febrile seizures only, and one third have both febrile and non-febrile seizures.
Among non-febrile seizures, generalized tonic-clonic, focal, and absence seizures have been described.
There is no specific pattern of EEG changes noted in people with Shashi-Pena syndrome, but EEG findings tend to be consistent with the reported seizure type.
Seizures are typically well controlled with standard anti-seizure medications when needed (see
About two thirds of affected individuals have scoliosis/kyphosis (11/16; 69%) and/or joint hypermobility (9/14; 64%), although without frank joint dislocations.
Scoliosis/kyphosis may require significant surgical intervention.
A predisposition to fractures (5/17; 29%) and hip dysplasia have been noted in fewer than one third of affected individuals.
Ventricular septal defects
Coarctation of the aorta
Pulmonary artery valve thickening
Pulmonary artery stenosis
The exact presentation is variable. Some affected individuals experienced hypoglycemia only in the neonatal period, others had episodic hypoglycemia, and one affected individual had severe hypoglycemia requiring continuous feeds.
Hyperinsulinism has been documented in at least two affected individuals, and one was successfully treated with octreotide [
• Gingival overgrowth
• Microdontia
• Sialorrhea
• Increased alveolar bone density
• Gross motor delays have manifested as delayed walking (range: age 18 months to after age 4 years).
• Verbal communication may be achieved as early as age two years, although some affected individuals continued to be nonverbal at age four years.
• The range of intellectual abilities extends from low-average IQ (reported in one such person) to severe ID.
• Of these, about one third have febrile seizures only, one third have non-febrile seizures only, and one third have both febrile and non-febrile seizures.
• Among non-febrile seizures, generalized tonic-clonic, focal, and absence seizures have been described.
• There is no specific pattern of EEG changes noted in people with Shashi-Pena syndrome, but EEG findings tend to be consistent with the reported seizure type.
• Seizures are typically well controlled with standard anti-seizure medications when needed (see
• Of these, about one third have febrile seizures only, one third have non-febrile seizures only, and one third have both febrile and non-febrile seizures.
• Among non-febrile seizures, generalized tonic-clonic, focal, and absence seizures have been described.
• There is no specific pattern of EEG changes noted in people with Shashi-Pena syndrome, but EEG findings tend to be consistent with the reported seizure type.
• Seizures are typically well controlled with standard anti-seizure medications when needed (see
• Of these, about one third have febrile seizures only, one third have non-febrile seizures only, and one third have both febrile and non-febrile seizures.
• Among non-febrile seizures, generalized tonic-clonic, focal, and absence seizures have been described.
• There is no specific pattern of EEG changes noted in people with Shashi-Pena syndrome, but EEG findings tend to be consistent with the reported seizure type.
• Seizures are typically well controlled with standard anti-seizure medications when needed (see
• About two thirds of affected individuals have scoliosis/kyphosis (11/16; 69%) and/or joint hypermobility (9/14; 64%), although without frank joint dislocations.
• Scoliosis/kyphosis may require significant surgical intervention.
• A predisposition to fractures (5/17; 29%) and hip dysplasia have been noted in fewer than one third of affected individuals.
• Ventricular septal defects
• Coarctation of the aorta
• Pulmonary artery valve thickening
• Pulmonary artery stenosis
• The exact presentation is variable. Some affected individuals experienced hypoglycemia only in the neonatal period, others had episodic hypoglycemia, and one affected individual had severe hypoglycemia requiring continuous feeds.
• Hyperinsulinism has been documented in at least two affected individuals, and one was successfully treated with octreotide [
## Genotype-Phenotype Correlations
Although no genotype-phenotype correlations have been identified, thus far all pathogenic variants associated with the classic findings of Shashi-Pena syndrome have been
## Prevalence
The exact prevalence of Shashi-Pena syndrome is unknown; it likely is an ultra-rare condition [
## Genetically Related (Allelic) Disorders
No phenotypes other than that discussed in this
A few individuals with missense variants or genetic rearrangements involving
One family with a balanced t(2;11)(p23;q23) translocation that disrupted normal expression of
• One family with a balanced t(2;11)(p23;q23) translocation that disrupted normal expression of
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of Shashi-Pena Syndrome
Glabellar nevus simplex
Hypertelorism, prominent eyes
Hypertrichosis
Seizures
Poor postnatal weight gain & linear growth
Microcephaly
More severe feeding difficulties incl cyclic vomiting
High myopia
BOS posture
Severe-to profound-ID
DD
Hypotonia
Feeding difficulties
Epilepsy
Marfanoid habitus
Pectus excavatum
Joint flexion w/contractures
Macrosomia
Glabellar nevus simplex
Distinctive facial appearance (in some persons)
Asymmetric growth
Macrosomia
Widely spaced eyes
Coarse facial features
Macroglossia
Bifid uvula
Overgrowth (height &/or head circumference ≥2 SD above mean)
ID
Congenital heart defects
Advanced bone age
Overall facial gestalt
Prognathism
Macrocephaly
DD
Hamartomatous polyps
Cancer
Glabellar nevus simplex
Macrocephaly
Hypertelorism
AD = autosomal dominant; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; XL = X-linked
The Bohring-Opitz syndrome (BOS) posture, which is most striking in early childhood and often becomes less apparent with age, is characterized by flexion at the elbows with ulnar deviation and flexion of the wrists and metacarpophalangeal joints.
Beckwith-Wiedemann syndrome (BWS) is associated with either an epigenetic or genomic alteration leading to abnormal methylation at 11p15.5 or a heterozygous BWS-causing pathogenic variant in
• Glabellar nevus simplex
• Hypertelorism, prominent eyes
• Hypertrichosis
• Seizures
• Poor postnatal weight gain & linear growth
• Microcephaly
• More severe feeding difficulties incl cyclic vomiting
• High myopia
• BOS posture
• Severe-to profound-ID
• DD
• Hypotonia
• Feeding difficulties
• Epilepsy
• Marfanoid habitus
• Pectus excavatum
• Joint flexion w/contractures
• Macrosomia
• Glabellar nevus simplex
• Distinctive facial appearance (in some persons)
• Asymmetric growth
• Macrosomia
• Widely spaced eyes
• Coarse facial features
• Macroglossia
• Bifid uvula
• Overgrowth (height &/or head circumference ≥2 SD above mean)
• ID
• Congenital heart defects
• Advanced bone age
• Overall facial gestalt
• Prognathism
• Macrocephaly
• DD
• Hamartomatous polyps
• Cancer
• Glabellar nevus simplex
• Macrocephaly
• Hypertelorism
## Management
No clinical practice guidelines for Shashi-Pena syndrome have been published.
To establish the extent of disease and needs in an individual diagnosed with Shashi-Pena syndrome, the evaluations summarized in
Shashi-Pena Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI for rapidly ↑ head circumference or focal seizures.
Consider EEG if seizures are a concern.
Incl assessment for temperature dysregulation.
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/feeding difficulties.
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)
Clinical assessment for scoliosis/kyphosis & history of fractures
In neonates, obtain serum blood glucose level
In older infants & children, assess for signs/symptoms of hypoglycemia; consider obtaining a serum glucose level in those w/suspicious symptoms.
Community or
Social work involvement for parental support
AAP = American Academy of Pediatrics; ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; M-CHAT-R/F
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for Shashi-Pena syndrome. 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
Shashi-Pena Syndrome: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Nasogastric or gastrostomy tube placement may be required for persistent feeding issues.
Review of healthy eating habits
Surveillance for euglycemia, hyperlipidemia, hypertension
Rapid assessment & mgmt of recurrent otitis media; PE tubes may be indicated.
Hearing aids may be helpful per otolaryngologist.
Community hearing services through early intervention or school district
1 affected person received cochlear implants.
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
ASD = atrial septal defect; ASM = anti-seizure medication; OT = occupational therapy; PE = pressure-equalizing; 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.
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
Shashi-Pena Syndrome: Recommended Surveillance
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
Monitor for difficulties w/attention, anger outbursts, & aggression.
Monitor for signs of ADHD, autism spectrum disorder, & anxiety.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures & changes in tone.
Monitor for signs/symptoms of temperature dysregulation.
Physical medicine, OT/PT assessment of mobility, self-help skills
Clinical exam for scoliosis/kyphosis
Assess for signs/symptoms of hypoglycemia.
Monitor & educate caregivers re symptoms of hypoglycemia or hyperglycemia.
ADHD = attention-deficit/hyperactivity disorder; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
Referral to a developmental pediatrician or mental health provider with experience working with children with complex needs may be indicated.
Prolonged fasting should be avoided in those with hypoglycemia.
See
In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [
See
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI for rapidly ↑ head circumference or focal seizures.
• Consider EEG if seizures are a concern.
• Incl assessment for temperature dysregulation.
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/feeding difficulties.
• 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)
• Clinical assessment for scoliosis/kyphosis & history of fractures
• In neonates, obtain serum blood glucose level
• In older infants & children, assess for signs/symptoms of hypoglycemia; consider obtaining a serum glucose level in those w/suspicious symptoms.
• Community or
• Social work involvement for parental support
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Feeding therapy
• Nasogastric or gastrostomy tube placement may be required for persistent feeding issues.
• Review of healthy eating habits
• Surveillance for euglycemia, hyperlipidemia, hypertension
• Rapid assessment & mgmt of recurrent otitis media; PE tubes may be indicated.
• Hearing aids may be helpful per otolaryngologist.
• Community hearing services through early intervention or school district
• 1 affected person received cochlear implants.
• 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.
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
• Monitor for difficulties w/attention, anger outbursts, & aggression.
• Monitor for signs of ADHD, autism spectrum disorder, & anxiety.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures & changes in tone.
• Monitor for signs/symptoms of temperature dysregulation.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Clinical exam for scoliosis/kyphosis
• Assess for signs/symptoms of hypoglycemia.
• Monitor & educate caregivers re symptoms of hypoglycemia or hyperglycemia.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Shashi-Pena syndrome, the evaluations summarized in
Shashi-Pena Syndrome: Recommended Evaluations Following Initial Diagnosis
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI for rapidly ↑ head circumference or focal seizures.
Consider EEG if seizures are a concern.
Incl assessment for temperature dysregulation.
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in those w/feeding difficulties.
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)
Clinical assessment for scoliosis/kyphosis & history of fractures
In neonates, obtain serum blood glucose level
In older infants & children, assess for signs/symptoms of hypoglycemia; consider obtaining a serum glucose level in those w/suspicious symptoms.
Community or
Social work involvement for parental support
AAP = American Academy of Pediatrics; ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; ASD = autism spectrum disorder; M-CHAT-R/F
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI for rapidly ↑ head circumference or focal seizures.
• Consider EEG if seizures are a concern.
• Incl assessment for temperature dysregulation.
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in those w/feeding difficulties.
• 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)
• Clinical assessment for scoliosis/kyphosis & history of fractures
• In neonates, obtain serum blood glucose level
• In older infants & children, assess for signs/symptoms of hypoglycemia; consider obtaining a serum glucose level in those w/suspicious symptoms.
• Community or
• Social work involvement for parental support
## Treatment of Manifestations
There is no cure for Shashi-Pena syndrome. 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
Shashi-Pena Syndrome: Treatment of Manifestations
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Feeding therapy
Nasogastric or gastrostomy tube placement may be required for persistent feeding issues.
Review of healthy eating habits
Surveillance for euglycemia, hyperlipidemia, hypertension
Rapid assessment & mgmt of recurrent otitis media; PE tubes may be indicated.
Hearing aids may be helpful per otolaryngologist.
Community hearing services through early intervention or school district
1 affected person received cochlear implants.
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
ASD = atrial septal defect; ASM = anti-seizure medication; OT = occupational therapy; PE = pressure-equalizing; 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.
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
• Nasogastric or gastrostomy tube placement may be required for persistent feeding issues.
• Review of healthy eating habits
• Surveillance for euglycemia, hyperlipidemia, hypertension
• Rapid assessment & mgmt of recurrent otitis media; PE tubes may be indicated.
• Hearing aids may be helpful per otolaryngologist.
• Community hearing services through early intervention or school district
• 1 affected person received cochlear implants.
• 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.
## Motor Dysfunction
## 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
Shashi-Pena Syndrome: Recommended Surveillance
Measure growth parameters.
Evaluate nutritional status & safety of oral intake.
Monitor for difficulties w/attention, anger outbursts, & aggression.
Monitor for signs of ADHD, autism spectrum disorder, & anxiety.
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures & changes in tone.
Monitor for signs/symptoms of temperature dysregulation.
Physical medicine, OT/PT assessment of mobility, self-help skills
Clinical exam for scoliosis/kyphosis
Assess for signs/symptoms of hypoglycemia.
Monitor & educate caregivers re symptoms of hypoglycemia or hyperglycemia.
ADHD = attention-deficit/hyperactivity disorder; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
Referral to a developmental pediatrician or mental health provider with experience working with children with complex needs may be indicated.
• Measure growth parameters.
• Evaluate nutritional status & safety of oral intake.
• Monitor for difficulties w/attention, anger outbursts, & aggression.
• Monitor for signs of ADHD, autism spectrum disorder, & anxiety.
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures & changes in tone.
• Monitor for signs/symptoms of temperature dysregulation.
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Clinical exam for scoliosis/kyphosis
• Assess for signs/symptoms of hypoglycemia.
• Monitor & educate caregivers re symptoms of hypoglycemia or hyperglycemia.
## Agents/Circumstances to Avoid
Prolonged fasting should be avoided in those with hypoglycemia.
## Evaluation of Relatives at Risk
See
## Pregnancy Management
In general, women with epilepsy or a seizure disorder of any cause are at greater risk for mortality during pregnancy than pregnant women without a seizure disorder; use of anti-seizure medication (ASM) during pregnancy reduces this risk. However, exposure to ASMs may increase the risk for adverse fetal outcome (depending on the drug used, the dose, and the stage of pregnancy at which medication is taken). Nevertheless, the risk of an adverse outcome to the fetus from ASM exposure is often less than that associated with exposure to an untreated maternal seizure disorder. Therefore, use of ASMs to treat a maternal seizure disorder during pregnancy is typically recommended. Discussion of the risks and benefits of using a given ASM during pregnancy should ideally take place prior to conception. Transitioning to a lower-risk medication prior to pregnancy may be possible [
See
## Therapies Under Investigation
Search
## Genetic Counseling
Shashi-Pena syndrome is an autosomal dominant disorder typically caused by a
To date, all known individuals with Shashi-Pena syndrome 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.
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 an
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 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 health care professionals would consider use of prenatal and preimplantation genetic testing to be a personal decision, discussion of these issues may be helpful.
• To date, all known individuals with Shashi-Pena syndrome 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.
• 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 an
• 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 an
• 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 an
• 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 parents of affected individuals.
## Mode of Inheritance
Shashi-Pena syndrome is an autosomal dominant disorder typically caused by a
## Risk to Family Members
To date, all known individuals with Shashi-Pena syndrome 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.
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 an
If a parent of the proband is heterozygous for the
If the
• To date, all known individuals with Shashi-Pena syndrome 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.
• 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 an
• 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 an
• 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 an
• If a parent of the proband is heterozygous for 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 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
Natural History Study
•
•
•
• Natural History Study
## Molecular Genetics
Shashi-Pena Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Shashi-Pena Syndrome (
## Molecular Pathogenesis
## Chapter Notes
We gratefully acknowledge the families with Shashi-Pena syndrome and the ARRE Foundation for their support in data gathering as we expand our understanding of the disorder.
We would like to acknowledge Wenying Zhang, MD, PhD, MBA, and Yaning Wu, MD, PhD, from Cincinnati Children's Hospital for assistance in interpretation of genomic data.
The authors also wish to acknowledge funding support from the Undiagnosed Diseases Network, which made the 2016 publication of the initial cohort of affected individuals possible.
7 November 2024 (ma) Review posted live
8 March 2024 (lp) Original submission
• 7 November 2024 (ma) Review posted live
• 8 March 2024 (lp) Original submission
## Acknowledgments
We gratefully acknowledge the families with Shashi-Pena syndrome and the ARRE Foundation for their support in data gathering as we expand our understanding of the disorder.
We would like to acknowledge Wenying Zhang, MD, PhD, MBA, and Yaning Wu, MD, PhD, from Cincinnati Children's Hospital for assistance in interpretation of genomic data.
The authors also wish to acknowledge funding support from the Undiagnosed Diseases Network, which made the 2016 publication of the initial cohort of affected individuals possible.
## Revision History
7 November 2024 (ma) Review posted live
8 March 2024 (lp) Original submission
• 7 November 2024 (ma) Review posted live
• 8 March 2024 (lp) Original submission
## References
## Literature Cited
Photographs of six affected individuals at different ages. Distinctive facial features include epicanthal folds, widely spaced eyes, a wide nasal bridge, broad nasal tip, and a glabellar nevus simplex.
Reproduced with permission from
|
[] |
7/11/2024
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
short
|
short
|
[
"Phosphatidylinositol 3-kinase regulatory subunit alpha",
"PIK3R1",
"SHORT Syndrome"
] |
SHORT Syndrome
|
A Micheil Innes, David A Dyment
|
Summary SHORT syndrome is a mnemonic for The diagnosis of SHORT syndrome is established in a proband with compatible clinical features (with emphasis on the facial gestalt) and a heterozygous pathogenic variant in SHORT syndrome is inherited in an autosomal dominant manner. The proportion of individuals with SHORT syndrome caused by a
|
## Diagnosis
The designation SHORT syndrome was coined by
SHORT syndrome
Intrauterine growth restriction
Short stature
Partial lipodystrophy
Characteristic facial gestalt (see
Axenfeld-Rieger anomaly or related anterior chamber ocular anomalies
Delayed dentition
Insulin resistance / diabetes mellitus
No formal diagnostic criteria have been published for SHORT syndrome; however, to date the presence of characteristic facial features is highly predictive for identifying a heterozygous
The diagnosis of SHORT 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
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive and recognizable facial features of SHORT syndrome described in
When the phenotypic and laboratory findings suggest the diagnosis of SHORT syndrome, 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 short stature or partial lipodystrophy,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SHORT 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
To date, a
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.
• Intrauterine growth restriction
• Short stature
• Partial lipodystrophy
• Characteristic facial gestalt (see
• Axenfeld-Rieger anomaly or related anterior chamber ocular anomalies
• Delayed dentition
• Insulin resistance / diabetes mellitus
• For an introduction to multigene panels click
## Suggestive Findings
SHORT syndrome
Intrauterine growth restriction
Short stature
Partial lipodystrophy
Characteristic facial gestalt (see
Axenfeld-Rieger anomaly or related anterior chamber ocular anomalies
Delayed dentition
Insulin resistance / diabetes mellitus
No formal diagnostic criteria have been published for SHORT syndrome; however, to date the presence of characteristic facial features is highly predictive for identifying a heterozygous
• Intrauterine growth restriction
• Short stature
• Partial lipodystrophy
• Characteristic facial gestalt (see
• Axenfeld-Rieger anomaly or related anterior chamber ocular anomalies
• Delayed dentition
• Insulin resistance / diabetes mellitus
## Establishing the Diagnosis
The diagnosis of SHORT 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
Gene-targeted testing requires that the clinician determine which gene(s) are likely involved, whereas genomic testing does not. Individuals with the distinctive and recognizable facial features of SHORT syndrome described in
When the phenotypic and laboratory findings suggest the diagnosis of SHORT syndrome, 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 short stature or partial lipodystrophy,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SHORT 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
To date, a
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 laboratory findings suggest the diagnosis of SHORT 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 phenotype is indistinguishable from many other inherited disorders characterized by short stature or partial lipodystrophy,
If exome sequencing is not diagnostic,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SHORT 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
To date, a
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, a pathogenic variant in
Select Features of SHORT Syndrome
The remaining 8/40 individuals are described as short but with height between -2 SD and -1 SD.
Mild-to-moderate short stature is usually present throughout childhood. Bone age may or may not be delayed. Other skeletal changes include gracile diaphyses and large and coned-shaped epiphyses [
Mild short stature has been seen in most adults reported to date. Adult height in males with a molecularly confirmed diagnosis of SHORT syndrome was between 155 and 163 cm and in females between 143 and 160 cm [
The body habitus is described as thin. All four adult males reported to date with a molecularly confirmed diagnosis had a body mass index (BMI) below 18.5 (range 13.5-17.9); four of eight adult females also had a BMI below 18.5 (range 15.1-22.5) [
The majority of individuals with a
Sensorineural hearing loss of 80-90 dB has been diagnosed within the first year of life. Among individuals with a molecularly confirmed diagnosis of SHORT syndrome, six have been reported with hearing loss [
While cognition is not affected in SHORT syndrome, some affected children have mild speech delay.
Some, but not all, affected individuals exhibit hyperextensible joints and/or inguinal hernias.
Although there does not appear to be an increased risk for life-threatening infections or evidence of clinical immunodeficiency, there have been reports of a nonspecific history of frequent infections [
Nephrocalcinosis has been reported in a mother-son pair with a molecularly confirmed diagnosis [
Pulmonic stenosis and ectopic kidney have also been reported [
Fertility is generally preserved in SHORT syndrome; ovarian cysts are commonly reported in affected females.
To date no clear genotype-phenotype correlation is evident; however, pathogenic variants appear to cluster in the C-terminal SH2 domain of
The recurrent missense pathogenic variant
The penetrance of SHORT syndrome appears complete in all individuals undergoing molecular genetic testing to date: all simplex cases (i.e., a single occurrence in a family) with parents available for testing have had a
Since it was first described in the early 1970s, what appears to be SHORT syndrome has been described by different terms, including:
Low-birthweight Rieger syndrome
Autosomal partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes *
Absent iris stroma, narrow body build, and small facial bones *
* Individuals with the latter two disorders have subsequently been demonstrated to have a
SHORT syndrome is very rare; fewer than 50 cases have been reported in the literature.
No ethnic predilection is known.
• Mild-to-moderate short stature is usually present throughout childhood. Bone age may or may not be delayed. Other skeletal changes include gracile diaphyses and large and coned-shaped epiphyses [
• Mild short stature has been seen in most adults reported to date. Adult height in males with a molecularly confirmed diagnosis of SHORT syndrome was between 155 and 163 cm and in females between 143 and 160 cm [
• Sensorineural hearing loss of 80-90 dB has been diagnosed within the first year of life. Among individuals with a molecularly confirmed diagnosis of SHORT syndrome, six have been reported with hearing loss [
• While cognition is not affected in SHORT syndrome, some affected children have mild speech delay.
• Some, but not all, affected individuals exhibit hyperextensible joints and/or inguinal hernias.
• Although there does not appear to be an increased risk for life-threatening infections or evidence of clinical immunodeficiency, there have been reports of a nonspecific history of frequent infections [
• Nephrocalcinosis has been reported in a mother-son pair with a molecularly confirmed diagnosis [
• Pulmonic stenosis and ectopic kidney have also been reported [
• Fertility is generally preserved in SHORT syndrome; ovarian cysts are commonly reported in affected females.
• Low-birthweight Rieger syndrome
• Autosomal partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes *
• Absent iris stroma, narrow body build, and small facial bones *
## Clinical Description
To date, a pathogenic variant in
Select Features of SHORT Syndrome
The remaining 8/40 individuals are described as short but with height between -2 SD and -1 SD.
Mild-to-moderate short stature is usually present throughout childhood. Bone age may or may not be delayed. Other skeletal changes include gracile diaphyses and large and coned-shaped epiphyses [
Mild short stature has been seen in most adults reported to date. Adult height in males with a molecularly confirmed diagnosis of SHORT syndrome was between 155 and 163 cm and in females between 143 and 160 cm [
The body habitus is described as thin. All four adult males reported to date with a molecularly confirmed diagnosis had a body mass index (BMI) below 18.5 (range 13.5-17.9); four of eight adult females also had a BMI below 18.5 (range 15.1-22.5) [
The majority of individuals with a
Sensorineural hearing loss of 80-90 dB has been diagnosed within the first year of life. Among individuals with a molecularly confirmed diagnosis of SHORT syndrome, six have been reported with hearing loss [
While cognition is not affected in SHORT syndrome, some affected children have mild speech delay.
Some, but not all, affected individuals exhibit hyperextensible joints and/or inguinal hernias.
Although there does not appear to be an increased risk for life-threatening infections or evidence of clinical immunodeficiency, there have been reports of a nonspecific history of frequent infections [
Nephrocalcinosis has been reported in a mother-son pair with a molecularly confirmed diagnosis [
Pulmonic stenosis and ectopic kidney have also been reported [
Fertility is generally preserved in SHORT syndrome; ovarian cysts are commonly reported in affected females.
• Mild-to-moderate short stature is usually present throughout childhood. Bone age may or may not be delayed. Other skeletal changes include gracile diaphyses and large and coned-shaped epiphyses [
• Mild short stature has been seen in most adults reported to date. Adult height in males with a molecularly confirmed diagnosis of SHORT syndrome was between 155 and 163 cm and in females between 143 and 160 cm [
• Sensorineural hearing loss of 80-90 dB has been diagnosed within the first year of life. Among individuals with a molecularly confirmed diagnosis of SHORT syndrome, six have been reported with hearing loss [
• While cognition is not affected in SHORT syndrome, some affected children have mild speech delay.
• Some, but not all, affected individuals exhibit hyperextensible joints and/or inguinal hernias.
• Although there does not appear to be an increased risk for life-threatening infections or evidence of clinical immunodeficiency, there have been reports of a nonspecific history of frequent infections [
• Nephrocalcinosis has been reported in a mother-son pair with a molecularly confirmed diagnosis [
• Pulmonic stenosis and ectopic kidney have also been reported [
• Fertility is generally preserved in SHORT syndrome; ovarian cysts are commonly reported in affected females.
## Genotype-Phenotype Correlations
To date no clear genotype-phenotype correlation is evident; however, pathogenic variants appear to cluster in the C-terminal SH2 domain of
The recurrent missense pathogenic variant
## Penetrance
The penetrance of SHORT syndrome appears complete in all individuals undergoing molecular genetic testing to date: all simplex cases (i.e., a single occurrence in a family) with parents available for testing have had a
## Nomenclature
Since it was first described in the early 1970s, what appears to be SHORT syndrome has been described by different terms, including:
Low-birthweight Rieger syndrome
Autosomal partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes *
Absent iris stroma, narrow body build, and small facial bones *
* Individuals with the latter two disorders have subsequently been demonstrated to have a
• Low-birthweight Rieger syndrome
• Autosomal partial lipodystrophy associated with Rieger anomaly, short stature, and insulinopenic diabetes *
• Absent iris stroma, narrow body build, and small facial bones *
## Prevalence
SHORT syndrome is very rare; fewer than 50 cases have been reported in the literature.
No ethnic predilection is known.
## Genetically Related (Allelic) Disorders
To date, individuals with three different phenotypes have been reported with germline pathogenic variants in
One individual with an amino acid substitution in the N-terminal SH2 domain of
One individual homozygous for a premature stop codon in exon 6 of
Immunodeficiency type 36, also known as activated PI3K delta syndrome 2 (APDS2; see
Sporadically occurring single tumors in the absence of any other findings of SHORT syndrome may contain somatic variants in
• One individual with an amino acid substitution in the N-terminal SH2 domain of
• One individual homozygous for a premature stop codon in exon 6 of
• Immunodeficiency type 36, also known as activated PI3K delta syndrome 2 (APDS2; see
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of SHORT Syndrome
IUGR & postnatal growth deficiency
Nonspecific facial features incl triangular-shaped face
More significiant short stature in SRS than in SHORT syndrome
No eye anomalies or lipodystrophy in SRS
BSCL is usually diagnosed at birth or shortly thereafter; severe BSCL may have prenatal-onset w/IUGR.
All children w/neonatal or infantile presentation demonstrate lipoatrophy in 1st yr of life.
Insulin resistance & subsequent diabetes mellitus become common in late adolescence & early adulthood.
Absence of facial features of SHORT syndrome
↑ IGF1
Clinical features of HGPS develop in childhood (vs typically evident at birth in SHORT syndrome).
Some features of accelerated aging w/disease progression in HGPS are distinct from those in SHORT syndrome.
AD = autosomal dominant; AR = autosomal recessive; IGF1 = insulin-like growth factor 1; IUGR = intrauterine growth restriction; MOI = mode of inheritance; mUPD = maternal uniparental disomy
Silver-Russell syndrome (SRS) is genetically heterogeneous. Hypomethylation of the imprinted control region 1 (ICR1) at 11p15.5 causes SRS in 35%-50% of individuals, and mUPD7 causes SRS in 7%-10% of individuals. A small number of individuals with SRS have duplications, deletions, or translocations involving the imprinting centers at 11p15.5 or duplications, deletions, or translocations involving chromosome 7. Rarely, affected individuals with pathogenic variants in
Accurate assessment of SRS recurrence requires identification of the causative genetic mechanism in the proband.
Since it is possible that some individuals with a clinical diagnosis of SRS and normal molecular studies have a diagnosis of SHORT syndrome, careful consideration of the facial phenotype in these individuals is warranted.
Alagille syndrome is a complex multisystem disorder involving the liver, heart, eyes, face, and skeleton.
Note: Copy number variations at several loci including
• IUGR & postnatal growth deficiency
• Nonspecific facial features incl triangular-shaped face
• More significiant short stature in SRS than in SHORT syndrome
• No eye anomalies or lipodystrophy in SRS
• BSCL is usually diagnosed at birth or shortly thereafter; severe BSCL may have prenatal-onset w/IUGR.
• All children w/neonatal or infantile presentation demonstrate lipoatrophy in 1st yr of life.
• Insulin resistance & subsequent diabetes mellitus become common in late adolescence & early adulthood.
• Absence of facial features of SHORT syndrome
• ↑ IGF1
• Clinical features of HGPS develop in childhood (vs typically evident at birth in SHORT syndrome).
• Some features of accelerated aging w/disease progression in HGPS are distinct from those in SHORT syndrome.
## Management
To establish the extent of disease and needs in an individual diagnosed with SHORT syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SHORT Syndrome
DD = developmental delay; 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 SHORT Syndrome
Recommended Surveillance for Individuals with SHORT Syndrome
Given the increased risk for insulin resistance in individuals taking growth hormone, it has been suggested that growth hormone be contraindicated in individuals with SHORT syndrome [
One report observed a worsening of insulin resistance in a child with SHORT syndrome treated with metformin [
See
Successful pregnancies have occurred in women with SHORT syndrome. If present, diabetes mellitus is managed as appropriate.
Search
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SHORT syndrome, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SHORT Syndrome
DD = developmental delay; 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
Treatment of Manifestations in Individuals with SHORT Syndrome
## Surveillance
Recommended Surveillance for Individuals with SHORT Syndrome
## Agents/Circumstances to Avoid
Given the increased risk for insulin resistance in individuals taking growth hormone, it has been suggested that growth hormone be contraindicated in individuals with SHORT syndrome [
One report observed a worsening of insulin resistance in a child with SHORT syndrome treated with metformin [
## Evaluation of Relatives at Risk
See
## Pregnancy Management
Successful pregnancies have occurred in women with SHORT syndrome. If present, diabetes mellitus is managed as appropriate.
## Therapies Under Investigation
Search
## Genetic Counseling
SHORT syndrome is inherited in an autosomal dominant manner.
Some individuals diagnosed with SHORT syndrome have an affected parent.
Twelve of the 40 individuals with SHORT syndrome diagnosed to date were found to have 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 leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with SHORT syndrome may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. Note: To date, all parents found to be heterozygous 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 is 50%.
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.
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.
• Some individuals diagnosed with SHORT syndrome have an affected parent.
• Twelve of the 40 individuals with SHORT syndrome diagnosed to date were found to have 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 leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with SHORT syndrome may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. Note: To date, all parents found to be heterozygous 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 is 50%.
• 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
SHORT syndrome is inherited in an autosomal dominant manner.
## Risk to Family Members
Some individuals diagnosed with SHORT syndrome have an affected parent.
Twelve of the 40 individuals with SHORT syndrome diagnosed to date were found to have 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 leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a
* Misattributed parentage can also be explored as an alternative explanation for an apparent
The family history of some individuals diagnosed with SHORT syndrome may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. Note: To date, all parents found to be heterozygous 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 is 50%.
If the proband has a known
If the parents have not been tested for the
• Some individuals diagnosed with SHORT syndrome have an affected parent.
• Twelve of the 40 individuals with SHORT syndrome diagnosed to date were found to have 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 leukocyte DNA of either parent, two possible explanations are germline mosaicism in a parent or a
• * Misattributed parentage can also be explored as an alternative explanation for an apparent
• The family history of some individuals diagnosed with SHORT syndrome may appear to be negative because of failure to recognize the disorder in family members because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed unless appropriate clinical evaluation and/or molecular genetic testing has been performed on the parents of the proband. Note: To date, all parents found to be heterozygous 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 is 50%.
• If the proband has a known
• 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 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
SHORT Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SHORT Syndrome (
Studies of fibroblasts and lymphoblasts of individuals with SHORT syndrome show a diminished capacity to activate the AKT pathway and downstream targets. Reduced p85α results in p110α not being available for downstream effects.
Notable
Variants listed in the table have been provided by the authors.
Sporadic tumors (including glioblastomas, breast, endometrial, bladder, uroepithelial, ovarian, colorectal, and gastric) occurring as single tumors in the absence of any other findings of SHORT syndrome may contain a somatic
## Molecular Pathogenesis
Studies of fibroblasts and lymphoblasts of individuals with SHORT syndrome show a diminished capacity to activate the AKT pathway and downstream targets. Reduced p85α results in p110α not being available for downstream effects.
Notable
Variants listed in the table have been provided by the authors.
Sporadic tumors (including glioblastomas, breast, endometrial, bladder, uroepithelial, ovarian, colorectal, and gastric) occurring as single tumors in the absence of any other findings of SHORT syndrome may contain a somatic
## Cancer and Benign Tumors
Sporadic tumors (including glioblastomas, breast, endometrial, bladder, uroepithelial, ovarian, colorectal, and gastric) occurring as single tumors in the absence of any other findings of SHORT syndrome may contain a somatic
## Chapter Notes
Dr A Micheil Innes's research is focused on both the clinical delineation and the identification of the molecular basis of rare genetic conditions.
Dr David Dyment's research interests are the identification of the molecular causes of rare syndromic and neurogenetic diseases.
Both Dr Innes and Dr Dyment are investigators with
4 June 2020 (ha) Comprehensive update posted live
15 May 2014 (me) Review posted live
29 December 2013 (dd) Original submission
• 4 June 2020 (ha) Comprehensive update posted live
• 15 May 2014 (me) Review posted live
• 29 December 2013 (dd) Original submission
## Author Notes
Dr A Micheil Innes's research is focused on both the clinical delineation and the identification of the molecular basis of rare genetic conditions.
Dr David Dyment's research interests are the identification of the molecular causes of rare syndromic and neurogenetic diseases.
Both Dr Innes and Dr Dyment are investigators with
## Revision History
4 June 2020 (ha) Comprehensive update posted live
15 May 2014 (me) Review posted live
29 December 2013 (dd) Original submission
• 4 June 2020 (ha) Comprehensive update posted live
• 15 May 2014 (me) Review posted live
• 29 December 2013 (dd) Original submission
## References
## Literature Cited
Facial features of SHORT syndrome. The face has a triangular appearance with a prominent forehead and deep-set eyes. The nose has characteristic thin nasal alae and a low-hanging columella. The corners of the mouth can be downturned and the chin can be dimpled. The ears are often pronounced, but not typically low set.
Image kindly provided by Dr Cynthia Curry
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[] |
15/5/2014
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4/6/2020
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GeneReviews®
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https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
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sickle
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sickle
|
[
"Sickle Cell Disease Due to Hb S/S",
"Sickle-Hemoglobin C Disease (Hb S/C)",
"Sickle Beta-Thalassemia",
"Hemoglobin subunit beta",
"HBB",
"Sickle Cell Disease"
] |
Sickle Cell Disease
|
MA Bender, Katie Carlberg
|
Summary Sickle cell disease (SCD) is characterized by intermittent vaso-occlusive events and chronic hemolytic anemia. Vaso-occlusive events result in tissue ischemia leading to acute and chronic pain as well as organ damage that can affect any organ system, including the bones, spleen, liver, brain, lungs, kidneys, and joints. Dactylitis (pain and/or swelling of the hands or feet) is often the earliest manifestation of SCD. In children, the spleen can become engorged with blood cells in a "splenic sequestration." The spleen is particularly vulnerable to infarction and the majority of individuals with SCD who are not on hydroxyurea or transfusion therapy become functionally asplenic in early childhood, increasing their risk for certain types of bacterial infections, primarily encapsulated organisms. Acute chest syndrome (ACS) is a major cause of mortality in SCD. Chronic hemolysis can result in varying degrees of anemia, jaundice, cholelithiasis, and delayed growth and sexual maturation as well as activating pathways that contribute to the pathophysiology directly. Individuals with the highest rates of hemolysis are at higher risk for pulmonary artery hypertension, priapism, and leg ulcers and may be relatively protected from vaso-occlusive pain. SCD encompasses a group of disorders characterized by the presence of at least one hemoglobin S allele (HbS; p.Glu6Val in The diagnosis of SCD is established by identification of significant quantities of HbS with or without an additional abnormal beta globin chain variant by hemoglobin assay or by identification of biallelic Newborn screening for SCD began in the United States in 1975 in New York and expanded to include all 50 states by 2006. Newborn screening programs perform isoelectric focusing and/or high-performance liquid chromatography (HPLC) of an eluate of dried blood spots. Some newborn screening programs confirm results with molecular testing. SCD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
Homozygous p.Glu6Val (Hb S/S)
Sickle cell disease due to Hb S/S
Compound heterozygosity for p.Glu6Val (HbS) and a second
Sickle-hemoglobin C disease (Hb S/C)
Sickle beta-thalassemia (Hb S/β
HbS and another pathogenic beta globin chain variant (e.g., Hb S/D, Hb S/O
For synonyms and outdated names see
• Homozygous p.Glu6Val (Hb S/S)
• Sickle cell disease due to Hb S/S
• Sickle cell disease due to Hb S/S
• Compound heterozygosity for p.Glu6Val (HbS) and a second
• Sickle-hemoglobin C disease (Hb S/C)
• Sickle beta-thalassemia (Hb S/β
• HbS and another pathogenic beta globin chain variant (e.g., Hb S/D, Hb S/O
• Sickle-hemoglobin C disease (Hb S/C)
• Sickle beta-thalassemia (Hb S/β
• HbS and another pathogenic beta globin chain variant (e.g., Hb S/D, Hb S/O
• Sickle cell disease due to Hb S/S
• Sickle-hemoglobin C disease (Hb S/C)
• Sickle beta-thalassemia (Hb S/β
• HbS and another pathogenic beta globin chain variant (e.g., Hb S/D, Hb S/O
## Diagnosis
The term "sickle cell disease" (SCD) encompasses a group of disorders characterized by the presence of at least one hemoglobin S allele (HbS;
NBS for SCD identifies the relative quantification of hemoglobins (e.g., fetal hemoglobin [HbF], adult hemoglobin [HbA], sickle hemoglobin [HbS]) using isoelectric focusing and/or high-performance liquid chromatography (HPLC) on an eluate of dried blood spots. Hemoglobins identified by NBS are reported in order of quantity.
The normal newborn screening result is "FA" (i.e., HbF > HbA)
Infants with HbS identified on NBS require additional confirmatory testing of a separate blood sample within four weeks (see
A symptomatic individual who was not previously followed for SCD may present with findings of SCD if NBS was not performed or caregivers did not follow through with recommended NBS follow up. NBS technology is highly sensitive, but false negative NBS can occur when S/β
Suggestive clinical, laboratory, and family history features can include the following.
Infants with spontaneous painful swelling of the hands and feet
Recurrent episodes of severe pain with no other identified etiology
Pallor
Jaundice
Pneumococcal sepsis or meningitis
Severe anemia with splenic enlargement
Stroke, especially in a child
Note: Most individuals with SCD are healthy at birth and become symptomatic later in infancy or childhood after fetal hemoglobin levels decrease.
Normocytic anemia (though some forms of SCD cause microcytic anemia)
Sickle cells, nucleated red blood cells (RBCs), target cells, and other abnormal RBCs on peripheral blood smear; Howell-Jolly bodies indicate hyposplenism.
Presence of HbS on a hemoglobin assay (e.g., HPLC, isoelectric focusing, cellulose acetate electrophoresis, citrate agar electrophoresis) with an absence or diminished amount of HbA (For information about advantages and disadvantages of various hemoglobin assays, click
The diagnosis of SCD
Hemoglobin assay identifies adult hemoglobins (HbA, HbS, and other beta globin variants [e.g., HbC, HbE]) in addition to fetal hemoglobin (HbF), which is normally the predominant hemoglobin in newborns but decreases over the first year of life.
Identification of HbS as the sole adult beta chain on Hb assay indicates either Hb S/S or Hb S/β
Hb S/β
Identification of HbS and an additional beta chain variant (e.g., HbC, HbD, HbO, HbE) on Hb assay can establish the diagnosis in individuals who are compound heterozygous for specific
Sickle Cell Disease: Diagnostic Test Results
Table shows typical results; exceptions occur. Less common genotypes (e.g., Hb S/D, Hb S/O, Hb S/E) are not included.
↑ = increased; ↓ = decreased; β = beta; HbA = adult hemoglobin; HbC = hemoglobin C; HbF = fetal hemoglobin; HbS = sickle hemoglobin; MCV = mean corpuscular volume; N = normal; thal = thalassemia
The beta-thalassemias are divided into β
Hemoglobins are reported in order of quantity (e.g., HbF, HbS, HbA = HbF > HbS> HbA).
Normal mean corpuscular volume: ≥70 fL at age six to 12 months; ≥72 fL at age one to two years; ≥81 fL in adults
Interpretation can be difficult as coexisting iron deficiency and alpha-thalassemia are common in individuals with SCD and can also reduce the mean corpuscular volume.
HbA
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Sickle Cell 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
Note: All affected individuals have at least one copy of 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.
• The normal newborn screening result is "FA" (i.e., HbF > HbA)
• Infants with HbS identified on NBS require additional confirmatory testing of a separate blood sample within four weeks (see
• Infants with spontaneous painful swelling of the hands and feet
• Recurrent episodes of severe pain with no other identified etiology
• Pallor
• Jaundice
• Pneumococcal sepsis or meningitis
• Severe anemia with splenic enlargement
• Stroke, especially in a child
• Normocytic anemia (though some forms of SCD cause microcytic anemia)
• Sickle cells, nucleated red blood cells (RBCs), target cells, and other abnormal RBCs on peripheral blood smear; Howell-Jolly bodies indicate hyposplenism.
• Presence of HbS on a hemoglobin assay (e.g., HPLC, isoelectric focusing, cellulose acetate electrophoresis, citrate agar electrophoresis) with an absence or diminished amount of HbA (For information about advantages and disadvantages of various hemoglobin assays, click
• Identification of HbS as the sole adult beta chain on Hb assay indicates either Hb S/S or Hb S/β
• Hb S/β
• Identification of HbS and an additional beta chain variant (e.g., HbC, HbD, HbO, HbE) on Hb assay can establish the diagnosis in individuals who are compound heterozygous for specific
• For an introduction to multigene panels click
## Suggestive Findings
NBS for SCD identifies the relative quantification of hemoglobins (e.g., fetal hemoglobin [HbF], adult hemoglobin [HbA], sickle hemoglobin [HbS]) using isoelectric focusing and/or high-performance liquid chromatography (HPLC) on an eluate of dried blood spots. Hemoglobins identified by NBS are reported in order of quantity.
The normal newborn screening result is "FA" (i.e., HbF > HbA)
Infants with HbS identified on NBS require additional confirmatory testing of a separate blood sample within four weeks (see
A symptomatic individual who was not previously followed for SCD may present with findings of SCD if NBS was not performed or caregivers did not follow through with recommended NBS follow up. NBS technology is highly sensitive, but false negative NBS can occur when S/β
Suggestive clinical, laboratory, and family history features can include the following.
Infants with spontaneous painful swelling of the hands and feet
Recurrent episodes of severe pain with no other identified etiology
Pallor
Jaundice
Pneumococcal sepsis or meningitis
Severe anemia with splenic enlargement
Stroke, especially in a child
Note: Most individuals with SCD are healthy at birth and become symptomatic later in infancy or childhood after fetal hemoglobin levels decrease.
Normocytic anemia (though some forms of SCD cause microcytic anemia)
Sickle cells, nucleated red blood cells (RBCs), target cells, and other abnormal RBCs on peripheral blood smear; Howell-Jolly bodies indicate hyposplenism.
Presence of HbS on a hemoglobin assay (e.g., HPLC, isoelectric focusing, cellulose acetate electrophoresis, citrate agar electrophoresis) with an absence or diminished amount of HbA (For information about advantages and disadvantages of various hemoglobin assays, click
• The normal newborn screening result is "FA" (i.e., HbF > HbA)
• Infants with HbS identified on NBS require additional confirmatory testing of a separate blood sample within four weeks (see
• Infants with spontaneous painful swelling of the hands and feet
• Recurrent episodes of severe pain with no other identified etiology
• Pallor
• Jaundice
• Pneumococcal sepsis or meningitis
• Severe anemia with splenic enlargement
• Stroke, especially in a child
• Normocytic anemia (though some forms of SCD cause microcytic anemia)
• Sickle cells, nucleated red blood cells (RBCs), target cells, and other abnormal RBCs on peripheral blood smear; Howell-Jolly bodies indicate hyposplenism.
• Presence of HbS on a hemoglobin assay (e.g., HPLC, isoelectric focusing, cellulose acetate electrophoresis, citrate agar electrophoresis) with an absence or diminished amount of HbA (For information about advantages and disadvantages of various hemoglobin assays, click
## Scenario 1: Abnormal Newborn Screening (NBS) Result
NBS for SCD identifies the relative quantification of hemoglobins (e.g., fetal hemoglobin [HbF], adult hemoglobin [HbA], sickle hemoglobin [HbS]) using isoelectric focusing and/or high-performance liquid chromatography (HPLC) on an eluate of dried blood spots. Hemoglobins identified by NBS are reported in order of quantity.
The normal newborn screening result is "FA" (i.e., HbF > HbA)
Infants with HbS identified on NBS require additional confirmatory testing of a separate blood sample within four weeks (see
• The normal newborn screening result is "FA" (i.e., HbF > HbA)
• Infants with HbS identified on NBS require additional confirmatory testing of a separate blood sample within four weeks (see
## Scenario 2: Symptomatic Individual
A symptomatic individual who was not previously followed for SCD may present with findings of SCD if NBS was not performed or caregivers did not follow through with recommended NBS follow up. NBS technology is highly sensitive, but false negative NBS can occur when S/β
Suggestive clinical, laboratory, and family history features can include the following.
Infants with spontaneous painful swelling of the hands and feet
Recurrent episodes of severe pain with no other identified etiology
Pallor
Jaundice
Pneumococcal sepsis or meningitis
Severe anemia with splenic enlargement
Stroke, especially in a child
Note: Most individuals with SCD are healthy at birth and become symptomatic later in infancy or childhood after fetal hemoglobin levels decrease.
Normocytic anemia (though some forms of SCD cause microcytic anemia)
Sickle cells, nucleated red blood cells (RBCs), target cells, and other abnormal RBCs on peripheral blood smear; Howell-Jolly bodies indicate hyposplenism.
Presence of HbS on a hemoglobin assay (e.g., HPLC, isoelectric focusing, cellulose acetate electrophoresis, citrate agar electrophoresis) with an absence or diminished amount of HbA (For information about advantages and disadvantages of various hemoglobin assays, click
• Infants with spontaneous painful swelling of the hands and feet
• Recurrent episodes of severe pain with no other identified etiology
• Pallor
• Jaundice
• Pneumococcal sepsis or meningitis
• Severe anemia with splenic enlargement
• Stroke, especially in a child
• Normocytic anemia (though some forms of SCD cause microcytic anemia)
• Sickle cells, nucleated red blood cells (RBCs), target cells, and other abnormal RBCs on peripheral blood smear; Howell-Jolly bodies indicate hyposplenism.
• Presence of HbS on a hemoglobin assay (e.g., HPLC, isoelectric focusing, cellulose acetate electrophoresis, citrate agar electrophoresis) with an absence or diminished amount of HbA (For information about advantages and disadvantages of various hemoglobin assays, click
## Establishing the Diagnosis
The diagnosis of SCD
Hemoglobin assay identifies adult hemoglobins (HbA, HbS, and other beta globin variants [e.g., HbC, HbE]) in addition to fetal hemoglobin (HbF), which is normally the predominant hemoglobin in newborns but decreases over the first year of life.
Identification of HbS as the sole adult beta chain on Hb assay indicates either Hb S/S or Hb S/β
Hb S/β
Identification of HbS and an additional beta chain variant (e.g., HbC, HbD, HbO, HbE) on Hb assay can establish the diagnosis in individuals who are compound heterozygous for specific
Sickle Cell Disease: Diagnostic Test Results
Table shows typical results; exceptions occur. Less common genotypes (e.g., Hb S/D, Hb S/O, Hb S/E) are not included.
↑ = increased; ↓ = decreased; β = beta; HbA = adult hemoglobin; HbC = hemoglobin C; HbF = fetal hemoglobin; HbS = sickle hemoglobin; MCV = mean corpuscular volume; N = normal; thal = thalassemia
The beta-thalassemias are divided into β
Hemoglobins are reported in order of quantity (e.g., HbF, HbS, HbA = HbF > HbS> HbA).
Normal mean corpuscular volume: ≥70 fL at age six to 12 months; ≥72 fL at age one to two years; ≥81 fL in adults
Interpretation can be difficult as coexisting iron deficiency and alpha-thalassemia are common in individuals with SCD and can also reduce the mean corpuscular volume.
HbA
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Sickle Cell 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
Note: All affected individuals have at least one copy of 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.
• Identification of HbS as the sole adult beta chain on Hb assay indicates either Hb S/S or Hb S/β
• Hb S/β
• Identification of HbS and an additional beta chain variant (e.g., HbC, HbD, HbO, HbE) on Hb assay can establish the diagnosis in individuals who are compound heterozygous for specific
• For an introduction to multigene panels click
## Hemoglobin Assay
Hemoglobin assay identifies adult hemoglobins (HbA, HbS, and other beta globin variants [e.g., HbC, HbE]) in addition to fetal hemoglobin (HbF), which is normally the predominant hemoglobin in newborns but decreases over the first year of life.
Identification of HbS as the sole adult beta chain on Hb assay indicates either Hb S/S or Hb S/β
Hb S/β
Identification of HbS and an additional beta chain variant (e.g., HbC, HbD, HbO, HbE) on Hb assay can establish the diagnosis in individuals who are compound heterozygous for specific
Sickle Cell Disease: Diagnostic Test Results
Table shows typical results; exceptions occur. Less common genotypes (e.g., Hb S/D, Hb S/O, Hb S/E) are not included.
↑ = increased; ↓ = decreased; β = beta; HbA = adult hemoglobin; HbC = hemoglobin C; HbF = fetal hemoglobin; HbS = sickle hemoglobin; MCV = mean corpuscular volume; N = normal; thal = thalassemia
The beta-thalassemias are divided into β
Hemoglobins are reported in order of quantity (e.g., HbF, HbS, HbA = HbF > HbS> HbA).
Normal mean corpuscular volume: ≥70 fL at age six to 12 months; ≥72 fL at age one to two years; ≥81 fL in adults
Interpretation can be difficult as coexisting iron deficiency and alpha-thalassemia are common in individuals with SCD and can also reduce the mean corpuscular volume.
HbA
• Identification of HbS as the sole adult beta chain on Hb assay indicates either Hb S/S or Hb S/β
• Hb S/β
• Identification of HbS and an additional beta chain variant (e.g., HbC, HbD, HbO, HbE) on Hb assay can establish the diagnosis in individuals who are compound heterozygous for specific
## Molecular Genetic Testing
Molecular genetic testing approaches can include
For an introduction to multigene panels click
Molecular Genetic Testing Used in Sickle Cell 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
Note: All affected individuals have at least one copy of 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
## Clinical Characteristics
The clinical manifestations of sickle cell disease (SCD) result from intermittent episodes of microvascular occlusion leading to tissue ischemia/reperfusion injury and chronic hemolysis, both of which contribute to multiorgan dysfunction. The severity of disease manifestations varies, even in individuals with the same
A higher white blood cell count
A lower fetal hemoglobin level
Coexisting
Vessel flow resistance related to deoxygenation
Elevated plasma levels of lactate dehydrogenase (LDH)
A low hemoglobin level
A high reticulocyte count
Conversely, coexisting
Individuals with SCD are also at increased risk for other infections such as osteomyelitis caused by
While many have defined PAH in SCD based on elevated tricuspid regurgitant jet velocity (TRV) on transthoracic echocardiography (TTE), subsequent studies using direct measurement of pulmonary arterial pressure (PAP) by right heart catheterization indicate that this may overdiagnose PAH [
Other renal complications include acute kidney injury, hematuria, urinary tract infection and pyelonephritis, renal medullary carcinoma, and blood pressure abnormalities [
Individuals who receive frequent RBC transfusion can have complications of iron overload resulting from tissue iron deposition damaging the liver, lungs, and heart [
Systemic and institutional racism are major contributors to decreased quality of life and increased mortality in those with SCD [
The amount of HbS present in heterozygotes is insufficient to produce sickling manifestations under most circumstances and, thus, these individuals are usually asymptomatic. However, they are at risk for several complications [
Extremes of physical exertion, dehydration, and/or altitude can induce sickle cell vaso-occlusive events in some individuals with Hb A/S [
Splenic infarct at high altitudes can occur in some individuals with Hb A/S.
Renal medullary carcinoma is an extremely rare form of kidney cancer occurring almost exclusively in individuals with Hb A/S [
HB A/S may be associated with an increased risk for venous thromboembolism [
Individuals with Hb A/S are at increased risk for serious complications following traumatic hyphema [
Hb A/S has not been associated with avascular necrosis, stroke, leg ulcers, or cholelithiasis [
Although a tremendous amount of individual variability occurs, individuals with Hb S/S and S/β
Individuals with Hb S/C have longer RBC life span and higher hemoglobin concentration associated with fewer vaso-occlusive pain episodes. Splenomegaly and the associated risk for splenic sequestration can persist well beyond early childhood. Proliferative retinopathy and avascular necrosis are more likely to develop than in those with other sickle hemoglobinopathies.
The presence of
Historically in the US the term sickle cell anemia has been used to describe persons homozygous for
The HbS allele is common in persons of African, Mediterranean, Middle Eastern, and Indian ancestry and in persons from the Caribbean and parts of Central and South America but can be present in individuals of any ethnic background.
Among African Americans, the prevalence of sickle cell trait (Hb A/S) is about 10%, resulting in the birth of approximately 1,100 infants with SCD (Hb S/S) annually in the US. Approximately one in 300-500 African Americans born in the US has SCD; more than 100,000 individuals are estimated to have SCD (Hb S/S) [
The prevalence of
• A higher white blood cell count
• A lower fetal hemoglobin level
• Coexisting
• Vessel flow resistance related to deoxygenation
• Elevated plasma levels of lactate dehydrogenase (LDH)
• A low hemoglobin level
• A high reticulocyte count
• Individuals with SCD are also at increased risk for other infections such as osteomyelitis caused by
• Extremes of physical exertion, dehydration, and/or altitude can induce sickle cell vaso-occlusive events in some individuals with Hb A/S [
• Splenic infarct at high altitudes can occur in some individuals with Hb A/S.
• Renal medullary carcinoma is an extremely rare form of kidney cancer occurring almost exclusively in individuals with Hb A/S [
• HB A/S may be associated with an increased risk for venous thromboembolism [
• Individuals with Hb A/S are at increased risk for serious complications following traumatic hyphema [
• Hb A/S has not been associated with avascular necrosis, stroke, leg ulcers, or cholelithiasis [
## Clinical Description
The clinical manifestations of sickle cell disease (SCD) result from intermittent episodes of microvascular occlusion leading to tissue ischemia/reperfusion injury and chronic hemolysis, both of which contribute to multiorgan dysfunction. The severity of disease manifestations varies, even in individuals with the same
A higher white blood cell count
A lower fetal hemoglobin level
Coexisting
Vessel flow resistance related to deoxygenation
Elevated plasma levels of lactate dehydrogenase (LDH)
A low hemoglobin level
A high reticulocyte count
Conversely, coexisting
Individuals with SCD are also at increased risk for other infections such as osteomyelitis caused by
While many have defined PAH in SCD based on elevated tricuspid regurgitant jet velocity (TRV) on transthoracic echocardiography (TTE), subsequent studies using direct measurement of pulmonary arterial pressure (PAP) by right heart catheterization indicate that this may overdiagnose PAH [
Other renal complications include acute kidney injury, hematuria, urinary tract infection and pyelonephritis, renal medullary carcinoma, and blood pressure abnormalities [
Individuals who receive frequent RBC transfusion can have complications of iron overload resulting from tissue iron deposition damaging the liver, lungs, and heart [
Systemic and institutional racism are major contributors to decreased quality of life and increased mortality in those with SCD [
The amount of HbS present in heterozygotes is insufficient to produce sickling manifestations under most circumstances and, thus, these individuals are usually asymptomatic. However, they are at risk for several complications [
Extremes of physical exertion, dehydration, and/or altitude can induce sickle cell vaso-occlusive events in some individuals with Hb A/S [
Splenic infarct at high altitudes can occur in some individuals with Hb A/S.
Renal medullary carcinoma is an extremely rare form of kidney cancer occurring almost exclusively in individuals with Hb A/S [
HB A/S may be associated with an increased risk for venous thromboembolism [
Individuals with Hb A/S are at increased risk for serious complications following traumatic hyphema [
Hb A/S has not been associated with avascular necrosis, stroke, leg ulcers, or cholelithiasis [
• A higher white blood cell count
• A lower fetal hemoglobin level
• Coexisting
• Vessel flow resistance related to deoxygenation
• Elevated plasma levels of lactate dehydrogenase (LDH)
• A low hemoglobin level
• A high reticulocyte count
• Individuals with SCD are also at increased risk for other infections such as osteomyelitis caused by
• Extremes of physical exertion, dehydration, and/or altitude can induce sickle cell vaso-occlusive events in some individuals with Hb A/S [
• Splenic infarct at high altitudes can occur in some individuals with Hb A/S.
• Renal medullary carcinoma is an extremely rare form of kidney cancer occurring almost exclusively in individuals with Hb A/S [
• HB A/S may be associated with an increased risk for venous thromboembolism [
• Individuals with Hb A/S are at increased risk for serious complications following traumatic hyphema [
• Hb A/S has not been associated with avascular necrosis, stroke, leg ulcers, or cholelithiasis [
## Genotype-Phenotype Correlations
Although a tremendous amount of individual variability occurs, individuals with Hb S/S and S/β
Individuals with Hb S/C have longer RBC life span and higher hemoglobin concentration associated with fewer vaso-occlusive pain episodes. Splenomegaly and the associated risk for splenic sequestration can persist well beyond early childhood. Proliferative retinopathy and avascular necrosis are more likely to develop than in those with other sickle hemoglobinopathies.
The presence of
## Nomenclature
Historically in the US the term sickle cell anemia has been used to describe persons homozygous for
## Prevalence
The HbS allele is common in persons of African, Mediterranean, Middle Eastern, and Indian ancestry and in persons from the Caribbean and parts of Central and South America but can be present in individuals of any ethnic background.
Among African Americans, the prevalence of sickle cell trait (Hb A/S) is about 10%, resulting in the birth of approximately 1,100 infants with SCD (Hb S/S) annually in the US. Approximately one in 300-500 African Americans born in the US has SCD; more than 100,000 individuals are estimated to have SCD (Hb S/S) [
The prevalence of
## Genetically Related (Allelic) Disorders
## Differential Diagnosis
The following diagnoses may be considered in an individual presenting with clinical features of sickle cell disease (SCD) who did not have access to newborn screening. Each of these conditions would be easily distinguished from SCD by the absence of hemoglobin S on hemoglobin assay.
Acute or chronic anemia
Hemolytic anemia
Legg-Calve-Perthes disease
Osteomyelitis
Septic arthritis
• Acute or chronic anemia
• Hemolytic anemia
• Legg-Calve-Perthes disease
• Osteomyelitis
• Septic arthritis
## Management
Management guidelines for sickle cell disease (SCD) have been published [
To establish the extent of end-organ damage and needs in an individual diagnosed with SCD, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Sickle Cell Disease
CBC & reticulocyte count
Measurement of HbF (%)
Thalassemia testing: hemoglobin electrophoresis or HPLC & inclusion body prep
RBC genotyping so that antigen-matched blood may be given if transfusion is urgently needed
Baseline laboratory studies should be done in infants ≥12 mos
During childhood HLA typing should be offered to affected person & all full sibs that are unaffected or carry a hemoglobin trait.
Serum vitamin D level
Kidney function tests (BUN, serum creatinine, urinalysis, urine microalbumin)
Assessment of iron status (ferritin, TIBC, % saturation)
Liver function tests (ALT, direct & indirect bilirubin, LDH)
Community or
Social work involvement for parental support;
Home nursing referral.
ALT = alanine aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; HbF = fetal hemoglobin; HLA = Human leukocyte antigen; HPLC = high-performance liquid chromatography; LDH = lactate dehydrogenase; MOI = mode of inheritance; RBC = red blood cell; SCD = sickle cell disease; TIBC = total iron-binding capacity
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
Sickle Cell Disease: Targeted Therapies
Induction of HbF synthesis
Metabolized into nitric oxide, a potent vasodilator
Results in ↓ sickling & ↑ RBC survival
↓ WBC, reticulocyte, & platelet counts
↓ cell adhesion & overall improvement in blood flow
↓ vascular inflammation
HbF = fetal hemoglobin; HSCT = hematopoietic stem cell transplantation; RBC = red blood cell; SCD = sickle cell disease; WBC = white blood cell
Voxelotor, a disease-modulating pharmacotherapy approved by the FDA in 2019, was withdrawn from the market in 2024 due to safety concerns [
Decreased pain;
Decreased hospitalizations;
Decreased episodes of acute chest syndrome;
Decreased need for transfusion;
Primary stroke prevention;
Increased life span.
Oral hydroxyurea is safe to use in children as young as age six months [
While even low-dose hydroxyurea has clinical benefits, increasing evidence suggests that its benefits increase with higher dosing. Hydroxyurea can lead to myelosuppression. While relative myelosuppression has clinical benefit, with higher hydroxyurea dosing, complete blood counts (CBC) and reticulocyte counts must be monitored to avoid toxicity. To balance the benefits and risks of hydroxyurea, many suggest titration of the drug to determine the dose in each person that provides a reduction in WBC count into a target range without toxicity [
Maintaining hydration and avoiding extremes of climate
Learning to live a full life with modifications to avoid triggering complications
The importance of routine health maintenance visits, prophylactic medications, early intervention for both acute and chronic complications, and community support and resources
Warning signs of acute illness such as fever, respiratory symptoms, pallor, lethargy, splenic enlargement, priapism, and neurologic changes, including education for the affected individual, as developmentally appropriate
A systematic approach to pain management including identifying and reversing common triggers for SCD pain (and distinguishing it from other etiologies of pain), hydration, warmth, ambulation, distraction, and other comfort maneuvers, as well as initiation of NSAIDs and appropriate use of opiates
All families should:
Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
By age two months, all infants with SCD should receive penicillin V potassium prophylaxis (125 mg orally twice a day).
At age three years, the dose is increased to 250 mg orally, twice a day, and then continued until at least age five years.
Primary prevention of stroke in individuals with an abnormal transcranial Doppler (TCD), treatment of silent infarcts, and prevention of stroke recurrence
Prevention of stroke recurrence
Treatment of chronic pain refractory to other therapies
Pulmonary hypertension
Chronic kidney failure
Recurrent episodes of ACS
Severe end-organ damage
Complications of chronic RBC transfusion therapy include iron overload, alloimmunization, hyperhemolysis, and (rarely) infection. Transfusion is not indicated for isolated pain episodes. To limit alloimmunization and transfusion reactions, extended matching of RBC antigens should be performed, and blood products should be leuko-reduced (i.e., removal of white blood cells from the transfusion product). RBCs antigen matched at the full Rh locus (D, C, E) and Kell have been suggested to decrease alloimmunization rates, as well as other alleles when possible [
The initial focus should include the reversal of inciting triggers (e.g., cold, dehydration, acute infection).
Pain episodes are managed using a multimodal approach that may include warmth, hydration, massage, distraction, acupuncture, biofeedback, self-hypnosis, and pharmaceuticals.
Uncomplicated pain episodes may be managed at home with oral hydration and oral analgesics including NSAIDs and opiates.
More severe pain episodes require hospitalization and administration of parenteral fluids and analgesics in addition to adjunctive treatments such as massage and physical therapy.
Optimal analgesia is generally achieved with morphine (or other opiate) given around the clock by a patient-controlled analgesia device or by continuous infusion.
NSAIDs (e.g., ketorolac, ibuprofen, naproxen) may be used to augment the analgesic effect of opiates and decrease inflammation. Additional pharmaceuticals to consider include ketamine for both adults and children as well as serotonin and norepinephrine reuptake inhibitors in adults with chronic pain [
Adequate but not excessive IV hydration should be provided to maintain euvolemia, and individuals should be monitored closely for the development of other complications such as ACS, splenic sequestration, or opiate-induced constipation and pruritis.
A thorough evaluation for infection including blood culture, urine culture, and chest radiograph should be considered based on the clinical scenario.
Note: Transfusion and hydroxyurea are not useful treatments for acute pain episodes (see
Rapid triage and physical assessment;
Urgent complete blood count (CBC) with differential and reticulocyte count;
Blood culture (and other cultures as clinically indicated) and a low threshold for chest radiograph when respiratory symptoms are present, as ACS can often present with a normal physical examination;
Parenteral broad-spectrum empiric antibiotics such as ceftriaxone pending culture results. If ceftriaxone is used, an observation period should be required after administration given the risk of severe drug-induced hemolysis [
Note: With the changing natural history of fever and sepsis in individuals with SCD in the US there is increasing evidence that empiric treatment with parenteral antibiotics without obtaining cultures may be appropriate for well-appearing, fully immunized children with fever <39 °C; however, this work has not yet been replicated [
Perform chest radiograph examination.
Provide aggressive treatment with oxygen, analgesics, and antibiotics (including a macrolide).
Incentive spirometry should be encouraged.
Hypoxemia can progress to need for intubation and mechanical ventilatory support.
Simple RBC transfusion may be required for those who are critically ill, have multilobar disease, or have progressive disease despite conservative therapy.
Emergent RBC exchange should be considered in certain severe cases in which the hemoglobin is greater than 10 g/dL and/or the HbS is greater than 30%; however, the quality of evidence in this area is still low [
Treatment for children with acute ischemic stroke includes the following:
Neurologic status should be monitored and increased intracranial pressure and seizures aggressively treated if present.
Exchange transfusion with the goal of decreasing HbS percentage to less than 30% of the total hemoglobin followed by a chronic transfusion program can significantly decrease risk for recurrent stroke [
Hydroxyurea has been studied as an alternative to transfusion therapy [
Neurologic evaluation to assure that infarcts are classified as a silent cerebral infarct rather than overt stroke;
Discussion regarding secondary prevention options including regular blood transfusions and stem cell transplantation;
Discussion regarding cognitive screening assessment;
MRI surveillance every 12 to 24 months to assess for progression.
Aggressive evaluation and treatment of additional etiologies contributing to pulmonary hypertension (e.g., thrombotic disease, obstructive sleep apnea)
Optimization of SCD-related therapy to stop progression (e.g., chronic transfusions, hydroxyurea, oxygen therapy if hypoxemic)
Affected individuals should be seen routinely for evaluation of SCD-related comorbidities. Surveillance should be tailored to an individual's specific genotype and clinical history. Routine age-dependent screening allows for early detection and treatment of end-organ damage. While the National Heart, Lung, and Blood Institute in the US released guidelines for surveillance, the recommendations are not complete, and some have been modified since publication. The American Society of Hematology has been developing multiple sets of guidelines, but gaps remain, especially for genotypes other than Hb S/S and Hb S/β
Recommended Surveillance for Individuals with Sickle Cell Disease
Annually from age 2-16 yrs in all children w/Hb S/S & Hb S/β
Children w/normal velocities require ongoing annual eval.
Prior to school entry & repeated every 2-3 yrs
Immediately if concerns of decline
Initial MRI when child can tolerate w/o sedation
Repeat MRI in those w/new neurocognitive deficits or concerns
Serum vitamin D level
Assessment of kidney function (BUN, serum creatinine, urinalysis, & urine microalbumin or urine protein-to-creatinine ratio)
Echocardiogram to determine tricuspid regurgitant jet w/consideration of right heart catheterization
EKG in those on medications that may alter QTc
When indicated by signs/symptoms of cardiac manifestations
NT-proBNP, 6MWT, EKG, PFTs, & sleep study depending on clinical manifestations
Screening for end-organ manifestations vary.
Assessment of iron status (ferritin, TIBC, % saturation)
Liver function tests (ALT, direct & indirect bilirubin, alk phos, LDH)
Assess social determinants of health.
Social work assessment w/emphasis on medical & concrete needs & effect of SCD on lifestyle
6MWT = six-minute walk test; ACS = acute chest syndrome; ALT = alanine aminotransferase; alk phos = alkaline phosphatase; BUN = blood urea nitrogen; CBC = complete blood count; LDH = lactate dehydrogenase; NT-proBNP = N-terminal pro-brain natriuretic peptide; PFTs = pulmonary function tests; QTc = corrected QT interval; RBC = red blood cell; SCD = sickle cell disease; TIBC = total iron-binding capacity
Lab values should be provided to parents/caregivers and affected adults to allow long-term monitoring and comparison during times of illness.
Vitamin D level is indicated because of the high prevalence of vitamin D deficiency in individuals with SCD and the potential role in fetal hemoglobin expression.
See
See
See
Education for individuals with SCD involves learning how to control one's environment to minimize the chance of exacerbations. Environmental controls include avoiding the following:
Dehydration
Extremes of temperature (e.g., swimming in cold water, which can trigger a pain episode)
Physical exhaustion
Extremely high altitude without oxygen supplementation
Trauma
Infection
Cocaine. While alcohol and illegal drugs are never endorsed, cocaine and its derivatives, with their vasoconstrictive and cardiac stimulation effects, are particularly dangerous drugs in the setting of SCD.
The analgesic meperidine, which should be avoided as first-line therapy because of potential central nervous system toxicity
Early diagnosis of at-risk family members may allow for intervention before symptoms are present.
If born in the US, sibs with SCD are diagnosed by universal newborn screening soon after birth (at which time referral to a pediatric hematologist is appropriate). Many states also identify sickle cell trait on
If newborn screening data are not available for at-risk sibs, several diagnostic approaches can be considered:
If the
If the pathogenic variants in the family are not known, the gold standard is a combination of high-performance liquid chromatography or isoelectric focusing combined with a CBC and reticulocyte count. As microcytosis helps guide interpretation of results, a measure of iron status such as a zinc protoporphyrin test or serum iron and total iron-binding capacity is of benefit.
See
Pregnancy complications in SCD can be minimized with close follow up and collaboration between hematologic and obstetric teams [
Current guidelines recommend discontinuing hydroxyurea treatment during pregnancy. While reports of human infants exposed prenatally to hydroxyurea have not identified an increased risk of malformations, hydroxyurea has been noted to increase congenital anomalies in experimental animal models.
The role of chronic transfusions in lieu of hydroxyurea needs to be addressed. Chelation during pregnancy remains controversial and is generally not advised; both deferasirox and deferoxamine are category C medications in pregnancy, while deferiprone is category D. However, given the deleterious long-term effects of discontinuing iron chelation for nine months, many providers recommend resuming chelation therapy in the second and third trimesters, specifically with deferoxamine due to its larger molecular size, prohibiting it from crossing the placenta [
More than 99% of births to women with SCD occurring after 28 weeks' gestation are live births of infants with normal Apgar scores [
Increased understanding of SCD pathophysiology has led to the development of drugs that target different pathways as well as attempts to improve medications currently in use. While not comprehensive, several promising agents targeting different pathways are presented here, with emphasis on those that are in Phase II/III clinical trials [
Due to the rapid development of therapies for SCD, it is important to search
• CBC & reticulocyte count
• Measurement of HbF (%)
• Thalassemia testing: hemoglobin electrophoresis or HPLC & inclusion body prep
• RBC genotyping so that antigen-matched blood may be given if transfusion is urgently needed
• Baseline laboratory studies should be done in infants ≥12 mos
• During childhood HLA typing should be offered to affected person & all full sibs that are unaffected or carry a hemoglobin trait.
• Serum vitamin D level
• Kidney function tests (BUN, serum creatinine, urinalysis, urine microalbumin)
• Assessment of iron status (ferritin, TIBC, % saturation)
• Liver function tests (ALT, direct & indirect bilirubin, LDH)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Induction of HbF synthesis
• Metabolized into nitric oxide, a potent vasodilator
• Results in ↓ sickling & ↑ RBC survival
• ↓ WBC, reticulocyte, & platelet counts
• ↓ cell adhesion & overall improvement in blood flow
• ↓ vascular inflammation
• Decreased pain;
• Decreased hospitalizations;
• Decreased episodes of acute chest syndrome;
• Decreased need for transfusion;
• Primary stroke prevention;
• Increased life span.
• Maintaining hydration and avoiding extremes of climate
• Learning to live a full life with modifications to avoid triggering complications
• The importance of routine health maintenance visits, prophylactic medications, early intervention for both acute and chronic complications, and community support and resources
• Warning signs of acute illness such as fever, respiratory symptoms, pallor, lethargy, splenic enlargement, priapism, and neurologic changes, including education for the affected individual, as developmentally appropriate
• A systematic approach to pain management including identifying and reversing common triggers for SCD pain (and distinguishing it from other etiologies of pain), hydration, warmth, ambulation, distraction, and other comfort maneuvers, as well as initiation of NSAIDs and appropriate use of opiates
• All families should:
• Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
• Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
• Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
• Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
• Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
• Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
• By age two months, all infants with SCD should receive penicillin V potassium prophylaxis (125 mg orally twice a day).
• At age three years, the dose is increased to 250 mg orally, twice a day, and then continued until at least age five years.
• Primary prevention of stroke in individuals with an abnormal transcranial Doppler (TCD), treatment of silent infarcts, and prevention of stroke recurrence
• Prevention of stroke recurrence
• Treatment of chronic pain refractory to other therapies
• Pulmonary hypertension
• Chronic kidney failure
• Recurrent episodes of ACS
• Severe end-organ damage
• The initial focus should include the reversal of inciting triggers (e.g., cold, dehydration, acute infection).
• Pain episodes are managed using a multimodal approach that may include warmth, hydration, massage, distraction, acupuncture, biofeedback, self-hypnosis, and pharmaceuticals.
• Uncomplicated pain episodes may be managed at home with oral hydration and oral analgesics including NSAIDs and opiates.
• More severe pain episodes require hospitalization and administration of parenteral fluids and analgesics in addition to adjunctive treatments such as massage and physical therapy.
• Optimal analgesia is generally achieved with morphine (or other opiate) given around the clock by a patient-controlled analgesia device or by continuous infusion.
• NSAIDs (e.g., ketorolac, ibuprofen, naproxen) may be used to augment the analgesic effect of opiates and decrease inflammation. Additional pharmaceuticals to consider include ketamine for both adults and children as well as serotonin and norepinephrine reuptake inhibitors in adults with chronic pain [
• Adequate but not excessive IV hydration should be provided to maintain euvolemia, and individuals should be monitored closely for the development of other complications such as ACS, splenic sequestration, or opiate-induced constipation and pruritis.
• A thorough evaluation for infection including blood culture, urine culture, and chest radiograph should be considered based on the clinical scenario.
• Rapid triage and physical assessment;
• Urgent complete blood count (CBC) with differential and reticulocyte count;
• Blood culture (and other cultures as clinically indicated) and a low threshold for chest radiograph when respiratory symptoms are present, as ACS can often present with a normal physical examination;
• Parenteral broad-spectrum empiric antibiotics such as ceftriaxone pending culture results. If ceftriaxone is used, an observation period should be required after administration given the risk of severe drug-induced hemolysis [
• Perform chest radiograph examination.
• Provide aggressive treatment with oxygen, analgesics, and antibiotics (including a macrolide).
• Incentive spirometry should be encouraged.
• Hypoxemia can progress to need for intubation and mechanical ventilatory support.
• Simple RBC transfusion may be required for those who are critically ill, have multilobar disease, or have progressive disease despite conservative therapy.
• Emergent RBC exchange should be considered in certain severe cases in which the hemoglobin is greater than 10 g/dL and/or the HbS is greater than 30%; however, the quality of evidence in this area is still low [
• Neurologic status should be monitored and increased intracranial pressure and seizures aggressively treated if present.
• Exchange transfusion with the goal of decreasing HbS percentage to less than 30% of the total hemoglobin followed by a chronic transfusion program can significantly decrease risk for recurrent stroke [
• Hydroxyurea has been studied as an alternative to transfusion therapy [
• Neurologic evaluation to assure that infarcts are classified as a silent cerebral infarct rather than overt stroke;
• Discussion regarding secondary prevention options including regular blood transfusions and stem cell transplantation;
• Discussion regarding cognitive screening assessment;
• MRI surveillance every 12 to 24 months to assess for progression.
• Aggressive evaluation and treatment of additional etiologies contributing to pulmonary hypertension (e.g., thrombotic disease, obstructive sleep apnea)
• Optimization of SCD-related therapy to stop progression (e.g., chronic transfusions, hydroxyurea, oxygen therapy if hypoxemic)
• Annually from age 2-16 yrs in all children w/Hb S/S & Hb S/β
• Children w/normal velocities require ongoing annual eval.
• Prior to school entry & repeated every 2-3 yrs
• Immediately if concerns of decline
• Initial MRI when child can tolerate w/o sedation
• Repeat MRI in those w/new neurocognitive deficits or concerns
• Serum vitamin D level
• Assessment of kidney function (BUN, serum creatinine, urinalysis, & urine microalbumin or urine protein-to-creatinine ratio)
• Echocardiogram to determine tricuspid regurgitant jet w/consideration of right heart catheterization
• EKG in those on medications that may alter QTc
• When indicated by signs/symptoms of cardiac manifestations
• NT-proBNP, 6MWT, EKG, PFTs, & sleep study depending on clinical manifestations
• Screening for end-organ manifestations vary.
• Assessment of iron status (ferritin, TIBC, % saturation)
• Liver function tests (ALT, direct & indirect bilirubin, alk phos, LDH)
• Assess social determinants of health.
• Social work assessment w/emphasis on medical & concrete needs & effect of SCD on lifestyle
• Dehydration
• Extremes of temperature (e.g., swimming in cold water, which can trigger a pain episode)
• Physical exhaustion
• Extremely high altitude without oxygen supplementation
• Trauma
• Infection
• Cocaine. While alcohol and illegal drugs are never endorsed, cocaine and its derivatives, with their vasoconstrictive and cardiac stimulation effects, are particularly dangerous drugs in the setting of SCD.
• The analgesic meperidine, which should be avoided as first-line therapy because of potential central nervous system toxicity
• If the
• If the pathogenic variants in the family are not known, the gold standard is a combination of high-performance liquid chromatography or isoelectric focusing combined with a CBC and reticulocyte count. As microcytosis helps guide interpretation of results, a measure of iron status such as a zinc protoporphyrin test or serum iron and total iron-binding capacity is of benefit.
## Evaluations Following Initial Diagnosis
To establish the extent of end-organ damage and needs in an individual diagnosed with SCD, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Sickle Cell Disease
CBC & reticulocyte count
Measurement of HbF (%)
Thalassemia testing: hemoglobin electrophoresis or HPLC & inclusion body prep
RBC genotyping so that antigen-matched blood may be given if transfusion is urgently needed
Baseline laboratory studies should be done in infants ≥12 mos
During childhood HLA typing should be offered to affected person & all full sibs that are unaffected or carry a hemoglobin trait.
Serum vitamin D level
Kidney function tests (BUN, serum creatinine, urinalysis, urine microalbumin)
Assessment of iron status (ferritin, TIBC, % saturation)
Liver function tests (ALT, direct & indirect bilirubin, LDH)
Community or
Social work involvement for parental support;
Home nursing referral.
ALT = alanine aminotransferase; BUN = blood urea nitrogen; CBC = complete blood count; HbF = fetal hemoglobin; HLA = Human leukocyte antigen; HPLC = high-performance liquid chromatography; LDH = lactate dehydrogenase; MOI = mode of inheritance; RBC = red blood cell; SCD = sickle cell disease; TIBC = total iron-binding capacity
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• CBC & reticulocyte count
• Measurement of HbF (%)
• Thalassemia testing: hemoglobin electrophoresis or HPLC & inclusion body prep
• RBC genotyping so that antigen-matched blood may be given if transfusion is urgently needed
• Baseline laboratory studies should be done in infants ≥12 mos
• During childhood HLA typing should be offered to affected person & all full sibs that are unaffected or carry a hemoglobin trait.
• Serum vitamin D level
• Kidney function tests (BUN, serum creatinine, urinalysis, urine microalbumin)
• Assessment of iron status (ferritin, TIBC, % saturation)
• Liver function tests (ALT, direct & indirect bilirubin, LDH)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Sickle Cell Disease: Targeted Therapies
Induction of HbF synthesis
Metabolized into nitric oxide, a potent vasodilator
Results in ↓ sickling & ↑ RBC survival
↓ WBC, reticulocyte, & platelet counts
↓ cell adhesion & overall improvement in blood flow
↓ vascular inflammation
HbF = fetal hemoglobin; HSCT = hematopoietic stem cell transplantation; RBC = red blood cell; SCD = sickle cell disease; WBC = white blood cell
Voxelotor, a disease-modulating pharmacotherapy approved by the FDA in 2019, was withdrawn from the market in 2024 due to safety concerns [
Decreased pain;
Decreased hospitalizations;
Decreased episodes of acute chest syndrome;
Decreased need for transfusion;
Primary stroke prevention;
Increased life span.
Oral hydroxyurea is safe to use in children as young as age six months [
While even low-dose hydroxyurea has clinical benefits, increasing evidence suggests that its benefits increase with higher dosing. Hydroxyurea can lead to myelosuppression. While relative myelosuppression has clinical benefit, with higher hydroxyurea dosing, complete blood counts (CBC) and reticulocyte counts must be monitored to avoid toxicity. To balance the benefits and risks of hydroxyurea, many suggest titration of the drug to determine the dose in each person that provides a reduction in WBC count into a target range without toxicity [
Maintaining hydration and avoiding extremes of climate
Learning to live a full life with modifications to avoid triggering complications
The importance of routine health maintenance visits, prophylactic medications, early intervention for both acute and chronic complications, and community support and resources
Warning signs of acute illness such as fever, respiratory symptoms, pallor, lethargy, splenic enlargement, priapism, and neurologic changes, including education for the affected individual, as developmentally appropriate
A systematic approach to pain management including identifying and reversing common triggers for SCD pain (and distinguishing it from other etiologies of pain), hydration, warmth, ambulation, distraction, and other comfort maneuvers, as well as initiation of NSAIDs and appropriate use of opiates
All families should:
Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
By age two months, all infants with SCD should receive penicillin V potassium prophylaxis (125 mg orally twice a day).
At age three years, the dose is increased to 250 mg orally, twice a day, and then continued until at least age five years.
Primary prevention of stroke in individuals with an abnormal transcranial Doppler (TCD), treatment of silent infarcts, and prevention of stroke recurrence
Prevention of stroke recurrence
Treatment of chronic pain refractory to other therapies
Pulmonary hypertension
Chronic kidney failure
Recurrent episodes of ACS
Severe end-organ damage
Complications of chronic RBC transfusion therapy include iron overload, alloimmunization, hyperhemolysis, and (rarely) infection. Transfusion is not indicated for isolated pain episodes. To limit alloimmunization and transfusion reactions, extended matching of RBC antigens should be performed, and blood products should be leuko-reduced (i.e., removal of white blood cells from the transfusion product). RBCs antigen matched at the full Rh locus (D, C, E) and Kell have been suggested to decrease alloimmunization rates, as well as other alleles when possible [
The initial focus should include the reversal of inciting triggers (e.g., cold, dehydration, acute infection).
Pain episodes are managed using a multimodal approach that may include warmth, hydration, massage, distraction, acupuncture, biofeedback, self-hypnosis, and pharmaceuticals.
Uncomplicated pain episodes may be managed at home with oral hydration and oral analgesics including NSAIDs and opiates.
More severe pain episodes require hospitalization and administration of parenteral fluids and analgesics in addition to adjunctive treatments such as massage and physical therapy.
Optimal analgesia is generally achieved with morphine (or other opiate) given around the clock by a patient-controlled analgesia device or by continuous infusion.
NSAIDs (e.g., ketorolac, ibuprofen, naproxen) may be used to augment the analgesic effect of opiates and decrease inflammation. Additional pharmaceuticals to consider include ketamine for both adults and children as well as serotonin and norepinephrine reuptake inhibitors in adults with chronic pain [
Adequate but not excessive IV hydration should be provided to maintain euvolemia, and individuals should be monitored closely for the development of other complications such as ACS, splenic sequestration, or opiate-induced constipation and pruritis.
A thorough evaluation for infection including blood culture, urine culture, and chest radiograph should be considered based on the clinical scenario.
Note: Transfusion and hydroxyurea are not useful treatments for acute pain episodes (see
Rapid triage and physical assessment;
Urgent complete blood count (CBC) with differential and reticulocyte count;
Blood culture (and other cultures as clinically indicated) and a low threshold for chest radiograph when respiratory symptoms are present, as ACS can often present with a normal physical examination;
Parenteral broad-spectrum empiric antibiotics such as ceftriaxone pending culture results. If ceftriaxone is used, an observation period should be required after administration given the risk of severe drug-induced hemolysis [
Note: With the changing natural history of fever and sepsis in individuals with SCD in the US there is increasing evidence that empiric treatment with parenteral antibiotics without obtaining cultures may be appropriate for well-appearing, fully immunized children with fever <39 °C; however, this work has not yet been replicated [
Perform chest radiograph examination.
Provide aggressive treatment with oxygen, analgesics, and antibiotics (including a macrolide).
Incentive spirometry should be encouraged.
Hypoxemia can progress to need for intubation and mechanical ventilatory support.
Simple RBC transfusion may be required for those who are critically ill, have multilobar disease, or have progressive disease despite conservative therapy.
Emergent RBC exchange should be considered in certain severe cases in which the hemoglobin is greater than 10 g/dL and/or the HbS is greater than 30%; however, the quality of evidence in this area is still low [
Treatment for children with acute ischemic stroke includes the following:
Neurologic status should be monitored and increased intracranial pressure and seizures aggressively treated if present.
Exchange transfusion with the goal of decreasing HbS percentage to less than 30% of the total hemoglobin followed by a chronic transfusion program can significantly decrease risk for recurrent stroke [
Hydroxyurea has been studied as an alternative to transfusion therapy [
Neurologic evaluation to assure that infarcts are classified as a silent cerebral infarct rather than overt stroke;
Discussion regarding secondary prevention options including regular blood transfusions and stem cell transplantation;
Discussion regarding cognitive screening assessment;
MRI surveillance every 12 to 24 months to assess for progression.
Aggressive evaluation and treatment of additional etiologies contributing to pulmonary hypertension (e.g., thrombotic disease, obstructive sleep apnea)
Optimization of SCD-related therapy to stop progression (e.g., chronic transfusions, hydroxyurea, oxygen therapy if hypoxemic)
• Induction of HbF synthesis
• Metabolized into nitric oxide, a potent vasodilator
• Results in ↓ sickling & ↑ RBC survival
• ↓ WBC, reticulocyte, & platelet counts
• ↓ cell adhesion & overall improvement in blood flow
• ↓ vascular inflammation
• Decreased pain;
• Decreased hospitalizations;
• Decreased episodes of acute chest syndrome;
• Decreased need for transfusion;
• Primary stroke prevention;
• Increased life span.
• Maintaining hydration and avoiding extremes of climate
• Learning to live a full life with modifications to avoid triggering complications
• The importance of routine health maintenance visits, prophylactic medications, early intervention for both acute and chronic complications, and community support and resources
• Warning signs of acute illness such as fever, respiratory symptoms, pallor, lethargy, splenic enlargement, priapism, and neurologic changes, including education for the affected individual, as developmentally appropriate
• A systematic approach to pain management including identifying and reversing common triggers for SCD pain (and distinguishing it from other etiologies of pain), hydration, warmth, ambulation, distraction, and other comfort maneuvers, as well as initiation of NSAIDs and appropriate use of opiates
• All families should:
• Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
• Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
• Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
• Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
• Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
• Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
• By age two months, all infants with SCD should receive penicillin V potassium prophylaxis (125 mg orally twice a day).
• At age three years, the dose is increased to 250 mg orally, twice a day, and then continued until at least age five years.
• Primary prevention of stroke in individuals with an abnormal transcranial Doppler (TCD), treatment of silent infarcts, and prevention of stroke recurrence
• Prevention of stroke recurrence
• Treatment of chronic pain refractory to other therapies
• Pulmonary hypertension
• Chronic kidney failure
• Recurrent episodes of ACS
• Severe end-organ damage
• The initial focus should include the reversal of inciting triggers (e.g., cold, dehydration, acute infection).
• Pain episodes are managed using a multimodal approach that may include warmth, hydration, massage, distraction, acupuncture, biofeedback, self-hypnosis, and pharmaceuticals.
• Uncomplicated pain episodes may be managed at home with oral hydration and oral analgesics including NSAIDs and opiates.
• More severe pain episodes require hospitalization and administration of parenteral fluids and analgesics in addition to adjunctive treatments such as massage and physical therapy.
• Optimal analgesia is generally achieved with morphine (or other opiate) given around the clock by a patient-controlled analgesia device or by continuous infusion.
• NSAIDs (e.g., ketorolac, ibuprofen, naproxen) may be used to augment the analgesic effect of opiates and decrease inflammation. Additional pharmaceuticals to consider include ketamine for both adults and children as well as serotonin and norepinephrine reuptake inhibitors in adults with chronic pain [
• Adequate but not excessive IV hydration should be provided to maintain euvolemia, and individuals should be monitored closely for the development of other complications such as ACS, splenic sequestration, or opiate-induced constipation and pruritis.
• A thorough evaluation for infection including blood culture, urine culture, and chest radiograph should be considered based on the clinical scenario.
• Rapid triage and physical assessment;
• Urgent complete blood count (CBC) with differential and reticulocyte count;
• Blood culture (and other cultures as clinically indicated) and a low threshold for chest radiograph when respiratory symptoms are present, as ACS can often present with a normal physical examination;
• Parenteral broad-spectrum empiric antibiotics such as ceftriaxone pending culture results. If ceftriaxone is used, an observation period should be required after administration given the risk of severe drug-induced hemolysis [
• Perform chest radiograph examination.
• Provide aggressive treatment with oxygen, analgesics, and antibiotics (including a macrolide).
• Incentive spirometry should be encouraged.
• Hypoxemia can progress to need for intubation and mechanical ventilatory support.
• Simple RBC transfusion may be required for those who are critically ill, have multilobar disease, or have progressive disease despite conservative therapy.
• Emergent RBC exchange should be considered in certain severe cases in which the hemoglobin is greater than 10 g/dL and/or the HbS is greater than 30%; however, the quality of evidence in this area is still low [
• Neurologic status should be monitored and increased intracranial pressure and seizures aggressively treated if present.
• Exchange transfusion with the goal of decreasing HbS percentage to less than 30% of the total hemoglobin followed by a chronic transfusion program can significantly decrease risk for recurrent stroke [
• Hydroxyurea has been studied as an alternative to transfusion therapy [
• Neurologic evaluation to assure that infarcts are classified as a silent cerebral infarct rather than overt stroke;
• Discussion regarding secondary prevention options including regular blood transfusions and stem cell transplantation;
• Discussion regarding cognitive screening assessment;
• MRI surveillance every 12 to 24 months to assess for progression.
• Aggressive evaluation and treatment of additional etiologies contributing to pulmonary hypertension (e.g., thrombotic disease, obstructive sleep apnea)
• Optimization of SCD-related therapy to stop progression (e.g., chronic transfusions, hydroxyurea, oxygen therapy if hypoxemic)
## Targeted Therapies
Sickle Cell Disease: Targeted Therapies
Induction of HbF synthesis
Metabolized into nitric oxide, a potent vasodilator
Results in ↓ sickling & ↑ RBC survival
↓ WBC, reticulocyte, & platelet counts
↓ cell adhesion & overall improvement in blood flow
↓ vascular inflammation
HbF = fetal hemoglobin; HSCT = hematopoietic stem cell transplantation; RBC = red blood cell; SCD = sickle cell disease; WBC = white blood cell
Voxelotor, a disease-modulating pharmacotherapy approved by the FDA in 2019, was withdrawn from the market in 2024 due to safety concerns [
Decreased pain;
Decreased hospitalizations;
Decreased episodes of acute chest syndrome;
Decreased need for transfusion;
Primary stroke prevention;
Increased life span.
Oral hydroxyurea is safe to use in children as young as age six months [
While even low-dose hydroxyurea has clinical benefits, increasing evidence suggests that its benefits increase with higher dosing. Hydroxyurea can lead to myelosuppression. While relative myelosuppression has clinical benefit, with higher hydroxyurea dosing, complete blood counts (CBC) and reticulocyte counts must be monitored to avoid toxicity. To balance the benefits and risks of hydroxyurea, many suggest titration of the drug to determine the dose in each person that provides a reduction in WBC count into a target range without toxicity [
• Induction of HbF synthesis
• Metabolized into nitric oxide, a potent vasodilator
• Results in ↓ sickling & ↑ RBC survival
• ↓ WBC, reticulocyte, & platelet counts
• ↓ cell adhesion & overall improvement in blood flow
• ↓ vascular inflammation
• Decreased pain;
• Decreased hospitalizations;
• Decreased episodes of acute chest syndrome;
• Decreased need for transfusion;
• Primary stroke prevention;
• Increased life span.
## Supportive Care
Maintaining hydration and avoiding extremes of climate
Learning to live a full life with modifications to avoid triggering complications
The importance of routine health maintenance visits, prophylactic medications, early intervention for both acute and chronic complications, and community support and resources
Warning signs of acute illness such as fever, respiratory symptoms, pallor, lethargy, splenic enlargement, priapism, and neurologic changes, including education for the affected individual, as developmentally appropriate
A systematic approach to pain management including identifying and reversing common triggers for SCD pain (and distinguishing it from other etiologies of pain), hydration, warmth, ambulation, distraction, and other comfort maneuvers, as well as initiation of NSAIDs and appropriate use of opiates
All families should:
Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
By age two months, all infants with SCD should receive penicillin V potassium prophylaxis (125 mg orally twice a day).
At age three years, the dose is increased to 250 mg orally, twice a day, and then continued until at least age five years.
Primary prevention of stroke in individuals with an abnormal transcranial Doppler (TCD), treatment of silent infarcts, and prevention of stroke recurrence
Prevention of stroke recurrence
Treatment of chronic pain refractory to other therapies
Pulmonary hypertension
Chronic kidney failure
Recurrent episodes of ACS
Severe end-organ damage
Complications of chronic RBC transfusion therapy include iron overload, alloimmunization, hyperhemolysis, and (rarely) infection. Transfusion is not indicated for isolated pain episodes. To limit alloimmunization and transfusion reactions, extended matching of RBC antigens should be performed, and blood products should be leuko-reduced (i.e., removal of white blood cells from the transfusion product). RBCs antigen matched at the full Rh locus (D, C, E) and Kell have been suggested to decrease alloimmunization rates, as well as other alleles when possible [
• Maintaining hydration and avoiding extremes of climate
• Learning to live a full life with modifications to avoid triggering complications
• The importance of routine health maintenance visits, prophylactic medications, early intervention for both acute and chronic complications, and community support and resources
• Warning signs of acute illness such as fever, respiratory symptoms, pallor, lethargy, splenic enlargement, priapism, and neurologic changes, including education for the affected individual, as developmentally appropriate
• A systematic approach to pain management including identifying and reversing common triggers for SCD pain (and distinguishing it from other etiologies of pain), hydration, warmth, ambulation, distraction, and other comfort maneuvers, as well as initiation of NSAIDs and appropriate use of opiates
• All families should:
• Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
• Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
• Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
• Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
• Have a plan in place for 24-hour access to a medical facility that can provide urgent evaluation and treatment of acute illnesses such as fever, acute chest syndrome (ACS), splenic sequestration, priapism, and stroke;
• Be informed of the affected family member's baseline (steady state) laboratory values for purposes of comparison, as values often change during acute illness.
• By age two months, all infants with SCD should receive penicillin V potassium prophylaxis (125 mg orally twice a day).
• At age three years, the dose is increased to 250 mg orally, twice a day, and then continued until at least age five years.
• Primary prevention of stroke in individuals with an abnormal transcranial Doppler (TCD), treatment of silent infarcts, and prevention of stroke recurrence
• Prevention of stroke recurrence
• Treatment of chronic pain refractory to other therapies
• Pulmonary hypertension
• Chronic kidney failure
• Recurrent episodes of ACS
• Severe end-organ damage
## Management of Specific Complications
The initial focus should include the reversal of inciting triggers (e.g., cold, dehydration, acute infection).
Pain episodes are managed using a multimodal approach that may include warmth, hydration, massage, distraction, acupuncture, biofeedback, self-hypnosis, and pharmaceuticals.
Uncomplicated pain episodes may be managed at home with oral hydration and oral analgesics including NSAIDs and opiates.
More severe pain episodes require hospitalization and administration of parenteral fluids and analgesics in addition to adjunctive treatments such as massage and physical therapy.
Optimal analgesia is generally achieved with morphine (or other opiate) given around the clock by a patient-controlled analgesia device or by continuous infusion.
NSAIDs (e.g., ketorolac, ibuprofen, naproxen) may be used to augment the analgesic effect of opiates and decrease inflammation. Additional pharmaceuticals to consider include ketamine for both adults and children as well as serotonin and norepinephrine reuptake inhibitors in adults with chronic pain [
Adequate but not excessive IV hydration should be provided to maintain euvolemia, and individuals should be monitored closely for the development of other complications such as ACS, splenic sequestration, or opiate-induced constipation and pruritis.
A thorough evaluation for infection including blood culture, urine culture, and chest radiograph should be considered based on the clinical scenario.
Note: Transfusion and hydroxyurea are not useful treatments for acute pain episodes (see
Rapid triage and physical assessment;
Urgent complete blood count (CBC) with differential and reticulocyte count;
Blood culture (and other cultures as clinically indicated) and a low threshold for chest radiograph when respiratory symptoms are present, as ACS can often present with a normal physical examination;
Parenteral broad-spectrum empiric antibiotics such as ceftriaxone pending culture results. If ceftriaxone is used, an observation period should be required after administration given the risk of severe drug-induced hemolysis [
Note: With the changing natural history of fever and sepsis in individuals with SCD in the US there is increasing evidence that empiric treatment with parenteral antibiotics without obtaining cultures may be appropriate for well-appearing, fully immunized children with fever <39 °C; however, this work has not yet been replicated [
Perform chest radiograph examination.
Provide aggressive treatment with oxygen, analgesics, and antibiotics (including a macrolide).
Incentive spirometry should be encouraged.
Hypoxemia can progress to need for intubation and mechanical ventilatory support.
Simple RBC transfusion may be required for those who are critically ill, have multilobar disease, or have progressive disease despite conservative therapy.
Emergent RBC exchange should be considered in certain severe cases in which the hemoglobin is greater than 10 g/dL and/or the HbS is greater than 30%; however, the quality of evidence in this area is still low [
Treatment for children with acute ischemic stroke includes the following:
Neurologic status should be monitored and increased intracranial pressure and seizures aggressively treated if present.
Exchange transfusion with the goal of decreasing HbS percentage to less than 30% of the total hemoglobin followed by a chronic transfusion program can significantly decrease risk for recurrent stroke [
Hydroxyurea has been studied as an alternative to transfusion therapy [
Neurologic evaluation to assure that infarcts are classified as a silent cerebral infarct rather than overt stroke;
Discussion regarding secondary prevention options including regular blood transfusions and stem cell transplantation;
Discussion regarding cognitive screening assessment;
MRI surveillance every 12 to 24 months to assess for progression.
Aggressive evaluation and treatment of additional etiologies contributing to pulmonary hypertension (e.g., thrombotic disease, obstructive sleep apnea)
Optimization of SCD-related therapy to stop progression (e.g., chronic transfusions, hydroxyurea, oxygen therapy if hypoxemic)
• The initial focus should include the reversal of inciting triggers (e.g., cold, dehydration, acute infection).
• Pain episodes are managed using a multimodal approach that may include warmth, hydration, massage, distraction, acupuncture, biofeedback, self-hypnosis, and pharmaceuticals.
• Uncomplicated pain episodes may be managed at home with oral hydration and oral analgesics including NSAIDs and opiates.
• More severe pain episodes require hospitalization and administration of parenteral fluids and analgesics in addition to adjunctive treatments such as massage and physical therapy.
• Optimal analgesia is generally achieved with morphine (or other opiate) given around the clock by a patient-controlled analgesia device or by continuous infusion.
• NSAIDs (e.g., ketorolac, ibuprofen, naproxen) may be used to augment the analgesic effect of opiates and decrease inflammation. Additional pharmaceuticals to consider include ketamine for both adults and children as well as serotonin and norepinephrine reuptake inhibitors in adults with chronic pain [
• Adequate but not excessive IV hydration should be provided to maintain euvolemia, and individuals should be monitored closely for the development of other complications such as ACS, splenic sequestration, or opiate-induced constipation and pruritis.
• A thorough evaluation for infection including blood culture, urine culture, and chest radiograph should be considered based on the clinical scenario.
• Rapid triage and physical assessment;
• Urgent complete blood count (CBC) with differential and reticulocyte count;
• Blood culture (and other cultures as clinically indicated) and a low threshold for chest radiograph when respiratory symptoms are present, as ACS can often present with a normal physical examination;
• Parenteral broad-spectrum empiric antibiotics such as ceftriaxone pending culture results. If ceftriaxone is used, an observation period should be required after administration given the risk of severe drug-induced hemolysis [
• Perform chest radiograph examination.
• Provide aggressive treatment with oxygen, analgesics, and antibiotics (including a macrolide).
• Incentive spirometry should be encouraged.
• Hypoxemia can progress to need for intubation and mechanical ventilatory support.
• Simple RBC transfusion may be required for those who are critically ill, have multilobar disease, or have progressive disease despite conservative therapy.
• Emergent RBC exchange should be considered in certain severe cases in which the hemoglobin is greater than 10 g/dL and/or the HbS is greater than 30%; however, the quality of evidence in this area is still low [
• Neurologic status should be monitored and increased intracranial pressure and seizures aggressively treated if present.
• Exchange transfusion with the goal of decreasing HbS percentage to less than 30% of the total hemoglobin followed by a chronic transfusion program can significantly decrease risk for recurrent stroke [
• Hydroxyurea has been studied as an alternative to transfusion therapy [
• Neurologic evaluation to assure that infarcts are classified as a silent cerebral infarct rather than overt stroke;
• Discussion regarding secondary prevention options including regular blood transfusions and stem cell transplantation;
• Discussion regarding cognitive screening assessment;
• MRI surveillance every 12 to 24 months to assess for progression.
• Aggressive evaluation and treatment of additional etiologies contributing to pulmonary hypertension (e.g., thrombotic disease, obstructive sleep apnea)
• Optimization of SCD-related therapy to stop progression (e.g., chronic transfusions, hydroxyurea, oxygen therapy if hypoxemic)
## Surveillance
Affected individuals should be seen routinely for evaluation of SCD-related comorbidities. Surveillance should be tailored to an individual's specific genotype and clinical history. Routine age-dependent screening allows for early detection and treatment of end-organ damage. While the National Heart, Lung, and Blood Institute in the US released guidelines for surveillance, the recommendations are not complete, and some have been modified since publication. The American Society of Hematology has been developing multiple sets of guidelines, but gaps remain, especially for genotypes other than Hb S/S and Hb S/β
Recommended Surveillance for Individuals with Sickle Cell Disease
Annually from age 2-16 yrs in all children w/Hb S/S & Hb S/β
Children w/normal velocities require ongoing annual eval.
Prior to school entry & repeated every 2-3 yrs
Immediately if concerns of decline
Initial MRI when child can tolerate w/o sedation
Repeat MRI in those w/new neurocognitive deficits or concerns
Serum vitamin D level
Assessment of kidney function (BUN, serum creatinine, urinalysis, & urine microalbumin or urine protein-to-creatinine ratio)
Echocardiogram to determine tricuspid regurgitant jet w/consideration of right heart catheterization
EKG in those on medications that may alter QTc
When indicated by signs/symptoms of cardiac manifestations
NT-proBNP, 6MWT, EKG, PFTs, & sleep study depending on clinical manifestations
Screening for end-organ manifestations vary.
Assessment of iron status (ferritin, TIBC, % saturation)
Liver function tests (ALT, direct & indirect bilirubin, alk phos, LDH)
Assess social determinants of health.
Social work assessment w/emphasis on medical & concrete needs & effect of SCD on lifestyle
6MWT = six-minute walk test; ACS = acute chest syndrome; ALT = alanine aminotransferase; alk phos = alkaline phosphatase; BUN = blood urea nitrogen; CBC = complete blood count; LDH = lactate dehydrogenase; NT-proBNP = N-terminal pro-brain natriuretic peptide; PFTs = pulmonary function tests; QTc = corrected QT interval; RBC = red blood cell; SCD = sickle cell disease; TIBC = total iron-binding capacity
Lab values should be provided to parents/caregivers and affected adults to allow long-term monitoring and comparison during times of illness.
Vitamin D level is indicated because of the high prevalence of vitamin D deficiency in individuals with SCD and the potential role in fetal hemoglobin expression.
See
See
See
• Annually from age 2-16 yrs in all children w/Hb S/S & Hb S/β
• Children w/normal velocities require ongoing annual eval.
• Prior to school entry & repeated every 2-3 yrs
• Immediately if concerns of decline
• Initial MRI when child can tolerate w/o sedation
• Repeat MRI in those w/new neurocognitive deficits or concerns
• Serum vitamin D level
• Assessment of kidney function (BUN, serum creatinine, urinalysis, & urine microalbumin or urine protein-to-creatinine ratio)
• Echocardiogram to determine tricuspid regurgitant jet w/consideration of right heart catheterization
• EKG in those on medications that may alter QTc
• When indicated by signs/symptoms of cardiac manifestations
• NT-proBNP, 6MWT, EKG, PFTs, & sleep study depending on clinical manifestations
• Screening for end-organ manifestations vary.
• Assessment of iron status (ferritin, TIBC, % saturation)
• Liver function tests (ALT, direct & indirect bilirubin, alk phos, LDH)
• Assess social determinants of health.
• Social work assessment w/emphasis on medical & concrete needs & effect of SCD on lifestyle
## Agents/Circumstances to Avoid
Education for individuals with SCD involves learning how to control one's environment to minimize the chance of exacerbations. Environmental controls include avoiding the following:
Dehydration
Extremes of temperature (e.g., swimming in cold water, which can trigger a pain episode)
Physical exhaustion
Extremely high altitude without oxygen supplementation
Trauma
Infection
Cocaine. While alcohol and illegal drugs are never endorsed, cocaine and its derivatives, with their vasoconstrictive and cardiac stimulation effects, are particularly dangerous drugs in the setting of SCD.
The analgesic meperidine, which should be avoided as first-line therapy because of potential central nervous system toxicity
• Dehydration
• Extremes of temperature (e.g., swimming in cold water, which can trigger a pain episode)
• Physical exhaustion
• Extremely high altitude without oxygen supplementation
• Trauma
• Infection
• Cocaine. While alcohol and illegal drugs are never endorsed, cocaine and its derivatives, with their vasoconstrictive and cardiac stimulation effects, are particularly dangerous drugs in the setting of SCD.
• The analgesic meperidine, which should be avoided as first-line therapy because of potential central nervous system toxicity
## Evaluation of Relatives at Risk
Early diagnosis of at-risk family members may allow for intervention before symptoms are present.
If born in the US, sibs with SCD are diagnosed by universal newborn screening soon after birth (at which time referral to a pediatric hematologist is appropriate). Many states also identify sickle cell trait on
If newborn screening data are not available for at-risk sibs, several diagnostic approaches can be considered:
If the
If the pathogenic variants in the family are not known, the gold standard is a combination of high-performance liquid chromatography or isoelectric focusing combined with a CBC and reticulocyte count. As microcytosis helps guide interpretation of results, a measure of iron status such as a zinc protoporphyrin test or serum iron and total iron-binding capacity is of benefit.
See
• If the
• If the pathogenic variants in the family are not known, the gold standard is a combination of high-performance liquid chromatography or isoelectric focusing combined with a CBC and reticulocyte count. As microcytosis helps guide interpretation of results, a measure of iron status such as a zinc protoporphyrin test or serum iron and total iron-binding capacity is of benefit.
## Pregnancy Management
Pregnancy complications in SCD can be minimized with close follow up and collaboration between hematologic and obstetric teams [
Current guidelines recommend discontinuing hydroxyurea treatment during pregnancy. While reports of human infants exposed prenatally to hydroxyurea have not identified an increased risk of malformations, hydroxyurea has been noted to increase congenital anomalies in experimental animal models.
The role of chronic transfusions in lieu of hydroxyurea needs to be addressed. Chelation during pregnancy remains controversial and is generally not advised; both deferasirox and deferoxamine are category C medications in pregnancy, while deferiprone is category D. However, given the deleterious long-term effects of discontinuing iron chelation for nine months, many providers recommend resuming chelation therapy in the second and third trimesters, specifically with deferoxamine due to its larger molecular size, prohibiting it from crossing the placenta [
More than 99% of births to women with SCD occurring after 28 weeks' gestation are live births of infants with normal Apgar scores [
## Therapies Under Investigation
Increased understanding of SCD pathophysiology has led to the development of drugs that target different pathways as well as attempts to improve medications currently in use. While not comprehensive, several promising agents targeting different pathways are presented here, with emphasis on those that are in Phase II/III clinical trials [
Due to the rapid development of therapies for SCD, it is important to search
## Genetic Counseling
Sickle cell disease (SCD) is inherited in an autosomal recessive manner.
The parents of an individual with SCD are typically heterozygous for one
Alternatively, it is possible that one or both parents have biallelic beta globin chain variants (e.g., Hb S/S or compound heterozygous
Typical parental alleles are described in
Evaluation of the parents is recommended to determine their genetic status and to allow reliable recurrence risk assessment.
If both SCD-related
If only one (or neither) SCD-related
Note: HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). However, HPLC cannot definitively distinguish Hb S/β
If one parent is found to have an HbS allele, a beta globin chain variant is not identified in the other parent, and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the beta globin chain variants identified in the proband occurred as the result of 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 HbS allele that resulted in homozygosity for the
Heterozygotes for HbS have hemoglobins A and S (i.e., Hb A/S or sickle cell trait). The amount of HbS present in individuals with sickle cell trait is insufficient to produce sickling manifestations under most circumstances; thus, such individuals are usually asymptomatic, but are at risk for several complications (see
Sickle Cell Disease: Typical Proband and Parent Hemoglobin Alleles
Table shows typical results; exceptions occur. Some rare beta globin chain variants (e.g., Hb S/D, Hb S/E, Hb S/O) are not included.
Hb = hemoglobin; HbA = adult hemoglobin; HbF = fetal hemoglobin; Hb S/C = sickle-hemoglobin C disease; Hb S/S = homozygous for
Assumes that uniparental disomy is absent and that both parents are heterozygous. Some parents may be homozygous or compound heterozygous.
HbA is detectable in individuals with Hb S/β
If both parents are known to be heterozygous for an
If one parent is known to be heterozygous for a beta globin chain variant and the other parent is affected with SCD, each sib of an affected individual has a 50% chance of inheriting biallelic beta globin chain variants and being affected and a 50% chance of inheriting one beta globin chain variant and being heterozygous.
If both parents have biallelic beta globin chain variants (i.e., both parents have homozygous or compound heterozygous
Because a tremendous amount of individual variability occurs in SCD, the severity of disease manifestations in a sib who inherits biallelic beta globin chain variants cannot be predicted on the basis of the clinical course observed in the proband (see
Heterozygotes for HbS have hemoglobins A (adult) and S (sickle) (i.e., Hb A/S or sickle cell trait). The concentration of HbS present in individuals with sickle cell trait is insufficient to produce sickling manifestations under most circumstances; thus, these individuals are usually asymptomatic but are at risk for several complications (see
Does not have a beta globin chain variant (or variants), offspring will be heterozygous for a beta globin chain variant (i.e., heterozygous for an
Is heterozygous for a beta globin chain variant, offspring will have a 50% chance of having SCD and a 50% chance of being heterozygous for a beta globin chain variant;
Is also affected with SCD, all offspring will have biallelic beta globin chain variants (i.e., biallelic
Note: Because a tremendous amount of individual variability occurs in SCD, the severity of disease manifestations in offspring who inherit biallelic beta chain variants cannot be predicted on the basis of the clinical course observed in other affected family members (see
See Management,
It must be kept in mind that non-sickle hemoglobin disorders (e.g.,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
Molecular genetic prenatal testing and preimplantation genetic testing for SCD are possible when:
Both
The genetic status of the parents is known. Because one parent may have a non-HbS
Because of the extreme variation in clinical course, it is not currently possible to accurately predict the severity of SCD based on the prenatal finding of biallelic SCD-related
When the mother is known to be heterozygous and the father is unknown and/or unavailable for testing, options for prenatal testing can be explored in the context of formal genetic counseling.
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 individual with SCD are typically heterozygous for one
• Alternatively, it is possible that one or both parents have biallelic beta globin chain variants (e.g., Hb S/S or compound heterozygous
• Typical parental alleles are described in
• Evaluation of the parents is recommended to determine their genetic status and to allow reliable recurrence risk assessment.
• If both SCD-related
• If only one (or neither) SCD-related
• Note: HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). However, HPLC cannot definitively distinguish Hb S/β
• If both SCD-related
• If only one (or neither) SCD-related
• Note: HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). However, HPLC cannot definitively distinguish Hb S/β
• If one parent is found to have an HbS allele, a beta globin chain variant is not identified in the other parent, and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the beta globin chain variants identified in the proband occurred as the result of 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 HbS allele that resulted in homozygosity for the
• 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 HbS allele that resulted in homozygosity for the
• Heterozygotes for HbS have hemoglobins A and S (i.e., Hb A/S or sickle cell trait). The amount of HbS present in individuals with sickle cell trait is insufficient to produce sickling manifestations under most circumstances; thus, such individuals are usually asymptomatic, but are at risk for several complications (see
• If both SCD-related
• If only one (or neither) SCD-related
• Note: HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). However, HPLC cannot definitively distinguish Hb S/β
• 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 HbS allele that resulted in homozygosity for the
• If both parents are known to be heterozygous for an
• If one parent is known to be heterozygous for a beta globin chain variant and the other parent is affected with SCD, each sib of an affected individual has a 50% chance of inheriting biallelic beta globin chain variants and being affected and a 50% chance of inheriting one beta globin chain variant and being heterozygous.
• If both parents have biallelic beta globin chain variants (i.e., both parents have homozygous or compound heterozygous
• Because a tremendous amount of individual variability occurs in SCD, the severity of disease manifestations in a sib who inherits biallelic beta globin chain variants cannot be predicted on the basis of the clinical course observed in the proband (see
• Heterozygotes for HbS have hemoglobins A (adult) and S (sickle) (i.e., Hb A/S or sickle cell trait). The concentration of HbS present in individuals with sickle cell trait is insufficient to produce sickling manifestations under most circumstances; thus, these individuals are usually asymptomatic but are at risk for several complications (see
• Does not have a beta globin chain variant (or variants), offspring will be heterozygous for a beta globin chain variant (i.e., heterozygous for an
• Is heterozygous for a beta globin chain variant, offspring will have a 50% chance of having SCD and a 50% chance of being heterozygous for a beta globin chain variant;
• Is also affected with SCD, all offspring will have biallelic beta globin chain variants (i.e., biallelic
• It must be kept in mind that non-sickle hemoglobin disorders (e.g.,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
• Both
• The genetic status of the parents is known. Because one parent may have a non-HbS
## Mode of Inheritance
Sickle cell disease (SCD) is inherited in an autosomal recessive manner.
## Risk to Family Members
The parents of an individual with SCD are typically heterozygous for one
Alternatively, it is possible that one or both parents have biallelic beta globin chain variants (e.g., Hb S/S or compound heterozygous
Typical parental alleles are described in
Evaluation of the parents is recommended to determine their genetic status and to allow reliable recurrence risk assessment.
If both SCD-related
If only one (or neither) SCD-related
Note: HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). However, HPLC cannot definitively distinguish Hb S/β
If one parent is found to have an HbS allele, a beta globin chain variant is not identified in the other parent, and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the beta globin chain variants identified in the proband occurred as the result of 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 HbS allele that resulted in homozygosity for the
Heterozygotes for HbS have hemoglobins A and S (i.e., Hb A/S or sickle cell trait). The amount of HbS present in individuals with sickle cell trait is insufficient to produce sickling manifestations under most circumstances; thus, such individuals are usually asymptomatic, but are at risk for several complications (see
Sickle Cell Disease: Typical Proband and Parent Hemoglobin Alleles
Table shows typical results; exceptions occur. Some rare beta globin chain variants (e.g., Hb S/D, Hb S/E, Hb S/O) are not included.
Hb = hemoglobin; HbA = adult hemoglobin; HbF = fetal hemoglobin; Hb S/C = sickle-hemoglobin C disease; Hb S/S = homozygous for
Assumes that uniparental disomy is absent and that both parents are heterozygous. Some parents may be homozygous or compound heterozygous.
HbA is detectable in individuals with Hb S/β
If both parents are known to be heterozygous for an
If one parent is known to be heterozygous for a beta globin chain variant and the other parent is affected with SCD, each sib of an affected individual has a 50% chance of inheriting biallelic beta globin chain variants and being affected and a 50% chance of inheriting one beta globin chain variant and being heterozygous.
If both parents have biallelic beta globin chain variants (i.e., both parents have homozygous or compound heterozygous
Because a tremendous amount of individual variability occurs in SCD, the severity of disease manifestations in a sib who inherits biallelic beta globin chain variants cannot be predicted on the basis of the clinical course observed in the proband (see
Heterozygotes for HbS have hemoglobins A (adult) and S (sickle) (i.e., Hb A/S or sickle cell trait). The concentration of HbS present in individuals with sickle cell trait is insufficient to produce sickling manifestations under most circumstances; thus, these individuals are usually asymptomatic but are at risk for several complications (see
Does not have a beta globin chain variant (or variants), offspring will be heterozygous for a beta globin chain variant (i.e., heterozygous for an
Is heterozygous for a beta globin chain variant, offspring will have a 50% chance of having SCD and a 50% chance of being heterozygous for a beta globin chain variant;
Is also affected with SCD, all offspring will have biallelic beta globin chain variants (i.e., biallelic
Note: Because a tremendous amount of individual variability occurs in SCD, the severity of disease manifestations in offspring who inherit biallelic beta chain variants cannot be predicted on the basis of the clinical course observed in other affected family members (see
• The parents of an individual with SCD are typically heterozygous for one
• Alternatively, it is possible that one or both parents have biallelic beta globin chain variants (e.g., Hb S/S or compound heterozygous
• Typical parental alleles are described in
• Evaluation of the parents is recommended to determine their genetic status and to allow reliable recurrence risk assessment.
• If both SCD-related
• If only one (or neither) SCD-related
• Note: HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). However, HPLC cannot definitively distinguish Hb S/β
• If both SCD-related
• If only one (or neither) SCD-related
• Note: HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). However, HPLC cannot definitively distinguish Hb S/β
• If one parent is found to have an HbS allele, a beta globin chain variant is not identified in the other parent, and parental identity testing has confirmed biological maternity and paternity, it is possible that one of the beta globin chain variants identified in the proband occurred as the result of 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 HbS allele that resulted in homozygosity for the
• 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 HbS allele that resulted in homozygosity for the
• Heterozygotes for HbS have hemoglobins A and S (i.e., Hb A/S or sickle cell trait). The amount of HbS present in individuals with sickle cell trait is insufficient to produce sickling manifestations under most circumstances; thus, such individuals are usually asymptomatic, but are at risk for several complications (see
• If both SCD-related
• If only one (or neither) SCD-related
• Note: HPLC can be used to detect common qualitative abnormalities (i.e., abnormal hemoglobins). However, HPLC cannot definitively distinguish Hb S/β
• 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 HbS allele that resulted in homozygosity for the
• If both parents are known to be heterozygous for an
• If one parent is known to be heterozygous for a beta globin chain variant and the other parent is affected with SCD, each sib of an affected individual has a 50% chance of inheriting biallelic beta globin chain variants and being affected and a 50% chance of inheriting one beta globin chain variant and being heterozygous.
• If both parents have biallelic beta globin chain variants (i.e., both parents have homozygous or compound heterozygous
• Because a tremendous amount of individual variability occurs in SCD, the severity of disease manifestations in a sib who inherits biallelic beta globin chain variants cannot be predicted on the basis of the clinical course observed in the proband (see
• Heterozygotes for HbS have hemoglobins A (adult) and S (sickle) (i.e., Hb A/S or sickle cell trait). The concentration of HbS present in individuals with sickle cell trait is insufficient to produce sickling manifestations under most circumstances; thus, these individuals are usually asymptomatic but are at risk for several complications (see
• Does not have a beta globin chain variant (or variants), offspring will be heterozygous for a beta globin chain variant (i.e., heterozygous for an
• Is heterozygous for a beta globin chain variant, offspring will have a 50% chance of having SCD and a 50% chance of being heterozygous for a beta globin chain variant;
• Is also affected with SCD, all offspring will have biallelic beta globin chain variants (i.e., biallelic
## Heterozygote Detection
## Related Genetic Counseling Issues
See Management,
It must be kept in mind that non-sickle hemoglobin disorders (e.g.,
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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.
• It must be kept in mind that non-sickle hemoglobin disorders (e.g.,
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
Molecular genetic prenatal testing and preimplantation genetic testing for SCD are possible when:
Both
The genetic status of the parents is known. Because one parent may have a non-HbS
Because of the extreme variation in clinical course, it is not currently possible to accurately predict the severity of SCD based on the prenatal finding of biallelic SCD-related
When the mother is known to be heterozygous and the father is unknown and/or unavailable for testing, options for prenatal testing can be explored in the context of formal genetic counseling.
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
• The genetic status of the parents is known. Because one parent may have a non-HbS
## Resources
California Department of Public Health
Health Resources & Services Administration
United Kingdom
•
•
•
•
•
•
•
•
•
• California Department of Public Health
•
•
•
•
•
•
•
•
•
•
• Health Resources & Services Administration
•
•
• United Kingdom
•
## Molecular Genetics
Sickle Cell Disease: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Sickle Cell Disease (
Polymerized hemoglobin is also injurious to the RBC membrane, resulting in cellular dehydration, oxidative damage, and increased adherence to endothelial cells [
Notable
Variants listed in the table have been provided by the authors.
DNA nucleotide changes follow current nomenclature guidelines, where the number 1 corresponds to the first nucleotide of the initiating methionine.
In this column and throughout the text of the
## Molecular Pathogenesis
Polymerized hemoglobin is also injurious to the RBC membrane, resulting in cellular dehydration, oxidative damage, and increased adherence to endothelial cells [
Notable
Variants listed in the table have been provided by the authors.
DNA nucleotide changes follow current nomenclature guidelines, where the number 1 corresponds to the first nucleotide of the initiating methionine.
In this column and throughout the text of the
## Chapter Notes
Dr Bender formally ran the Odessa Brown Children's Clinic Sickle Cell Program associated Seattle Children's and the University of Washington, and a basic science lab at the Fred Hutchinson Cancer Research Center focused on the regulation of the chromatin structure and gene expression using the beta globin locus as a model, gene therapy, and novel agents to treat sickle cell disease and thalassemia. Clinically, Dr Bender has a long-standing commitment to hemoglobinopathies with particular interest in patient and provider education, immigrant populations, community outreach, and optimizing access to health care, and he has a special admiration of and interest in understanding the diverse array of cultural beliefs about sickle cell disease and how to use this to optimize care. He has a special interest in newborn screening; he consults for the Washington Newborn Screening Program, works with the Association of Public Health Laboratories Hemoglobinopathy group, and contributes to the ACMG ACT sheets. Dr Bender has received the American Society of Hematology's Champion for Advocacy award, was a member of the NIH Sickle Cell Disease Advisory Committee, and worked with the Puget Sound Blood Center's Rare Blood Groups Task Force. He is honored to have the ability to work with patients and families affected by sickle cell disease. Email:
Dr Carlberg is a pediatric hematologist with a clinical focus on patients affected by hemoglobinopathies and other red blood cell disorders. She has a particular interest in simplifying and demystifying the process of transitioning from the pediatric to adult heath care system for those with chronic health care needs. Her research during fellowship focused on the development of a noninvasive prenatal test for hemoglobinopathies. Email:
The authors would like to acknowledge Katie Bergstrom, MS, CGC, for expert review and comments.
We are indebted to the patients and families with sickle cell disease who continuously inspire and teach us.
MA Bender, MD, PhD (2006-present)Katie Carlberg, MD (2022-present)Gabrielle Douthitt Seibel, MN, MPH, ARNP; Seattle Children's Hospital (2014-2017)William Hobbs, MD, PhD; Puget Sound Blood Center (2009-2014)Krysta Schlis, MD; Children's Hospital Oakland (2003-2006)Elliott Vichinsky, MD; Children's Hospital Oakland (2003-2006)
13 February 2025 (mb/aa) Revision: voxelotor (Oxbryta
28 December 2023 (mb/aa) Revision: Exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel) added to
17 November 2022 (sw) Comprehensive update posted live
17 August 2017 (sw) Comprehensive update posted live
23 October 2014 (me) Comprehensive update posted live
9 February 2012 (me) Comprehensive update posted live
6 August 2009 (me) Comprehensive update posted live
7 March 2006 (me) Comprehensive update posted live
15 September 2003 (me) Review posted live
21 April 2003 (ev) Original submission
• 13 February 2025 (mb/aa) Revision: voxelotor (Oxbryta
• 28 December 2023 (mb/aa) Revision: Exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel) added to
• 17 November 2022 (sw) Comprehensive update posted live
• 17 August 2017 (sw) Comprehensive update posted live
• 23 October 2014 (me) Comprehensive update posted live
• 9 February 2012 (me) Comprehensive update posted live
• 6 August 2009 (me) Comprehensive update posted live
• 7 March 2006 (me) Comprehensive update posted live
• 15 September 2003 (me) Review posted live
• 21 April 2003 (ev) Original submission
## Author Notes
Dr Bender formally ran the Odessa Brown Children's Clinic Sickle Cell Program associated Seattle Children's and the University of Washington, and a basic science lab at the Fred Hutchinson Cancer Research Center focused on the regulation of the chromatin structure and gene expression using the beta globin locus as a model, gene therapy, and novel agents to treat sickle cell disease and thalassemia. Clinically, Dr Bender has a long-standing commitment to hemoglobinopathies with particular interest in patient and provider education, immigrant populations, community outreach, and optimizing access to health care, and he has a special admiration of and interest in understanding the diverse array of cultural beliefs about sickle cell disease and how to use this to optimize care. He has a special interest in newborn screening; he consults for the Washington Newborn Screening Program, works with the Association of Public Health Laboratories Hemoglobinopathy group, and contributes to the ACMG ACT sheets. Dr Bender has received the American Society of Hematology's Champion for Advocacy award, was a member of the NIH Sickle Cell Disease Advisory Committee, and worked with the Puget Sound Blood Center's Rare Blood Groups Task Force. He is honored to have the ability to work with patients and families affected by sickle cell disease. Email:
Dr Carlberg is a pediatric hematologist with a clinical focus on patients affected by hemoglobinopathies and other red blood cell disorders. She has a particular interest in simplifying and demystifying the process of transitioning from the pediatric to adult heath care system for those with chronic health care needs. Her research during fellowship focused on the development of a noninvasive prenatal test for hemoglobinopathies. Email:
## Acknowledgments
The authors would like to acknowledge Katie Bergstrom, MS, CGC, for expert review and comments.
We are indebted to the patients and families with sickle cell disease who continuously inspire and teach us.
## Author History
MA Bender, MD, PhD (2006-present)Katie Carlberg, MD (2022-present)Gabrielle Douthitt Seibel, MN, MPH, ARNP; Seattle Children's Hospital (2014-2017)William Hobbs, MD, PhD; Puget Sound Blood Center (2009-2014)Krysta Schlis, MD; Children's Hospital Oakland (2003-2006)Elliott Vichinsky, MD; Children's Hospital Oakland (2003-2006)
## Revision History
13 February 2025 (mb/aa) Revision: voxelotor (Oxbryta
28 December 2023 (mb/aa) Revision: Exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel) added to
17 November 2022 (sw) Comprehensive update posted live
17 August 2017 (sw) Comprehensive update posted live
23 October 2014 (me) Comprehensive update posted live
9 February 2012 (me) Comprehensive update posted live
6 August 2009 (me) Comprehensive update posted live
7 March 2006 (me) Comprehensive update posted live
15 September 2003 (me) Review posted live
21 April 2003 (ev) Original submission
• 13 February 2025 (mb/aa) Revision: voxelotor (Oxbryta
• 28 December 2023 (mb/aa) Revision: Exagamglogene autotemcel (exa-cel) and lovotibeglogene autotemcel (lovo-cel) added to
• 17 November 2022 (sw) Comprehensive update posted live
• 17 August 2017 (sw) Comprehensive update posted live
• 23 October 2014 (me) Comprehensive update posted live
• 9 February 2012 (me) Comprehensive update posted live
• 6 August 2009 (me) Comprehensive update posted live
• 7 March 2006 (me) Comprehensive update posted live
• 15 September 2003 (me) Review posted live
• 21 April 2003 (ev) Original submission
## Key Sections in this
## References
American College of Emergency Physicians. Managing sickle cell disease in the ED. Available
Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, Kutlar A, Seisa M, Stinson J, Strouse JJ, Yusuf F, Zempsky W, Lang E. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4:2656-701. [
Chou ST, Alsawas M, Fasano RM, Field JJ, Hendrickson JE, Howard J, Kameka M, Kwiatkowski JL, Pirenne F, Shi PA, Stowell SR, Thein SL, Westhoff CM, Wong TE, Akl EA. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 2020;4:327-55. [
DeBaun MR, Jordan LC, King AA, Schatz J, Vichinsky E, Fox CK, McKinstry RC, Telfer P, Kraut MA, Daraz L, Kirkham FJ, Murad MH. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020;4:1554-88. [
Kanter J, Liem RI, Bernaudin F, Bolaños-Meade J, Fitzhugh CD, Hankins JS, Murad MH, Panepinto JA, Rondelli D, Shenoy S, Wagner J, Walters MC, Woolford T, Meerpohl JJ, Tisdale J. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021;5:3668-89. [
Liem RI, Lanzkron S, D Coates T, DeCastro L, Desai AA, Ataga KI, Cohen RT, Haynes J, Osunkwo I, Lebensburger JD, Lash JP, Wun T, Verhovsek M, Ontala E, Blaylark R, Alahdab F, Katabi A, Mustafa RA. American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Adv. 2019;3:3867-97. [
National Health Service. Sickle cell and thalassaemia screening programme: standards. 2019. Available
National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease: expert panel report. 2014. Available
Ryan K, Bain BJ, Worthington D, James J, Plews D, Mason A, Roper D, Rees DC, de la Salle B, Streetly A; British Committee for Standards in Haematology. Significant haemoglobinopathies: guidelines for screening and diagnosis. Br J Haematol. 2010;149:35-49. [
Sickle Cell Society. Standards for clinical care of adults with sickle cell disease in the UK. 2nd ed. 2018. Available
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312:1033-48. [
• American College of Emergency Physicians. Managing sickle cell disease in the ED. Available
• Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, Kutlar A, Seisa M, Stinson J, Strouse JJ, Yusuf F, Zempsky W, Lang E. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4:2656-701. [
• Chou ST, Alsawas M, Fasano RM, Field JJ, Hendrickson JE, Howard J, Kameka M, Kwiatkowski JL, Pirenne F, Shi PA, Stowell SR, Thein SL, Westhoff CM, Wong TE, Akl EA. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 2020;4:327-55. [
• DeBaun MR, Jordan LC, King AA, Schatz J, Vichinsky E, Fox CK, McKinstry RC, Telfer P, Kraut MA, Daraz L, Kirkham FJ, Murad MH. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020;4:1554-88. [
• Kanter J, Liem RI, Bernaudin F, Bolaños-Meade J, Fitzhugh CD, Hankins JS, Murad MH, Panepinto JA, Rondelli D, Shenoy S, Wagner J, Walters MC, Woolford T, Meerpohl JJ, Tisdale J. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021;5:3668-89. [
• Liem RI, Lanzkron S, D Coates T, DeCastro L, Desai AA, Ataga KI, Cohen RT, Haynes J, Osunkwo I, Lebensburger JD, Lash JP, Wun T, Verhovsek M, Ontala E, Blaylark R, Alahdab F, Katabi A, Mustafa RA. American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Adv. 2019;3:3867-97. [
• National Health Service. Sickle cell and thalassaemia screening programme: standards. 2019. Available
• National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease: expert panel report. 2014. Available
• Ryan K, Bain BJ, Worthington D, James J, Plews D, Mason A, Roper D, Rees DC, de la Salle B, Streetly A; British Committee for Standards in Haematology. Significant haemoglobinopathies: guidelines for screening and diagnosis. Br J Haematol. 2010;149:35-49. [
• Sickle Cell Society. Standards for clinical care of adults with sickle cell disease in the UK. 2nd ed. 2018. Available
• Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312:1033-48. [
## Published Guidelines / Consensus Statements
American College of Emergency Physicians. Managing sickle cell disease in the ED. Available
Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, Kutlar A, Seisa M, Stinson J, Strouse JJ, Yusuf F, Zempsky W, Lang E. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4:2656-701. [
Chou ST, Alsawas M, Fasano RM, Field JJ, Hendrickson JE, Howard J, Kameka M, Kwiatkowski JL, Pirenne F, Shi PA, Stowell SR, Thein SL, Westhoff CM, Wong TE, Akl EA. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 2020;4:327-55. [
DeBaun MR, Jordan LC, King AA, Schatz J, Vichinsky E, Fox CK, McKinstry RC, Telfer P, Kraut MA, Daraz L, Kirkham FJ, Murad MH. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020;4:1554-88. [
Kanter J, Liem RI, Bernaudin F, Bolaños-Meade J, Fitzhugh CD, Hankins JS, Murad MH, Panepinto JA, Rondelli D, Shenoy S, Wagner J, Walters MC, Woolford T, Meerpohl JJ, Tisdale J. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021;5:3668-89. [
Liem RI, Lanzkron S, D Coates T, DeCastro L, Desai AA, Ataga KI, Cohen RT, Haynes J, Osunkwo I, Lebensburger JD, Lash JP, Wun T, Verhovsek M, Ontala E, Blaylark R, Alahdab F, Katabi A, Mustafa RA. American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Adv. 2019;3:3867-97. [
National Health Service. Sickle cell and thalassaemia screening programme: standards. 2019. Available
National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease: expert panel report. 2014. Available
Ryan K, Bain BJ, Worthington D, James J, Plews D, Mason A, Roper D, Rees DC, de la Salle B, Streetly A; British Committee for Standards in Haematology. Significant haemoglobinopathies: guidelines for screening and diagnosis. Br J Haematol. 2010;149:35-49. [
Sickle Cell Society. Standards for clinical care of adults with sickle cell disease in the UK. 2nd ed. 2018. Available
Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312:1033-48. [
• American College of Emergency Physicians. Managing sickle cell disease in the ED. Available
• Brandow AM, Carroll CP, Creary S, Edwards-Elliott R, Glassberg J, Hurley RW, Kutlar A, Seisa M, Stinson J, Strouse JJ, Yusuf F, Zempsky W, Lang E. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4:2656-701. [
• Chou ST, Alsawas M, Fasano RM, Field JJ, Hendrickson JE, Howard J, Kameka M, Kwiatkowski JL, Pirenne F, Shi PA, Stowell SR, Thein SL, Westhoff CM, Wong TE, Akl EA. American Society of Hematology 2020 guidelines for sickle cell disease: transfusion support. Blood Adv. 2020;4:327-55. [
• DeBaun MR, Jordan LC, King AA, Schatz J, Vichinsky E, Fox CK, McKinstry RC, Telfer P, Kraut MA, Daraz L, Kirkham FJ, Murad MH. American Society of Hematology 2020 guidelines for sickle cell disease: prevention, diagnosis, and treatment of cerebrovascular disease in children and adults. Blood Adv. 2020;4:1554-88. [
• Kanter J, Liem RI, Bernaudin F, Bolaños-Meade J, Fitzhugh CD, Hankins JS, Murad MH, Panepinto JA, Rondelli D, Shenoy S, Wagner J, Walters MC, Woolford T, Meerpohl JJ, Tisdale J. American Society of Hematology 2021 guidelines for sickle cell disease: stem cell transplantation. Blood Adv. 2021;5:3668-89. [
• Liem RI, Lanzkron S, D Coates T, DeCastro L, Desai AA, Ataga KI, Cohen RT, Haynes J, Osunkwo I, Lebensburger JD, Lash JP, Wun T, Verhovsek M, Ontala E, Blaylark R, Alahdab F, Katabi A, Mustafa RA. American Society of Hematology 2019 guidelines for sickle cell disease: cardiopulmonary and kidney disease. Blood Adv. 2019;3:3867-97. [
• National Health Service. Sickle cell and thalassaemia screening programme: standards. 2019. Available
• National Heart, Lung, and Blood Institute. Evidence-based management of sickle cell disease: expert panel report. 2014. Available
• Ryan K, Bain BJ, Worthington D, James J, Plews D, Mason A, Roper D, Rees DC, de la Salle B, Streetly A; British Committee for Standards in Haematology. Significant haemoglobinopathies: guidelines for screening and diagnosis. Br J Haematol. 2010;149:35-49. [
• Sickle Cell Society. Standards for clinical care of adults with sickle cell disease in the UK. 2nd ed. 2018. Available
• Yawn BP, Buchanan GR, Afenyi-Annan AN, Ballas SK, Hassell KL, James AH, Jordan L, Lanzkron SM, Lottenberg R, Savage WJ, Tanabe PJ, Ware RE, Murad MH, Goldsmith JC, Ortiz E, Fulwood R, Horton A, John-Sowah J. Management of sickle cell disease: summary of the 2014 evidence-based report by expert panel members. JAMA. 2014;312:1033-48. [
## Literature Cited
|
[] |
15/9/2003
|
17/11/2022
|
13/2/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
sider-anemia
|
sider-anemia
|
[
"ATP-binding cassette sub-family B member 7, mitochondrial",
"ABCB7",
"X-Linked Sideroblastic Anemia and Ataxia"
] |
X-Linked Sideroblastic Anemia and Ataxia – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY
|
Soumeya Bekri, Marc D'Hooghe, Pieter Vermeersch
|
Summary X-linked sideroblastic anemia and ataxia (XLSA/A) is characterized by moderate anemia and early-onset spinocerebellar syndrome in males, manifest primarily as delayed walking, ataxia evident in early childhood, dysmetria, and dysdiadochokinesis. When present the intention tremor is mild and the dysarthria is mild to moderately severe. The ataxia has been described to be either non-progressive or slowly progressive. Upper motor neuron (UMN) signs in the legs, manifest by brisk deep tendon reflexes, unsustained ankle clonus, and equivocal or extensor plantar responses, are present in some males. Need for crutches or a wheelchair has been reported. Strabismus is seen in some males. Nystagmus and hypometric saccades may occur. Mild learning disability and depression are seen. The moderate hypochromic and microcytic anemia does not cause symptoms. Carrier (heterozygous) females have a normal neurologic examination and may show mild hematologic abnormalities. The diagnosis of XLSA/A is suspected in males with characteristic neurologic findings and the presence of moderate hypochromic and microcytic anemia, elevated whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP), and ring sideroblasts on bone marrow examination. Pappenheimer bodies are seen in peripheral blood smear. The diagnosis is confirmed in a male by identification of a hemizygous pathogenic variant in Females have a normal neurologic examination and may have a dimorphic blood smear with both hypochromic microcytic red blood cells and normal red blood cells; they may have ring sideroblasts on bone marrow examination. XLSA/A is inherited in an X-linked manner. Heterozygous females have a 50% chance of transmitting the pathogenic variant in each pregnancy. Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be carriers and will usually not be affected. Males with XLSA/A will pass the pathogenic variant to all of their daughters and none of their sons. Carrier testing of at-risk female relatives and prenatal testing for a pregnancy at increased risk are possible if the
|
## Diagnosis
Ataxia and incoordination. Note:
Upper motor neuron (UMN) signs (i.e., brisk deep tendon reflexes, unsustained ankle clonus, and equivocal or extensor plantar responses) in the legs (present in some males)
Mild asymptomatic hypochromic, microcytic anemia
Hematocrit ranges from 26% to 35%.
Mean corpuscular volume (MCV fl) is low (
Peripheral blood smears show in affected males: (1) microcytic and hypochromic red cells with marked poikilocytosis, reticulocytosis, and heavy stippling; (2) Pappenheimer bodies (iron inclusions in more mature erythrocytes). These siderocytes are present in the peripheral blood of affected males and in some heterozygous females.
Bone marrow examination shows increased iron stores with ring sideroblasts (
High levels of whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) further support the diagnosis [
Note: (1) Whole blood TEP may be used as a screening tool [
Mean Corpuscular Volume (MCV fl) in XLSA/A
For an introduction to multigene panels click
Molecular Genetic Testing Used in X-Linked Sideroblastic Anemia and Ataxia
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
Lack of amplification by PCR prior to sequence analysis can suggest a putative (multi)exon or whole-gene deletion on the X chromosome in affected males; confirmation may require additional testing by deletion/duplication analysis.
Testing that identifies exon or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Methods used may include quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.
No deletions/duplications of
• Ataxia and incoordination. Note:
• Upper motor neuron (UMN) signs (i.e., brisk deep tendon reflexes, unsustained ankle clonus, and equivocal or extensor plantar responses) in the legs (present in some males)
• Mild asymptomatic hypochromic, microcytic anemia
• Hematocrit ranges from 26% to 35%.
• Mean corpuscular volume (MCV fl) is low (
• Peripheral blood smears show in affected males: (1) microcytic and hypochromic red cells with marked poikilocytosis, reticulocytosis, and heavy stippling; (2) Pappenheimer bodies (iron inclusions in more mature erythrocytes). These siderocytes are present in the peripheral blood of affected males and in some heterozygous females.
• Bone marrow examination shows increased iron stores with ring sideroblasts (
• High levels of whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) further support the diagnosis [
• Note: (1) Whole blood TEP may be used as a screening tool [
• Hematocrit ranges from 26% to 35%.
• Mean corpuscular volume (MCV fl) is low (
• Peripheral blood smears show in affected males: (1) microcytic and hypochromic red cells with marked poikilocytosis, reticulocytosis, and heavy stippling; (2) Pappenheimer bodies (iron inclusions in more mature erythrocytes). These siderocytes are present in the peripheral blood of affected males and in some heterozygous females.
• Bone marrow examination shows increased iron stores with ring sideroblasts (
• High levels of whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) further support the diagnosis [
• Note: (1) Whole blood TEP may be used as a screening tool [
• Hematocrit ranges from 26% to 35%.
• Mean corpuscular volume (MCV fl) is low (
• Peripheral blood smears show in affected males: (1) microcytic and hypochromic red cells with marked poikilocytosis, reticulocytosis, and heavy stippling; (2) Pappenheimer bodies (iron inclusions in more mature erythrocytes). These siderocytes are present in the peripheral blood of affected males and in some heterozygous females.
• Bone marrow examination shows increased iron stores with ring sideroblasts (
• High levels of whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) further support the diagnosis [
• Note: (1) Whole blood TEP may be used as a screening tool [
• For an introduction to multigene panels click
## Clinical Characteristics
To date, four unrelated families with X-linked sideroblastic anemia and ataxia (XLSA/A) have been reported [
In some, but not all, affected members of one family, the ataxia appeared to improve with time, such that truncal titubation decreased and walking became progressively easier [
Need for crutches and/or a wheel chair have been reported.
Upper motor neuron (UMN) signs in the legs, manifest by brisk deep tendon reflexes, unsustained ankle clonus, and equivocal or extensor plantar responses are present in some males.
Strabismus is seen in some males. Extraocular movements are normal; however, nystagmus and hypometric saccades may occur.
Intellectual abilities are generally within the normal range. Mild learning disability and depression have been seen [Pagon & Bird, personal communication] and one person was reported to have "schizophrenia" [
Pes cavus, scoliosis, and muscle wasting are not present.
Impairment of visual acuity either from optic atrophy or retinal dystrophy is not seen.
In most cases brain MRI shows cerebellar atrophy/hypoplasia [
No genotype-phenotype correlations are known.
Four families and one male who was a simplex case (i.e., a single occurrence in a family) have been reported to date [
## Clinical Description
To date, four unrelated families with X-linked sideroblastic anemia and ataxia (XLSA/A) have been reported [
In some, but not all, affected members of one family, the ataxia appeared to improve with time, such that truncal titubation decreased and walking became progressively easier [
Need for crutches and/or a wheel chair have been reported.
Upper motor neuron (UMN) signs in the legs, manifest by brisk deep tendon reflexes, unsustained ankle clonus, and equivocal or extensor plantar responses are present in some males.
Strabismus is seen in some males. Extraocular movements are normal; however, nystagmus and hypometric saccades may occur.
Intellectual abilities are generally within the normal range. Mild learning disability and depression have been seen [Pagon & Bird, personal communication] and one person was reported to have "schizophrenia" [
Pes cavus, scoliosis, and muscle wasting are not present.
Impairment of visual acuity either from optic atrophy or retinal dystrophy is not seen.
In most cases brain MRI shows cerebellar atrophy/hypoplasia [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
## Prevalence
Four families and one male who was a simplex case (i.e., a single occurrence in a family) have been reported to date [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
In investigations of individuals with refractory anemia with ring sideroblasts (RARS), an acquired myelodysplastic syndrome (MDS) characterized by excess iron accumulation in the mitochondria of erythroblasts,
## Differential Diagnosis
The most common congenital sideroblastic anemia is X-linked sideroblastic anemia (XLSA) caused by mutation of
Other causes of congenital sideroblastic anemia include mutation of genes that encode proteins affecting mitochondrial metabolism [
Mitochondrial DNA deletions, duplications and rearrangements (Pearson marrow-pancreas syndrome) [
Another ataxia linked to Fe-S cluster protein is
Of note, in murine cultured fibroblasts with decreased levels of frataxin, some Fe-S cluster proteins are deficient, iron accumulates in mitochondria, and oxidant sensitivity is observed as in the human disease [
X-linked spinocerebellar ataxia has been reported, but is rare (see
• Mitochondrial DNA deletions, duplications and rearrangements (Pearson marrow-pancreas syndrome) [
## Management
To establish the extent of disease in an individual diagnosed with sideroblastic anemia and ataxia (XLSA/A), the following evaluations are recommended:
Neurologic examination
Brain CT or MRI
Psychological testing if indicated
Consultation with a clinical geneticist and/or genetic counselor
There is no effective treatment for XLSA/A.
Males with ataxia benefit from early physical therapy to facilitate acquisition of gross motor skills. Adaptive devices such as ankle fixation orthoses and walkers may be needed.
Weighted eating utensils may help promote independent skills in childhood.
Speech therapy may improve intelligibility problems resulting from dysarthria.
Difficulty with handwriting may be managed with computers for word processing.
The anemia is usually mild and asymptomatic and does not require treatment; hepatic and systemic iron overload does not occur.
It is debated whether monitoring for possible iron overload is warranted in older individuals through routine screening of serum iron concentration, total iron binding capacity (TIBC), and serum ferritin concentration; iron overload is theoretically possible but has not been reported.
See
One possible therapeutic approach to some of the disorders involving iron misdistribution is drug-mediated iron relocation. Deferiprone (DFP), an iron chelator used to treat iron overload, has iron-relocating abilities when used to treat disorders of regional iron accumulation. Because of their possible side effects, siderophores (small, high-affinity iron chelating compounds secreted by microorganisms) and other chelators must be administered with care; thus, the potential use of iron-redistributing agents in some iron-misdistribution diseases (such as XLSA/A) warrants rigorous investigation [
Search
• Neurologic examination
• Brain CT or MRI
• Psychological testing if indicated
• Consultation with a clinical geneticist and/or genetic counselor
## Evaluations Following Initial Diagnosis
To establish the extent of disease in an individual diagnosed with sideroblastic anemia and ataxia (XLSA/A), the following evaluations are recommended:
Neurologic examination
Brain CT or MRI
Psychological testing if indicated
Consultation with a clinical geneticist and/or genetic counselor
• Neurologic examination
• Brain CT or MRI
• Psychological testing if indicated
• Consultation with a clinical geneticist and/or genetic counselor
## Treatment of Manifestations
There is no effective treatment for XLSA/A.
Males with ataxia benefit from early physical therapy to facilitate acquisition of gross motor skills. Adaptive devices such as ankle fixation orthoses and walkers may be needed.
Weighted eating utensils may help promote independent skills in childhood.
Speech therapy may improve intelligibility problems resulting from dysarthria.
Difficulty with handwriting may be managed with computers for word processing.
The anemia is usually mild and asymptomatic and does not require treatment; hepatic and systemic iron overload does not occur.
## Surveillance
It is debated whether monitoring for possible iron overload is warranted in older individuals through routine screening of serum iron concentration, total iron binding capacity (TIBC), and serum ferritin concentration; iron overload is theoretically possible but has not been reported.
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
One possible therapeutic approach to some of the disorders involving iron misdistribution is drug-mediated iron relocation. Deferiprone (DFP), an iron chelator used to treat iron overload, has iron-relocating abilities when used to treat disorders of regional iron accumulation. Because of their possible side effects, siderophores (small, high-affinity iron chelating compounds secreted by microorganisms) and other chelators must be administered with care; thus, the potential use of iron-redistributing agents in some iron-misdistribution diseases (such as XLSA/A) warrants rigorous investigation [
Search
## Genetic Counseling
X-linked sideroblastic anemia and ataxia (XLSA/A) is inherited in an X-linked manner.
The father of an affected male will not have the disease nor will he be a carrier of the pathogenic
In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
If pedigree analysis reveals that a male proband is the only affected family member, his mother may be a carrier or the pathogenic variant may be
If a woman has more than one affected son and the pathogenic variant cannot be detected in her DNA, she has germline mosaicism. To date germline mosaicism has not been reported in XLSA/A.
The risk to sibs depends on the carrier status of the mother.
If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic
If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
Heterozygous females (carriers) are asymptomatic.
They have a normal neurologic examination with no cerebellar dysfunction.
They have a normal hematocrit, but may have a dimorphic blood smear with hypochromic microcytic red blood cells and normal red blood cells, sideroblasts on bone marrow examination. Some also have increased levels of whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) [
Carrier testing of at-risk female relatives is possible if the pathogenic variant has been identified in the family.
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, 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 father of an affected male will not have the disease nor will he be a carrier of the pathogenic
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
• If pedigree analysis reveals that a male proband is the only affected family member, his mother may be a carrier or the pathogenic variant may be
• If a woman has more than one affected son and the pathogenic variant cannot be detected in her DNA, she has germline mosaicism. To date germline mosaicism has not been reported in XLSA/A.
• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic
• If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• They have a normal neurologic examination with no cerebellar dysfunction.
• They have a normal hematocrit, but may have a dimorphic blood smear with hypochromic microcytic red blood cells and normal red blood cells, sideroblasts on bone marrow examination. Some also have increased levels of whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) [
• 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
X-linked sideroblastic anemia and ataxia (XLSA/A) 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 a carrier of the pathogenic
In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
If pedigree analysis reveals that a male proband is the only affected family member, his mother may be a carrier or the pathogenic variant may be
If a woman has more than one affected son and the pathogenic variant cannot be detected in her DNA, she has germline mosaicism. To date germline mosaicism has not been reported in XLSA/A.
The risk to sibs depends on the carrier status of the mother.
If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic
If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
• The father of an affected male will not have the disease nor will he be a carrier of the pathogenic
• In a family with more than one affected individual, the mother of an affected male is an obligate carrier.
• If pedigree analysis reveals that a male proband is the only affected family member, his mother may be a carrier or the pathogenic variant may be
• If a woman has more than one affected son and the pathogenic variant cannot be detected in her DNA, she has germline mosaicism. To date germline mosaicism has not been reported in XLSA/A.
• The risk to sibs depends on the carrier status of the mother.
• If the mother of the proband is a carrier, the chance of transmitting the pathogenic variant in each pregnancy is 50%. Male sibs who inherit the pathogenic
• If the pathogenic variant cannot be detected in the DNA of the mother of the only affected male in the family, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
## Heterozygote (Carrier) Detection
Heterozygous females (carriers) are asymptomatic.
They have a normal neurologic examination with no cerebellar dysfunction.
They have a normal hematocrit, but may have a dimorphic blood smear with hypochromic microcytic red blood cells and normal red blood cells, sideroblasts on bone marrow examination. Some also have increased levels of whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) [
Carrier testing of at-risk female relatives is possible if the pathogenic variant has been identified in the family.
• They have a normal neurologic examination with no cerebellar dysfunction.
• They have a normal hematocrit, but may have a dimorphic blood smear with hypochromic microcytic red blood cells and normal red blood cells, sideroblasts on bone marrow examination. Some also have increased levels of whole blood total erythrocyte protoporphyrin (TEP) and zinc erythrocyte protoporphyrin (ZnEP) [
## 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, 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
Ataxia UK
Lincoln House, Kennington Park, 1-3 Brixton Road
London SW9 6DE
United Kingdom
2600 Fernbrook Lane
Suite 119
Minneapolis MN 55447
•
• Ataxia UK
• Lincoln House, Kennington Park, 1-3 Brixton Road
• London SW9 6DE
• United Kingdom
•
•
•
•
• 2600 Fernbrook Lane
• Suite 119
• Minneapolis MN 55447
•
## Molecular Genetics
X-Linked Sideroblastic Anemia and Ataxia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for X-Linked Sideroblastic Anemia and Ataxia (
The substrate transported by the ABCB7 transporter is not fully characterized. Initially, ABCB7 was thought to be involved in transport of heme from the mitochondria to the cytosol [
See
Variants listed in the table have been provided by the authors.
See
## Molecular Pathogenesis
The substrate transported by the ABCB7 transporter is not fully characterized. Initially, ABCB7 was thought to be involved in transport of heme from the mitochondria to the cytosol [
See
Variants listed in the table have been provided by the authors.
See
## References
## Literature Cited
## Chapter Notes
Soumeya Bekri (2014-present)Marc D'Hooghe, MD (2014-present)Thomas D Bird, MD; University of Washington, Seattle (1998-2014)Roberta A Pagon, MD; University of Washington, Seattle (1998-2014)Pieter Vermeersch (2014-present)
20 August 2020 (ma) Chapter retired: extremely rare disorder
3 April 2014 (me) Comprehensive update posted live
7 April 2009 (me) Comprehensive update posted live
1 May 2008 (cd) Revision: sequencing of exons 5-16 and the intron/exon junctions available clinically
24 March 2008 (cd) Revision: clinical testing not available
1 March 2006 (me) Review posted live
12 November 1998 (bp) Original submission
• 20 August 2020 (ma) Chapter retired: extremely rare disorder
• 3 April 2014 (me) Comprehensive update posted live
• 7 April 2009 (me) Comprehensive update posted live
• 1 May 2008 (cd) Revision: sequencing of exons 5-16 and the intron/exon junctions available clinically
• 24 March 2008 (cd) Revision: clinical testing not available
• 1 March 2006 (me) Review posted live
• 12 November 1998 (bp) Original submission
## Author History
Soumeya Bekri (2014-present)Marc D'Hooghe, MD (2014-present)Thomas D Bird, MD; University of Washington, Seattle (1998-2014)Roberta A Pagon, MD; University of Washington, Seattle (1998-2014)Pieter Vermeersch (2014-present)
## Revision History
20 August 2020 (ma) Chapter retired: extremely rare disorder
3 April 2014 (me) Comprehensive update posted live
7 April 2009 (me) Comprehensive update posted live
1 May 2008 (cd) Revision: sequencing of exons 5-16 and the intron/exon junctions available clinically
24 March 2008 (cd) Revision: clinical testing not available
1 March 2006 (me) Review posted live
12 November 1998 (bp) Original submission
• 20 August 2020 (ma) Chapter retired: extremely rare disorder
• 3 April 2014 (me) Comprehensive update posted live
• 7 April 2009 (me) Comprehensive update posted live
• 1 May 2008 (cd) Revision: sequencing of exons 5-16 and the intron/exon junctions available clinically
• 24 March 2008 (cd) Revision: clinical testing not available
• 1 March 2006 (me) Review posted live
• 12 November 1998 (bp) Original submission
Ringed sideroblast
Prussian blue staining of the bone marrow aspirate (x1000) showing a normal erythroid precursor (straight arrow) and a ringed sideroblast containing many iron granules around the nucleus (curved arrow).
From
Fe-S cluster biogenesis, heme synthesis and hypothetic effects of defects in ABCB7
Adapted from
|
[
"R Allikmets, WH Raskind, A Hutchinson, ND Schueck, M Dean, DM Koeller. Mutation of a putative mitochondrial iron transporter gene (ABC7) in X-linked sideroblastic anemia and ataxia (XLSA/A).. Hum Mol Genet. 1999;8:743-9",
"S Bekri, G Kispal, H Lange, E Fitzsimons, J Tolmie, R Lill, DF Bishop. Human ABC7 transporter: gene structure and mutation causing X-linked sideroblastic anemia with ataxia with disruption of cytosolic iron-sulfur protein maturation.. Blood 2000;96:3256-64",
"AK Bergmann, DR Campagna, EM McLoughlin, S Agarwal, MD Fleming, SS Bottomley, EJ Neufeld. Systematic molecular genetic analysis of congenital sideroblastic anemia: evidence for genetic heterogeneity and identification of novel mutations.. Pediatr Blood Cancer. 2010;54:273-8",
"G Bernard, M. Shevell. The wobbly child: an approach to inherited ataxias.. Semin Pediatr Neurol 2008;15:194-208",
"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",
"J Boultwood, A Pellagatti, M Nikpour, B Pushkaran, C Fidler, H Cattan, TJ Littlewood, L Malcovati, MG Della Porta, M Jädersten, S Killick, A Giagounidis, D Bowen, E Hellström-Lindberg, M Cazzola, JS Wainscoat. The role of the iron transporter ABCB7 in refractory anemia with ring sideroblasts.. PLoS ONE 2008;3",
"MA Burke, H Ardehali. Mitochondrial ATP-binding cassette proteins.. Transl Res 2007;150:73-80",
"Y Bykhovskaya, K Casas, E Mengesha, A Inbal, N Fischel-Ghodsian. Missense mutation in pseudouridine synthase 1 (PUS1) causes mitochondrial myopathy and sideroblastic anemia (MLASA).. Am J Hum Genet 2004;74:1303-8",
"N Calmels, S Schmucker, M Wattenhofer-Donzé, A Martelli, N Vaucamps, L Reutenauer, N Messaddeq, C Bouton, M Koenig, H Puccio. The first cellular models based on frataxin missense mutations that reproduce spontaneously the defects associated with Friedreich ataxia.. PLoS One. 2009;4",
"C. Camaschella. Recent advances in the understanding of inherited sideroblastic anaemia.. Br J Haematol 2008;143:27-38",
"C Camaschella, A Campanella, L De Falco, L Boschetto, R Merlini, L Silvestri, S Levi, A Iolascon. The human counterpart of zebrafish shiraz shows sideroblastic-like microcytic anemia and iron overload.. Blood 2007;110:1353-8",
"M D'Hooghe, D Selleslag, G Mortier, R Van Coster, P Vermeersch, J Billiet, S Bekri. X-linked sideroblastic anemia and ataxia: a new family with identification of a fourth ABCB7 gene mutation.. Eur J Paediatr Neurol. 2012;16:730-5",
"MD Fleming. The genetics of inherited sideroblastic anemias.. Semin Hematol 2002;39:270-81",
"T Fujiwara, H Harigae. Pathophysiology and genetic mutations in congenital sideroblastic anemia.. Pediatr Int. 2013;55:675-9",
"DL Guernsey, H Jiang, DR Campagna, SC Evans, M Ferguson, MD Kellogg, M Lachance, M Matsuoka, M Nightingale, A Rideout, L Saint-Amant, PJ Schmidt, A Orr, SS Bottomley, MD Fleming, M Ludman, S Dyack, CV Fernandez, ME Samuels. Mutations in mitochondrial carrier family gene SLC25A38 cause nonsyndromic autosomal recessive congenital sideroblastic anemia.. Nat Genet. 2009;41:651-3",
"D Hart, S Piomelli. Simultaneous quantitation of zinc protoporphyrin and free protoporphyrin in erythrocytes by acetone extraction.. Clin Chem 1981;27:220-2",
"KD Hellier, E Hatchwell, AS Duncombe, J Kew, SR Hammans. X-linked sideroblastic anaemia with ataxia: another mitochondrial disease?. J Neurol Neurosurg Psychiatry 2001;70:65-9",
"IB Holland. ABC transporters, mechanisms and biology: an overview.. Essays Biochem 2011;50:1-17",
"O Kakhlon, W Breuer, A Munnich, ZI Cabantchik. Iron redistribution as a therapeutic strategy for treating diseases of localized iron accumulation.. Can J Physiol Pharmacol 2010;88:187-96",
"A Maguire, K Hellier, S Hammans, A May. X-linked cerebellar ataxia and sideroblastic anaemia associated with a missense mutation in the ABC7 gene predicting V411L.. Br J Haematol 2001;115:910-7",
"K Moitra, M. Dean. Evolution of ABC transporters by gene duplication and their role in human disease.. Biol Chem 2011;392:29-37",
"I Napier, P Ponka, DR Richardson. Iron trafficking in the mitochondrion: novel pathways revealed by disease.. Blood 2005;105:1867-74",
"M Nikpour, C Scharenberg, A Liu, S Conte, M Karimi, T Mortera-Blanco, V Giai, M Fernandez-Mercado, E Papaemmanuil, K Högstrand, M Jansson, I Vedin, J Stephen Wainscoat, P Campbell, M Cazzola, J Boultwood, A Grandien, E. Hellström-Lindberg. The transporter ABCB7 is a mediator of the phenotype of acquired refractory anemia with ring sideroblasts.. Leukemia. 2013;27:889-96",
"RA Pagon, TD Bird, JC Detter, I Pierce. Hereditary sideroblastic anaemia and ataxia: an X linked recessive disorder.. J Med Genet 1985;22:267-73",
"S Piomelli, AA Lamola, MF Poh-Fitzpatrick, C Seaman, LC Harber. Erythropoietic protoporphyria and lead intoxication: the molecular basis for difference in cutaneous photosensitivity. I. Different rates of disappearance of protoporphyrin from the erythrocytes, both in vivo and in vitro.. J Clin Invest 1975;56:1519-27",
"C Pondarré, BB Antiochos, DR Campagna, SL Clarke, EL Greer, KM Deck, A McDonald, AP Han, A Medlock, JL Kutok, SA Anderson, RS Eisenstein, MD Fleming. The mitochondrial ATP-binding cassette transporter Abcb7 is essential in mice and participates in cytosolic iron-sulphur cluster biogenesis.. Hum Mol Genet 2006;15:953-64",
"C Pondarré, DR Campagna, B Antiochos, L Sikorski, H Mulhern, MD Fleming. Abcb7, the gene responsible for X-linked sideroblastic anemia with ataxia, is essential for hematopoiesis.. Blood 2007;109:3567-9",
"WH Raskind, E Wijsman, RA Pagon, TC Cox, MJ Bawden, BK May, TD Bird. X-linked sideroblastic anemia and ataxia: linkage to phosphoglycerate kinase at Xq13.. Am J Hum Genet 1991;48:335-41",
"LG Riley, S Cooper, P Hickey, J Rudinger-Thirion, M McKenzie, A Compton, SC Lim, D Thorburn, MT Ryan, R Giegé, M Bahlo, J Christodoulou. Mutation of the mitochondrial tyrosyl-tRNA synthetase gene, YARS2, causes myopathy, lactic acidosis, and sideroblastic anemia--MLASA syndrome.. Am J Hum Genet. 2010;87:52-9",
"TA Rouault, WH Tong. Iron-sulfur cluster biogenesis and human disease.. Trends Genet 2008;24:398-407",
"DA Sears, MM Udden. Pappenheimer bodies: a brief historical review.. Am J Hematol 2004;75:249-50",
"A Sheftel, O Stehling, R Lill. Iron-sulfur proteins in health and disease.. Trends Endocrinol Metab 2010;21:302-14",
"Y Shimada, S Okuno, A Kawai, H Shinomiya, A Saito, M Suzuki, Y Omori, N Nishino, N Kanemoto, T Fujiwara, M Horie, E Takahashi. Cloning and chromosomal mapping of a novel ABC transporter gene (hABC7), a candidate for X-linked sideroblastic anemia with spinocerebellar ataxia.. J Hum Genet 1998;43:115-22",
"TL Stemmler, E Lesuisse, D Pain, A Dancis. Frataxin and mitochondrial FeS cluster biogenesis.. J Biol Chem 2010;285:26737-43",
"S Taketani, K Kakimoto, H Ueta, R Masaki, T Furukawa. Involvement of ABC7 in the biosynthesis of heme in erythroid cells: interaction of ABC7 with ferrochelatase.. Blood 2003;101:3274-80",
"H Ye, TA Rouault. Human iron-sulfur cluster assembly, cellular iron homeostasis, and disease.. Biochemistry 2010b;49:4945-56",
"K Yoshida, M Sanada, Y Shiraishi, D Nowak, Y Nagata, R Yamamoto, Y Sato, A Sato-Otsubo, A Kon, M Nagasaki, G Chalkidis, Y Suzuki, M Shiosaka, R Kawahata, T Yamaguchi, M Otsu, N Obara, M Sakata-Yanagimoto, K Ishiyama, H Mori, F Nolte, WK Hofmann, S Miyawaki, S Sugano, C Haferlach, HP Koeffler, LY Shih, T Haferlach, S Chiba, H Nakauchi, S Miyano, S Ogawa. Frequent pathway mutations of splicing machinery in myelodysplasia.. Nature. 2011;478:64-9",
"A Zutz, S Gompf, H Schagger, R. Tampe. Mitochondrial ABC proteins in health and disease.. Biochim Biophys Acta. 2009;1787:681-90"
] |
1/3/2006
|
3/4/2014
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
siod
|
siod
|
[
"SMARCAL1-Related Immuno-osseous Dysplasia (Schimke Type)",
"SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A-like protein 1",
"SMARCAL1",
"Schimke Immunoosseous Dysplasia"
] |
Schimke Immunoosseous Dysplasia
|
Elizabeth Lippner, Thomas Lücke, Carlos Salgado, Cornelius Boerkoel, David B Lewis
|
Summary Schimke immunoosseous dysplasia (SIOD) is characterized by spondyloepiphyseal dysplasia (SED) resulting in short stature, nephropathy, and T cell deficiency. Radiographic manifestations of SED include ovoid and mildly flattened vertebral bodies, small ilia with shallow dysplastic acetabular fossae, and small deformed capital femoral epiphyses. Nearly all affected individuals have progressive steroid-resistant nephropathy, usually developing within five years of the diagnosis of growth failure and terminating with end-stage renal disease. The majority of tested individuals have T cell deficiency and an associated risk for opportunistic infection, a common cause of death. SIOD involves a spectrum that ranges from an infantile or severe early-onset form with a greater risk of death during childhood to a juvenile or milder later-onset form with likely survival into adulthood if renal disease is appropriately treated. The diagnosis of SIOD is established in a proband with the characteristic clinical, laboratory, and radiographic features and/or biallelic pathogenic variants in SIOD is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for a
|
## Diagnosis
No consensus clinical diagnostic criteria for Schimke immunoosseous dysplasia (SIOD) have been published.
SIOD
Ovoid and mildly flattened vertebral bodies; endplate irregularities, wedged vertebrae, and narrowed vertebral spaces have been reported.
Small ilia with hypoplastic basilar portions and shallow dysplastic acetabular fossae
Capital femoral epiphyses are small, deformed, and laterally displaced; flattened epiphyses at the knees and shoulders.
The diagnosis of SIOD
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
For an introduction to multigene panels click
Note: Several reported splice site variants may not be identified on sequence analysis [
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schimke Immunoosseous Dysplasia
NA = not applicable
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
Several reported splice site variants may not be identified on sequence analysis [
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 multiexon deletion that included the promoter and exons 1-4 was reported in one individual [
The presence of individuals with clinical features of SIOD who do not have identifiable pathogenic variants in
•
• Ovoid and mildly flattened vertebral bodies; endplate irregularities, wedged vertebrae, and narrowed vertebral spaces have been reported.
• Small ilia with hypoplastic basilar portions and shallow dysplastic acetabular fossae
• Capital femoral epiphyses are small, deformed, and laterally displaced; flattened epiphyses at the knees and shoulders.
## Suggestive Findings
SIOD
Ovoid and mildly flattened vertebral bodies; endplate irregularities, wedged vertebrae, and narrowed vertebral spaces have been reported.
Small ilia with hypoplastic basilar portions and shallow dysplastic acetabular fossae
Capital femoral epiphyses are small, deformed, and laterally displaced; flattened epiphyses at the knees and shoulders.
•
• Ovoid and mildly flattened vertebral bodies; endplate irregularities, wedged vertebrae, and narrowed vertebral spaces have been reported.
• Small ilia with hypoplastic basilar portions and shallow dysplastic acetabular fossae
• Capital femoral epiphyses are small, deformed, and laterally displaced; flattened epiphyses at the knees and shoulders.
## Establishing the Diagnosis
The diagnosis of SIOD
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
For an introduction to multigene panels click
Note: Several reported splice site variants may not be identified on sequence analysis [
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schimke Immunoosseous Dysplasia
NA = not applicable
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
Several reported splice site variants may not be identified on sequence analysis [
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 multiexon deletion that included the promoter and exons 1-4 was reported in one individual [
The presence of individuals with clinical features of SIOD who do not have identifiable pathogenic variants in
## Option 1
For an introduction to multigene panels click
## Option 2
Note: Several reported splice site variants may not be identified on sequence analysis [
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in Schimke Immunoosseous Dysplasia
NA = not applicable
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
Several reported splice site variants may not be identified on sequence analysis [
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 multiexon deletion that included the promoter and exons 1-4 was reported in one individual [
The presence of individuals with clinical features of SIOD who do not have identifiable pathogenic variants in
## Clinical Characteristics
Schimke immunoosseous dysplasia (SIOD) is characterized by a constellation of clinical findings that affect a variety of organ systems. Nearly all affected individuals have disproportionate short stature, spondyloepiphyseal dysplasia causing hip disease, nephrotic syndrome that progresses to end-stage renal disease (ESRD), hyperpigmented macules, and immunodeficiency (primarily cellular immunodeficiency). Central nervous system vasculopathy (migraines, transient ischemic attacks, strokes), thyroid dysfunction, and cytopenias are also common. Secondary complications include hypertension, anemia, elevated lipids, recurrent infections, and osteopenia. Although not defining features of SIOD, bone marrow failure and lymphoproliferative disease have been reported [
Frequency of Physical, Radiographic, and Laboratory Features in Individuals with Schimke Immunoosseous Dysplasia Confirmed on Molecular Testing
ALL = acute lymphoblastic leukemia; FSGS = focal segmental glomerulosclerosis; IUGR = intrauterine growth restriction; TIAs = transient ischemic attacks
Short stature is not a result of renal failure. Comparison of the anthropometric measurements of persons with SIOD to persons with non-SIOD chronic kidney disease found that in nearly all parameters, persons with SIOD differed significantly from those with non-SIOD chronic renal disease. The most marked difference is that in non-SIOD chronic kidney disease, the median leg length is significantly more reduced than trunk length, while in persons with SIOD, the reduction in trunk length was significantly more than that of leg length. Therefore, a sitting height / leg length ratio of lower than 0.83 is suggestive of SIOD in persons with chronic kidney disease [
Hypoplastic pelvis and epiphyseal dysplasia leads to degenerative hip disease and chronic joint pain. Surgical intervention may be necessary, and treatment of hematopoietic and renal anomalies has not been shown to alter bony disease. The shoulder and other large joints are relatively spared.
Less frequent skeletal findings include a widened sella turcica and osteopenia. Individuals with SIOD and osteopenia are at risk for fractures. Systemic corticosteroids should be used with caution.
Neutropenia is also reported in 38% of individuals with SIOD and is likely a reflection of relative hypoplasia of the neutrophil lineage in the bone marrow [
Immunodeficiency increases the risk of opportunistic infections such as
In one affected individual with thrombocytopenia, the autoimmune features resolved spontaneously; in one they resolved after steroid and intravenous immunoglobulin treatments, and in one they cleared after splenectomy. One individual who developed immune thrombocytopenia two years after renal transplantation was not responsive to intravenous immunoglobulin or systemic corticosteroids and required plasmapheresis and thrombopoietin-receptor agonist therapy [
Anemia does not often respond to supplementation with erythropoietin or renal transplantation. However, it is possible that erythropoietin has a protective effect on the endothelia. A few individuals have been transfusion dependent due to anemia or thrombocytopenia. The individual with Evans syndrome was resistant to treatment with steroids, cyclosporin A, and rituximab [
A few individuals with SIOD have enteropathy. In most of these individuals, the enteropathy results from infection (e.g.,
The cause of the severe migraine-like headaches is unknown. Two case reports describe individuals presenting with severe headaches progressing to hemiplegia, aphasia, and seizures in whom brain imaging demonstrated reversible vasoconstriction and diminished cerebral perfusion [
Half of individuals with SIOD have symptoms suggestive of atherosclerosis (e.g., hypertension, cerebral ischemia, renal occlusive disease). Vascular changes observed on postmortem tissue from three individuals included focal intimal lipid deposition, focal myointimal proliferation, macrophage invasion, foam cells, fibrous transformation, and calcium deposits [
Most affected individuals develop other symptoms within one to five years of the diagnosis of growth deficiency. Those with severe symptoms usually die within four to eight years. The mean age of death is 11 years. Causes of death include infection (23%), stroke (13%), pulmonary hypertension and congestive heart failure (13%), renal failure (11%), complications of organ transplantation (9%), lymphoproliferative disease (4%), gastrointestinal complications (4%), respiratory failure (4%), bone marrow failure (2%), non-Hodgkin lymphoma (2%), pancreatitis (2%), and other causes not reported (13%).
Among those who have survived beyond puberty, it is unknown if any individuals with SIOD have reproduced. Women develop menses, although the menstrual cycle is usually irregular. Men develop secondary sexual characteristics, but histopathologic examination of the testes has identified azoospermia [
The early-onset, more severe phenotype has been associated with truncating
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
The prevalence is unknown. The incidence is estimated at 1:1,000,000 to 1:3,000,000 live births.
## Clinical Description
Schimke immunoosseous dysplasia (SIOD) is characterized by a constellation of clinical findings that affect a variety of organ systems. Nearly all affected individuals have disproportionate short stature, spondyloepiphyseal dysplasia causing hip disease, nephrotic syndrome that progresses to end-stage renal disease (ESRD), hyperpigmented macules, and immunodeficiency (primarily cellular immunodeficiency). Central nervous system vasculopathy (migraines, transient ischemic attacks, strokes), thyroid dysfunction, and cytopenias are also common. Secondary complications include hypertension, anemia, elevated lipids, recurrent infections, and osteopenia. Although not defining features of SIOD, bone marrow failure and lymphoproliferative disease have been reported [
Frequency of Physical, Radiographic, and Laboratory Features in Individuals with Schimke Immunoosseous Dysplasia Confirmed on Molecular Testing
ALL = acute lymphoblastic leukemia; FSGS = focal segmental glomerulosclerosis; IUGR = intrauterine growth restriction; TIAs = transient ischemic attacks
Short stature is not a result of renal failure. Comparison of the anthropometric measurements of persons with SIOD to persons with non-SIOD chronic kidney disease found that in nearly all parameters, persons with SIOD differed significantly from those with non-SIOD chronic renal disease. The most marked difference is that in non-SIOD chronic kidney disease, the median leg length is significantly more reduced than trunk length, while in persons with SIOD, the reduction in trunk length was significantly more than that of leg length. Therefore, a sitting height / leg length ratio of lower than 0.83 is suggestive of SIOD in persons with chronic kidney disease [
Hypoplastic pelvis and epiphyseal dysplasia leads to degenerative hip disease and chronic joint pain. Surgical intervention may be necessary, and treatment of hematopoietic and renal anomalies has not been shown to alter bony disease. The shoulder and other large joints are relatively spared.
Less frequent skeletal findings include a widened sella turcica and osteopenia. Individuals with SIOD and osteopenia are at risk for fractures. Systemic corticosteroids should be used with caution.
Neutropenia is also reported in 38% of individuals with SIOD and is likely a reflection of relative hypoplasia of the neutrophil lineage in the bone marrow [
Immunodeficiency increases the risk of opportunistic infections such as
In one affected individual with thrombocytopenia, the autoimmune features resolved spontaneously; in one they resolved after steroid and intravenous immunoglobulin treatments, and in one they cleared after splenectomy. One individual who developed immune thrombocytopenia two years after renal transplantation was not responsive to intravenous immunoglobulin or systemic corticosteroids and required plasmapheresis and thrombopoietin-receptor agonist therapy [
Anemia does not often respond to supplementation with erythropoietin or renal transplantation. However, it is possible that erythropoietin has a protective effect on the endothelia. A few individuals have been transfusion dependent due to anemia or thrombocytopenia. The individual with Evans syndrome was resistant to treatment with steroids, cyclosporin A, and rituximab [
A few individuals with SIOD have enteropathy. In most of these individuals, the enteropathy results from infection (e.g.,
The cause of the severe migraine-like headaches is unknown. Two case reports describe individuals presenting with severe headaches progressing to hemiplegia, aphasia, and seizures in whom brain imaging demonstrated reversible vasoconstriction and diminished cerebral perfusion [
Half of individuals with SIOD have symptoms suggestive of atherosclerosis (e.g., hypertension, cerebral ischemia, renal occlusive disease). Vascular changes observed on postmortem tissue from three individuals included focal intimal lipid deposition, focal myointimal proliferation, macrophage invasion, foam cells, fibrous transformation, and calcium deposits [
Most affected individuals develop other symptoms within one to five years of the diagnosis of growth deficiency. Those with severe symptoms usually die within four to eight years. The mean age of death is 11 years. Causes of death include infection (23%), stroke (13%), pulmonary hypertension and congestive heart failure (13%), renal failure (11%), complications of organ transplantation (9%), lymphoproliferative disease (4%), gastrointestinal complications (4%), respiratory failure (4%), bone marrow failure (2%), non-Hodgkin lymphoma (2%), pancreatitis (2%), and other causes not reported (13%).
Among those who have survived beyond puberty, it is unknown if any individuals with SIOD have reproduced. Women develop menses, although the menstrual cycle is usually irregular. Men develop secondary sexual characteristics, but histopathologic examination of the testes has identified azoospermia [
## Genotype-Phenotype Correlations
The early-onset, more severe phenotype has been associated with truncating
## Nomenclature
In the 2023 revision of the Nosology of Genetic Skeletal Disorders [
## Prevalence
The prevalence is unknown. The incidence is estimated at 1:1,000,000 to 1:3,000,000 live births.
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The differential diagnosis of Schimke immunoosseous dysplasia (SIOD) depends on the presenting features in the individual.
The co-occurrence of disproportionate short stature with spondyloepiphyseal dysplasia, progressive nephropathy, and T cell deficiency is unique to SIOD.
Differential Diagnosis of Schimke Immunoosseous Dysplasia: Hereditary Osteochondrodysplasias Associated with Nephrotic Syndrome
AD = autosomal dominant; AR = autosomal recessive; FSGS = focal segmental glomerulosclerosis; MOI = mode of inheritance; SIOD = Schimke immunoosseous dysplasia
Differential Diagnosis of Schimke Immunoosseous Dysplasia: Hereditary Osteochondrodysplasias Associated with Immune Defects
AR = autosomal recessive; DD = developmental delay; ID = intellectual disability; MOI = mode of inheritance; SED = spondyloepiphyseal dysplasia; SIOD = Schimke immunoosseous dysplasia
## Management
To establish the extent of disease and needs in an individual diagnosed with Schimke immunoosseous dysplasia (SIOD), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Schimke Immunoosseous Dysplasia
Orthopedic eval for symptoms of joint pain or evidence of scoliosis or kyphosis
Assessment for osteopenia at diagnosis or w/in 1 yr of diagnosis
Eval of renal function by measurement of serum concentrations of creatinine & urea, protein excretion in urine, & creatinine clearance
Referral to nephrologist for eval
Detailed history for headaches &/or neurologic abnormalities
Blood pressure
Consider brain MRI w/vessel imaging & perfusion studies (arterial spin labeling).
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; SIOD = Schimke immunoosseous dysplasia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Treatment of Manifestations in Individuals with Schimke Immunoosseous Dysplasia
Pain mgmt as needed
Hip replacement as indicated
Persons w/SIOD & osteopenia are at risk for fractures.
Use systemic corticosteroids w/caution.
Renal transplantation
Consider combined renal & HSCT in persons w/declining renal & immune function prior to onset of end-stage disease.
Neither nephropathy nor arteriosclerosis recurs in the graft.
Mild immunosuppressive therapy (immunosuppressive monotherapy), appears to improve outcome after renal transplant.
Performing HSCT prior to renal transplantation from same donor may allow for rapid weaning of immunosuppressive therapy.
Acyclovir for recurrent herpetic infections &/or shingles; consider prophylactic acyclovir.
Imiquimod & cidofovir for severe disseminated cutaneous papilloma virus infections
Vaccine protocol for other T cell immunodeficiencies (i.e., only inactivated vaccines w/avoidance of all live-attenuated vaccines) in those w/T cell immunodeficiency
Consider prophylaxis (trimethoprim/sulfamethoxazole or atovaquone) against
Using myeloablative conditioning, 1 person was successfully treated by HSCT,
3 children who underwent HSCT after ↓-intensity conditioning did well w/minimal post-transplant toxicity or graft-versus-host disease.
Immunosuppressive therapy (steroids, cyclophosphamide, or IVIG)
Thrombopoietin-receptor agonists
Platelet transfusions as needed
Splenectomy may be considered if recommended by hematologist.
Transfusions as needed
Anemia is often refractory to erythropoietin, but it can still be used.
Consider eval for bone marrow failure.
Agents that improve blood flow or ↓ coagulability (pentoxifylline, acetylsalicylic acid, dipyridamole, warfarin, heparin) may provide temporary improvement.
Blood pressure control
ACE inhibitors have also been used w/variable results.
To date, no curative or effective long-term therapies have been identified.
If RVCS is identified, consider use of calcium channel blockers w/neurologist consultation.
Treatments per oncologist
Blinatumomab was used in 1 person w/ALL.
Risk from genotoxic agents is present but no cancer therapeutics need to be avoided.
For HSCT, the authors have used ↓-intensity conditioning considering ↑ risk of sensitivity to genotoxic agents & telomere shortening that has been identified in several persons.
ALL = acute lymphoblastic leukemia; HSCT = hematopoietic stem cell transplantation; RVCS = reversible cerebral vasoconstriction syndrome; SIOD = Schimke immunoosseous dysplasia
Authors, unpublished data
Recommended Surveillance for Individuals with Schimke Immunoosseous Dysplasia
Persons w/SIOD usually have normal growth hormone studies.
No affected person treated w/growth hormone supplementation has responded w/improved growth.
Assessment of scoliosis &/or kyphosis & joint pain (degenerative hip disease)
Assessment for osteopenia w/DXA scan
Eval of renal function by measurement of serum concentrations of creatinine & urea, protein excretion in urine, & creatinine clearance
Serum calcium, phosphorus, alkaline phosphatase, vitamin D, parathyroid hormone
Complete blood count w/differential
Complete metabolic panel
T & B cell flow cytometry
Abdominal ultrasound
Clinical eval for lymphadenopathy
DXA = dual-energy x-ray absorptiometry
Avoid the following:
Note: Cells from individuals with SIOD and model organisms are hypersensitive to DNA-damaging agents [
It is appropriate to evaluate (see
See
Search
Studies of mitochondrial function and nitrous oxide production have not detected any impairment; therefore, empiric treatments addressing such etiologies would be expected to have little effect [
• Orthopedic eval for symptoms of joint pain or evidence of scoliosis or kyphosis
• Assessment for osteopenia at diagnosis or w/in 1 yr of diagnosis
• Eval of renal function by measurement of serum concentrations of creatinine & urea, protein excretion in urine, & creatinine clearance
• Referral to nephrologist for eval
• Detailed history for headaches &/or neurologic abnormalities
• Blood pressure
• Consider brain MRI w/vessel imaging & perfusion studies (arterial spin labeling).
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Pain mgmt as needed
• Hip replacement as indicated
• Persons w/SIOD & osteopenia are at risk for fractures.
• Use systemic corticosteroids w/caution.
• Renal transplantation
• Consider combined renal & HSCT in persons w/declining renal & immune function prior to onset of end-stage disease.
• Neither nephropathy nor arteriosclerosis recurs in the graft.
• Mild immunosuppressive therapy (immunosuppressive monotherapy), appears to improve outcome after renal transplant.
• Performing HSCT prior to renal transplantation from same donor may allow for rapid weaning of immunosuppressive therapy.
• Acyclovir for recurrent herpetic infections &/or shingles; consider prophylactic acyclovir.
• Imiquimod & cidofovir for severe disseminated cutaneous papilloma virus infections
• Vaccine protocol for other T cell immunodeficiencies (i.e., only inactivated vaccines w/avoidance of all live-attenuated vaccines) in those w/T cell immunodeficiency
• Consider prophylaxis (trimethoprim/sulfamethoxazole or atovaquone) against
• Using myeloablative conditioning, 1 person was successfully treated by HSCT,
• 3 children who underwent HSCT after ↓-intensity conditioning did well w/minimal post-transplant toxicity or graft-versus-host disease.
• Immunosuppressive therapy (steroids, cyclophosphamide, or IVIG)
• Thrombopoietin-receptor agonists
• Platelet transfusions as needed
• Splenectomy may be considered if recommended by hematologist.
• Transfusions as needed
• Anemia is often refractory to erythropoietin, but it can still be used.
• Consider eval for bone marrow failure.
• Agents that improve blood flow or ↓ coagulability (pentoxifylline, acetylsalicylic acid, dipyridamole, warfarin, heparin) may provide temporary improvement.
• Blood pressure control
• ACE inhibitors have also been used w/variable results.
• To date, no curative or effective long-term therapies have been identified.
• If RVCS is identified, consider use of calcium channel blockers w/neurologist consultation.
• Treatments per oncologist
• Blinatumomab was used in 1 person w/ALL.
• Risk from genotoxic agents is present but no cancer therapeutics need to be avoided.
• For HSCT, the authors have used ↓-intensity conditioning considering ↑ risk of sensitivity to genotoxic agents & telomere shortening that has been identified in several persons.
• Persons w/SIOD usually have normal growth hormone studies.
• No affected person treated w/growth hormone supplementation has responded w/improved growth.
• Assessment of scoliosis &/or kyphosis & joint pain (degenerative hip disease)
• Assessment for osteopenia w/DXA scan
• Eval of renal function by measurement of serum concentrations of creatinine & urea, protein excretion in urine, & creatinine clearance
• Serum calcium, phosphorus, alkaline phosphatase, vitamin D, parathyroid hormone
• Complete blood count w/differential
• Complete metabolic panel
• T & B cell flow cytometry
• Abdominal ultrasound
• Clinical eval for lymphadenopathy
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with Schimke immunoosseous dysplasia (SIOD), the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with Schimke Immunoosseous Dysplasia
Orthopedic eval for symptoms of joint pain or evidence of scoliosis or kyphosis
Assessment for osteopenia at diagnosis or w/in 1 yr of diagnosis
Eval of renal function by measurement of serum concentrations of creatinine & urea, protein excretion in urine, & creatinine clearance
Referral to nephrologist for eval
Detailed history for headaches &/or neurologic abnormalities
Blood pressure
Consider brain MRI w/vessel imaging & perfusion studies (arterial spin labeling).
Community or
Social work involvement for parental support;
Home nursing referral.
MOI = mode of inheritance; SIOD = Schimke immunoosseous dysplasia
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Orthopedic eval for symptoms of joint pain or evidence of scoliosis or kyphosis
• Assessment for osteopenia at diagnosis or w/in 1 yr of diagnosis
• Eval of renal function by measurement of serum concentrations of creatinine & urea, protein excretion in urine, & creatinine clearance
• Referral to nephrologist for eval
• Detailed history for headaches &/or neurologic abnormalities
• Blood pressure
• Consider brain MRI w/vessel imaging & perfusion studies (arterial spin labeling).
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Treatment of Manifestations in Individuals with Schimke Immunoosseous Dysplasia
Pain mgmt as needed
Hip replacement as indicated
Persons w/SIOD & osteopenia are at risk for fractures.
Use systemic corticosteroids w/caution.
Renal transplantation
Consider combined renal & HSCT in persons w/declining renal & immune function prior to onset of end-stage disease.
Neither nephropathy nor arteriosclerosis recurs in the graft.
Mild immunosuppressive therapy (immunosuppressive monotherapy), appears to improve outcome after renal transplant.
Performing HSCT prior to renal transplantation from same donor may allow for rapid weaning of immunosuppressive therapy.
Acyclovir for recurrent herpetic infections &/or shingles; consider prophylactic acyclovir.
Imiquimod & cidofovir for severe disseminated cutaneous papilloma virus infections
Vaccine protocol for other T cell immunodeficiencies (i.e., only inactivated vaccines w/avoidance of all live-attenuated vaccines) in those w/T cell immunodeficiency
Consider prophylaxis (trimethoprim/sulfamethoxazole or atovaquone) against
Using myeloablative conditioning, 1 person was successfully treated by HSCT,
3 children who underwent HSCT after ↓-intensity conditioning did well w/minimal post-transplant toxicity or graft-versus-host disease.
Immunosuppressive therapy (steroids, cyclophosphamide, or IVIG)
Thrombopoietin-receptor agonists
Platelet transfusions as needed
Splenectomy may be considered if recommended by hematologist.
Transfusions as needed
Anemia is often refractory to erythropoietin, but it can still be used.
Consider eval for bone marrow failure.
Agents that improve blood flow or ↓ coagulability (pentoxifylline, acetylsalicylic acid, dipyridamole, warfarin, heparin) may provide temporary improvement.
Blood pressure control
ACE inhibitors have also been used w/variable results.
To date, no curative or effective long-term therapies have been identified.
If RVCS is identified, consider use of calcium channel blockers w/neurologist consultation.
Treatments per oncologist
Blinatumomab was used in 1 person w/ALL.
Risk from genotoxic agents is present but no cancer therapeutics need to be avoided.
For HSCT, the authors have used ↓-intensity conditioning considering ↑ risk of sensitivity to genotoxic agents & telomere shortening that has been identified in several persons.
ALL = acute lymphoblastic leukemia; HSCT = hematopoietic stem cell transplantation; RVCS = reversible cerebral vasoconstriction syndrome; SIOD = Schimke immunoosseous dysplasia
Authors, unpublished data
• Pain mgmt as needed
• Hip replacement as indicated
• Persons w/SIOD & osteopenia are at risk for fractures.
• Use systemic corticosteroids w/caution.
• Renal transplantation
• Consider combined renal & HSCT in persons w/declining renal & immune function prior to onset of end-stage disease.
• Neither nephropathy nor arteriosclerosis recurs in the graft.
• Mild immunosuppressive therapy (immunosuppressive monotherapy), appears to improve outcome after renal transplant.
• Performing HSCT prior to renal transplantation from same donor may allow for rapid weaning of immunosuppressive therapy.
• Acyclovir for recurrent herpetic infections &/or shingles; consider prophylactic acyclovir.
• Imiquimod & cidofovir for severe disseminated cutaneous papilloma virus infections
• Vaccine protocol for other T cell immunodeficiencies (i.e., only inactivated vaccines w/avoidance of all live-attenuated vaccines) in those w/T cell immunodeficiency
• Consider prophylaxis (trimethoprim/sulfamethoxazole or atovaquone) against
• Using myeloablative conditioning, 1 person was successfully treated by HSCT,
• 3 children who underwent HSCT after ↓-intensity conditioning did well w/minimal post-transplant toxicity or graft-versus-host disease.
• Immunosuppressive therapy (steroids, cyclophosphamide, or IVIG)
• Thrombopoietin-receptor agonists
• Platelet transfusions as needed
• Splenectomy may be considered if recommended by hematologist.
• Transfusions as needed
• Anemia is often refractory to erythropoietin, but it can still be used.
• Consider eval for bone marrow failure.
• Agents that improve blood flow or ↓ coagulability (pentoxifylline, acetylsalicylic acid, dipyridamole, warfarin, heparin) may provide temporary improvement.
• Blood pressure control
• ACE inhibitors have also been used w/variable results.
• To date, no curative or effective long-term therapies have been identified.
• If RVCS is identified, consider use of calcium channel blockers w/neurologist consultation.
• Treatments per oncologist
• Blinatumomab was used in 1 person w/ALL.
• Risk from genotoxic agents is present but no cancer therapeutics need to be avoided.
• For HSCT, the authors have used ↓-intensity conditioning considering ↑ risk of sensitivity to genotoxic agents & telomere shortening that has been identified in several persons.
## Surveillance
Recommended Surveillance for Individuals with Schimke Immunoosseous Dysplasia
Persons w/SIOD usually have normal growth hormone studies.
No affected person treated w/growth hormone supplementation has responded w/improved growth.
Assessment of scoliosis &/or kyphosis & joint pain (degenerative hip disease)
Assessment for osteopenia w/DXA scan
Eval of renal function by measurement of serum concentrations of creatinine & urea, protein excretion in urine, & creatinine clearance
Serum calcium, phosphorus, alkaline phosphatase, vitamin D, parathyroid hormone
Complete blood count w/differential
Complete metabolic panel
T & B cell flow cytometry
Abdominal ultrasound
Clinical eval for lymphadenopathy
DXA = dual-energy x-ray absorptiometry
• Persons w/SIOD usually have normal growth hormone studies.
• No affected person treated w/growth hormone supplementation has responded w/improved growth.
• Assessment of scoliosis &/or kyphosis & joint pain (degenerative hip disease)
• Assessment for osteopenia w/DXA scan
• Eval of renal function by measurement of serum concentrations of creatinine & urea, protein excretion in urine, & creatinine clearance
• Serum calcium, phosphorus, alkaline phosphatase, vitamin D, parathyroid hormone
• Complete blood count w/differential
• Complete metabolic panel
• T & B cell flow cytometry
• Abdominal ultrasound
• Clinical eval for lymphadenopathy
## Agents/Circumstances to Avoid
Avoid the following:
Note: Cells from individuals with SIOD and model organisms are hypersensitive to DNA-damaging agents [
## Evaluation of Relatives at Risk
It is appropriate to evaluate (see
See
## Therapies Under Investigation
Search
## Other
Studies of mitochondrial function and nitrous oxide production have not detected any impairment; therefore, empiric treatments addressing such etiologies would be expected to have little effect [
## Genetic Counseling
Schimke immunoosseous dysplasia (SIOD) 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 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 with 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 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 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
• 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 with 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 carriers or are at risk of being carriers.
## Mode of Inheritance
Schimke immunoosseous dysplasia (SIOD) 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 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 with biallelic
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
• 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 with 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 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
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
Schimke Immunoosseous Dysplasia: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for Schimke Immunoosseous Dysplasia (
## Molecular Pathogenesis
## Chapter Notes
The
The authors gratefully acknowledge the Kruzn' for a Kure Foundation, Muscle Shoals, Alabama, and the Little Giants Foundation, Omaha, Nebraska, for their support of research on the mechanisms of disease and treatment of SIOD.
Alireza Baradaran-Heravi, MD; University of British Columbia (2011-2016)Cornelius F Boerkoel, MD, PhD (2002-present) Leah I Elizondo, BSc; Baylor College of Medicine (2006-2011)David B Lewis, MD (2016-present)Elizabeth Lippner, MD (2022-present)Shu Lou, MD; Baylor College of Medicine (2002-2006)Thomas Lücke, MD, PhD (2006-present)Marie Morimoto, BSc; University of British Columbia (2011-2022)Carlos Salgado, MD (2022-present)
30 March 2023 (sw) Revision: "
14 April 2022 (sw) Comprehensive update posted live
11 February 2016 (sw) Comprehensive update posted live
22 August 2013 (me) Comprehensive update posted live
29 December 2011 (cd) Revision: prenatal testing available clinically
22 March 2011 (me) Comprehensive update posted live
7 December 2006 (me) Comprehensive update posted live
30 August 2004 (me) Comprehensive update posted live
1 October 2002 (me) Review posted live
18 June 2002 (cfb) Original submission
• 30 March 2023 (sw) Revision: "
• 14 April 2022 (sw) Comprehensive update posted live
• 11 February 2016 (sw) Comprehensive update posted live
• 22 August 2013 (me) Comprehensive update posted live
• 29 December 2011 (cd) Revision: prenatal testing available clinically
• 22 March 2011 (me) Comprehensive update posted live
• 7 December 2006 (me) Comprehensive update posted live
• 30 August 2004 (me) Comprehensive update posted live
• 1 October 2002 (me) Review posted live
• 18 June 2002 (cfb) Original submission
## Author Notes
The
## Acknowledgments
The authors gratefully acknowledge the Kruzn' for a Kure Foundation, Muscle Shoals, Alabama, and the Little Giants Foundation, Omaha, Nebraska, for their support of research on the mechanisms of disease and treatment of SIOD.
## Author History
Alireza Baradaran-Heravi, MD; University of British Columbia (2011-2016)Cornelius F Boerkoel, MD, PhD (2002-present) Leah I Elizondo, BSc; Baylor College of Medicine (2006-2011)David B Lewis, MD (2016-present)Elizabeth Lippner, MD (2022-present)Shu Lou, MD; Baylor College of Medicine (2002-2006)Thomas Lücke, MD, PhD (2006-present)Marie Morimoto, BSc; University of British Columbia (2011-2022)Carlos Salgado, MD (2022-present)
## Revision History
30 March 2023 (sw) Revision: "
14 April 2022 (sw) Comprehensive update posted live
11 February 2016 (sw) Comprehensive update posted live
22 August 2013 (me) Comprehensive update posted live
29 December 2011 (cd) Revision: prenatal testing available clinically
22 March 2011 (me) Comprehensive update posted live
7 December 2006 (me) Comprehensive update posted live
30 August 2004 (me) Comprehensive update posted live
1 October 2002 (me) Review posted live
18 June 2002 (cfb) Original submission
• 30 March 2023 (sw) Revision: "
• 14 April 2022 (sw) Comprehensive update posted live
• 11 February 2016 (sw) Comprehensive update posted live
• 22 August 2013 (me) Comprehensive update posted live
• 29 December 2011 (cd) Revision: prenatal testing available clinically
• 22 March 2011 (me) Comprehensive update posted live
• 7 December 2006 (me) Comprehensive update posted live
• 30 August 2004 (me) Comprehensive update posted live
• 1 October 2002 (me) Review posted live
• 18 June 2002 (cfb) Original submission
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"T Lücke, D Tsikas, NK Kanzelmeyer, CF Boerkoel, JM Clewing, B Vaske, JH Ehrich, AM Das. Vaso-occlusion in Schimke-immuno-osseous dysplasia: is the NO pathway involved?. Horm Metab Res. 2006b;38:678-82",
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] |
1/10/2002
|
14/4/2022
|
30/3/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
slc12a5-e
|
slc12a5-e
|
[
"Early-Infantile Epileptic Encephalopathy 34 (EIEE34)",
"SLC12A5-EIMFS",
"Early-Infantile Epileptic Encephalopathy 34 (EIEE34)",
"SLC12A5-EIMFS",
"Solute carrier family 12 member 5",
"SLC12A5",
"SLC12A5-Related Epilepsy of Infancy with Migrating Focal Seizures"
] |
Amy McTague, Manju A Kurian
|
Summary The diagnosis of
|
## Diagnosis
Since 2010 a description of the characteristic symptoms and findings of epilepsy of infancy with migrating focal seizures (EIMFS) has been included in the classification of epilepsy syndromes by the International League Against Epilepsy. The diagnosis of
Seizure onset before age six months
Developmental delay or developmental regression with seizure onset
At onset in most children: focal motor seizures that also frequently involve head and eye deviation
Multifocal seizures proving intractable to conventional anti-seizure medication
Interictal multifocal spikes
In a single seizure, ictal-independent, unilateral, and migrating involvement of varying cortical areas with clinical-EEG correlation
Initial EEG may be normal shortly after seizure onset, but epileptiform abnormalities are usually present within one month after first presentation.
Migrating ictal foci may not be seen for several months after presentation.
The diagnosis of
Note: 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 [
Due to the genetic heterogeneity of early-onset epilepsy, use of either a multigene epilepsy panel or comprehensive genomic testing (exome or genome sequencing) is the preferred initial approach [
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
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.
• Seizure onset before age six months
• Developmental delay or developmental regression with seizure onset
• At onset in most children: focal motor seizures that also frequently involve head and eye deviation
• Multifocal seizures proving intractable to conventional anti-seizure medication
• Interictal multifocal spikes
• In a single seizure, ictal-independent, unilateral, and migrating involvement of varying cortical areas with clinical-EEG correlation
• Initial EEG may be normal shortly after seizure onset, but epileptiform abnormalities are usually present within one month after first presentation.
• Migrating ictal foci may not be seen for several months after presentation.
## Suggestive Findings
Seizure onset before age six months
Developmental delay or developmental regression with seizure onset
At onset in most children: focal motor seizures that also frequently involve head and eye deviation
Multifocal seizures proving intractable to conventional anti-seizure medication
Interictal multifocal spikes
In a single seizure, ictal-independent, unilateral, and migrating involvement of varying cortical areas with clinical-EEG correlation
Initial EEG may be normal shortly after seizure onset, but epileptiform abnormalities are usually present within one month after first presentation.
Migrating ictal foci may not be seen for several months after presentation.
• Seizure onset before age six months
• Developmental delay or developmental regression with seizure onset
• At onset in most children: focal motor seizures that also frequently involve head and eye deviation
• Multifocal seizures proving intractable to conventional anti-seizure medication
• Interictal multifocal spikes
• In a single seizure, ictal-independent, unilateral, and migrating involvement of varying cortical areas with clinical-EEG correlation
• Initial EEG may be normal shortly after seizure onset, but epileptiform abnormalities are usually present within one month after first presentation.
• Migrating ictal foci may not be seen for several months after presentation.
## Establishing the Diagnosis
The diagnosis of
Note: 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 [
Due to the genetic heterogeneity of early-onset epilepsy, use of either a multigene epilepsy panel or comprehensive genomic testing (exome or genome sequencing) is the preferred initial approach [
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
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.
## Testing Options to Consider
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
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.
## Clinical Characteristics
An
Seizures are characterized by apnea and focal clonic and tonic seizures with prominent head and eye deviation.
Subtle seizures with behavioral arrest, apnea, and cyanosis or generalized tonic or tonic-clonic seizures are also seen at onset. All children eventually develop focal motor seizures.
Clinically migrating seizures (which affect differing or alternating body parts) are seen in approximately 50% of children.
Autonomic features such as facial flushing, salivation, apnea, and cyanosis are common.
A
A
Severe developmental delay with no progression of skills was seen in six of the nine. In contrast, three of the nine had notable neurodevelopmental progress, either regaining lost skills or acquiring new skills during periods of good seizure control. Two achieved independent ambulation (at ages 2.9 and 4 years) and one spoke single words at age six years.
Postnatal (i.e., acquired) microcephaly and hypotonia was noted in eight of the nine children.
Of the four for whom feeding information was available, two had feeding difficulties; none had growth failure.
One had unilateral pyramidal signs.
Hyperkinetic movement disorders, seen in other causes of EIMFS including
Interictal EEG features included background slowing and multifocal abnormalities.
Delayed myelination
Thin corpus callosum
Cerebral atrophy, either predominantly frontal or global
Increased signal in white matter on diffusion-weighted imaging
The following focal abnormalities have been reported in
Unilateral hippocampal sclerosis noted at age four years (n=1) [
Cerebellar atrophy and bilateral hippocampal atrophy with increased signal on FLAIR imaging at ages ten and 20 years in the oldest individual imaged to date [
Magnetic resonance spectroscopy (MRS) in a child age eight months demonstrated reduction in the relative N-acetyl aspartate peak, consistent with delayed maturation of myelin [
No clear correlation exists between biallelic
EIMFS is a type of early-infantile epileptic encephalopathy (EIEE); OMIM classifies
Terms previously used for EIMFS include the following:
Migrating partial seizures of infancy (MPSI)
Malignant migrating partial seizures of infancy (MMPSI)
Migrating focal seizures of infancy (MFSI)
To date, nine probands with
The clinical syndrome epilepsy of infancy with migrating focal seizures (EIMFS) of all causes is itself rare. Prevalence of EIMFS was estimated at 0.11 per 100,000 children in the UK (using data that were not from a population-based epidemiologic study) [
• An
• Seizures are characterized by apnea and focal clonic and tonic seizures with prominent head and eye deviation.
• Subtle seizures with behavioral arrest, apnea, and cyanosis or generalized tonic or tonic-clonic seizures are also seen at onset. All children eventually develop focal motor seizures.
• Clinically migrating seizures (which affect differing or alternating body parts) are seen in approximately 50% of children.
• Autonomic features such as facial flushing, salivation, apnea, and cyanosis are common.
• Seizures are characterized by apnea and focal clonic and tonic seizures with prominent head and eye deviation.
• Subtle seizures with behavioral arrest, apnea, and cyanosis or generalized tonic or tonic-clonic seizures are also seen at onset. All children eventually develop focal motor seizures.
• Clinically migrating seizures (which affect differing or alternating body parts) are seen in approximately 50% of children.
• Autonomic features such as facial flushing, salivation, apnea, and cyanosis are common.
• A
• A
• Seizures are characterized by apnea and focal clonic and tonic seizures with prominent head and eye deviation.
• Subtle seizures with behavioral arrest, apnea, and cyanosis or generalized tonic or tonic-clonic seizures are also seen at onset. All children eventually develop focal motor seizures.
• Clinically migrating seizures (which affect differing or alternating body parts) are seen in approximately 50% of children.
• Autonomic features such as facial flushing, salivation, apnea, and cyanosis are common.
• Postnatal (i.e., acquired) microcephaly and hypotonia was noted in eight of the nine children.
• Of the four for whom feeding information was available, two had feeding difficulties; none had growth failure.
• One had unilateral pyramidal signs.
• Hyperkinetic movement disorders, seen in other causes of EIMFS including
• Delayed myelination
• Thin corpus callosum
• Cerebral atrophy, either predominantly frontal or global
• Increased signal in white matter on diffusion-weighted imaging
• Unilateral hippocampal sclerosis noted at age four years (n=1) [
• Cerebellar atrophy and bilateral hippocampal atrophy with increased signal on FLAIR imaging at ages ten and 20 years in the oldest individual imaged to date [
• Migrating partial seizures of infancy (MPSI)
• Malignant migrating partial seizures of infancy (MMPSI)
• Migrating focal seizures of infancy (MFSI)
## Clinical Description
An
Seizures are characterized by apnea and focal clonic and tonic seizures with prominent head and eye deviation.
Subtle seizures with behavioral arrest, apnea, and cyanosis or generalized tonic or tonic-clonic seizures are also seen at onset. All children eventually develop focal motor seizures.
Clinically migrating seizures (which affect differing or alternating body parts) are seen in approximately 50% of children.
Autonomic features such as facial flushing, salivation, apnea, and cyanosis are common.
A
A
Severe developmental delay with no progression of skills was seen in six of the nine. In contrast, three of the nine had notable neurodevelopmental progress, either regaining lost skills or acquiring new skills during periods of good seizure control. Two achieved independent ambulation (at ages 2.9 and 4 years) and one spoke single words at age six years.
Postnatal (i.e., acquired) microcephaly and hypotonia was noted in eight of the nine children.
Of the four for whom feeding information was available, two had feeding difficulties; none had growth failure.
One had unilateral pyramidal signs.
Hyperkinetic movement disorders, seen in other causes of EIMFS including
Interictal EEG features included background slowing and multifocal abnormalities.
Delayed myelination
Thin corpus callosum
Cerebral atrophy, either predominantly frontal or global
Increased signal in white matter on diffusion-weighted imaging
The following focal abnormalities have been reported in
Unilateral hippocampal sclerosis noted at age four years (n=1) [
Cerebellar atrophy and bilateral hippocampal atrophy with increased signal on FLAIR imaging at ages ten and 20 years in the oldest individual imaged to date [
Magnetic resonance spectroscopy (MRS) in a child age eight months demonstrated reduction in the relative N-acetyl aspartate peak, consistent with delayed maturation of myelin [
• An
• Seizures are characterized by apnea and focal clonic and tonic seizures with prominent head and eye deviation.
• Subtle seizures with behavioral arrest, apnea, and cyanosis or generalized tonic or tonic-clonic seizures are also seen at onset. All children eventually develop focal motor seizures.
• Clinically migrating seizures (which affect differing or alternating body parts) are seen in approximately 50% of children.
• Autonomic features such as facial flushing, salivation, apnea, and cyanosis are common.
• Seizures are characterized by apnea and focal clonic and tonic seizures with prominent head and eye deviation.
• Subtle seizures with behavioral arrest, apnea, and cyanosis or generalized tonic or tonic-clonic seizures are also seen at onset. All children eventually develop focal motor seizures.
• Clinically migrating seizures (which affect differing or alternating body parts) are seen in approximately 50% of children.
• Autonomic features such as facial flushing, salivation, apnea, and cyanosis are common.
• A
• A
• Seizures are characterized by apnea and focal clonic and tonic seizures with prominent head and eye deviation.
• Subtle seizures with behavioral arrest, apnea, and cyanosis or generalized tonic or tonic-clonic seizures are also seen at onset. All children eventually develop focal motor seizures.
• Clinically migrating seizures (which affect differing or alternating body parts) are seen in approximately 50% of children.
• Autonomic features such as facial flushing, salivation, apnea, and cyanosis are common.
• Postnatal (i.e., acquired) microcephaly and hypotonia was noted in eight of the nine children.
• Of the four for whom feeding information was available, two had feeding difficulties; none had growth failure.
• One had unilateral pyramidal signs.
• Hyperkinetic movement disorders, seen in other causes of EIMFS including
• Delayed myelination
• Thin corpus callosum
• Cerebral atrophy, either predominantly frontal or global
• Increased signal in white matter on diffusion-weighted imaging
• Unilateral hippocampal sclerosis noted at age four years (n=1) [
• Cerebellar atrophy and bilateral hippocampal atrophy with increased signal on FLAIR imaging at ages ten and 20 years in the oldest individual imaged to date [
## Genotype-Phenotype Correlations
No clear correlation exists between biallelic
## Nomenclature
EIMFS is a type of early-infantile epileptic encephalopathy (EIEE); OMIM classifies
Terms previously used for EIMFS include the following:
Migrating partial seizures of infancy (MPSI)
Malignant migrating partial seizures of infancy (MMPSI)
Migrating focal seizures of infancy (MFSI)
• Migrating partial seizures of infancy (MPSI)
• Malignant migrating partial seizures of infancy (MMPSI)
• Migrating focal seizures of infancy (MFSI)
## Prevalence
To date, nine probands with
The clinical syndrome epilepsy of infancy with migrating focal seizures (EIMFS) of all causes is itself rare. Prevalence of EIMFS was estimated at 0.11 per 100,000 children in the UK (using data that were not from a population-based epidemiologic study) [
## Genetically Related (Allelic) Disorders
Heterozygous (carrier) parents of a child with
## Differential Diagnosis
Since first described by
Other Disorders to Consider in the Differential Diagnosis of
Abnormalities: gastrointestinal problems, coagulopathy, dysmorphic facial features, spastic quadriparesis
Transferrin isoelectric focusing testing consistent w/CDG type I
On brain MRI: cerebellar atrophy in all; brain stem atrophy in 3/4
Note: Extensive metabolic investigation in EIMFS is usually unrevealing.
Adapted from "Supplementary Table 1: Genes Reported in Migrating Partial Seizures of Infancy (MPSI)" [
AD = autosomal dominant; AR = autosomal recessive; CDG = congenital disorder of glycosylation; EIEE = early-infantile epileptic encephalopathy; EIMFS = epilepsy of infancy with migrating focal seizures; MOI = mode of inheritance; XL = X-linked
Genes are in alphabetic order.
Typically
Autosomal recessive inheritance of EIMFS is often described in consanguineous families or families with more than one affected individual.
See
See
• Abnormalities: gastrointestinal problems, coagulopathy, dysmorphic facial features, spastic quadriparesis
• Transferrin isoelectric focusing testing consistent w/CDG type I
• On brain MRI: cerebellar atrophy in all; brain stem atrophy in 3/4
• Note: Extensive metabolic investigation in EIMFS is usually unrevealing.
## Management
To establish the extent of disease and needs in an individual diagnosed with
Recommended Evaluations Following Initial Diagnosis in Individuals with
PT = physical therapist
Periods free of seizures or with reduced seizure frequency have been achieved with a ketogenic diet or potassium bromides [
Seizure reduction has also been reported with:
Levetiracetam, rufinamide, stiripentol, and clonazepam [
Cannabinoids [
Epileptic apneas are reported to respond to acetazolamide [
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 of 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, 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.
Routine monitoring of:
Feeding, nutritional status, swallowing abilities, gastroesophageal reflux, risk of aspiration pneumonia / respiratory infection
Postural problems (resulting from such complications as scoliosis and hip abnormalities) with regular spine and hip x-rays
Effectiveness of seizure control
Development including motor skills, speech/language, and general cognitive and vocational skills
See
Search
• Levetiracetam, rufinamide, stiripentol, and clonazepam [
• Cannabinoids [
• 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 of 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).
• Feeding, nutritional status, swallowing abilities, gastroesophageal reflux, risk of aspiration pneumonia / respiratory infection
• Postural problems (resulting from such complications as scoliosis and hip abnormalities) with regular spine and hip x-rays
• Effectiveness of seizure control
• Development including motor skills, speech/language, and general cognitive and vocational skills
## 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
PT = physical therapist
## Treatment of Manifestations
Periods free of seizures or with reduced seizure frequency have been achieved with a ketogenic diet or potassium bromides [
Seizure reduction has also been reported with:
Levetiracetam, rufinamide, stiripentol, and clonazepam [
Cannabinoids [
Epileptic apneas are reported to respond to acetazolamide [
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 of 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, 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.
• Levetiracetam, rufinamide, stiripentol, and clonazepam [
• Cannabinoids [
• 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 of 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 of 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 of 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, 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
Routine monitoring of:
Feeding, nutritional status, swallowing abilities, gastroesophageal reflux, risk of aspiration pneumonia / respiratory infection
Postural problems (resulting from such complications as scoliosis and hip abnormalities) with regular spine and hip x-rays
Effectiveness of seizure control
Development including motor skills, speech/language, and general cognitive and vocational skills
• Feeding, nutritional status, swallowing abilities, gastroesophageal reflux, risk of aspiration pneumonia / respiratory infection
• Postural problems (resulting from such complications as scoliosis and hip abnormalities) with regular spine and hip x-rays
• Effectiveness of seizure control
• Development including motor skills, speech/language, and general cognitive and vocational skills
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
The parents of a child with
Heterozygous parents of a child with
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) of an EIMFS-related
Each child of an individual with
To date, individuals with biallelic
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 and 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 a child with
• Heterozygous parents of a child with
• 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) of an EIMFS-related
• Each child of an individual with
• To date, individuals with 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 parents of affected individuals and young adults who are carriers or are at risk of being carriers.
## Mode of Inheritance
## Risk to Family Members
The parents of a child with
Heterozygous parents of a child with
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) of an EIMFS-related
Each child of an individual with
To date, individuals with biallelic
• The parents of a child with
• Heterozygous parents of a child with
• 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) of an EIMFS-related
• Each child of an individual with
• To date, individuals with biallelic
## 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 and 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 parents of affected individuals and 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
United Kingdom
United Kingdom
Canada
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•
•
• Canada
•
•
• United Kingdom
•
•
• United Kingdom
•
•
• Canada
•
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## Molecular Genetics
SLC12A5-Related Epilepsy of Infancy with Migrating Focal Seizures: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SLC12A5-Related Epilepsy of Infancy with Migrating Focal Seizures (
KCC2 is the major extruder of chloride in neurons and is responsible for generating neuronal chloride gradients, which determine the magnitude and polarity of GABA-mediated currents. Thus, when GABA, which has an important role in neuronal inhibition, binds to the GABA-A receptor, the low intraneuronal chloride allows influx of chloride and subsequent hyperpolarization, contributing to neuronal inhibition. KCC2 has been implicated as the major factor in the developmental GABA
Selected
Variants listed in the table have been provided by the authors.
Shown in ( )s: variant designations as published on reference sequence position
KCC2 also plays a role at excitatory synapses and in dendritic spine formation [
The variants p.Arg952His and p.Arg1049Cys have also been studied for pathogenic effects. (See
The p.Arg952His variant was shown to have reduced cell surface expression and reduced chloride extrusion capacity compared to wild type KCC2 [
The p.Arg1049Cys variant was shown to have decreased chloride extrusion ability [
Both p.Arg952His and p.Arg1049Cys were also shown to have decreased phosphorylation at serine 940, a key site for the regulation of KCC2 function [
Complete knockout of
## Molecular Pathogenesis
KCC2 is the major extruder of chloride in neurons and is responsible for generating neuronal chloride gradients, which determine the magnitude and polarity of GABA-mediated currents. Thus, when GABA, which has an important role in neuronal inhibition, binds to the GABA-A receptor, the low intraneuronal chloride allows influx of chloride and subsequent hyperpolarization, contributing to neuronal inhibition. KCC2 has been implicated as the major factor in the developmental GABA
Selected
Variants listed in the table have been provided by the authors.
Shown in ( )s: variant designations as published on reference sequence position
KCC2 also plays a role at excitatory synapses and in dendritic spine formation [
The variants p.Arg952His and p.Arg1049Cys have also been studied for pathogenic effects. (See
The p.Arg952His variant was shown to have reduced cell surface expression and reduced chloride extrusion capacity compared to wild type KCC2 [
The p.Arg1049Cys variant was shown to have decreased chloride extrusion ability [
Both p.Arg952His and p.Arg1049Cys were also shown to have decreased phosphorylation at serine 940, a key site for the regulation of KCC2 function [
Complete knockout of
## Chapter Notes
Dr Amy McTague is a consultant pediatric neurologist and a NIHR Great Ormond Street BRC Catalyst Fellow who has recently completed a PhD investigating the molecular genetics of EIMFS in the Kurian group at the UCL Great Ormond Street Institute of Child Health.
Dr Manju Kurian is a NIHR Research Professor and group leader in the Developmental Neurosciences programme at the UCL Great Ormond Street Institute of Child Health and a consultant pediatric neurologist at Great Ormond Street Hospital.
14 February 2019 (bp) Review posted live
13 November 2017 (am) Original submission
• 14 February 2019 (bp) Review posted live
• 13 November 2017 (am) Original submission
## Author Notes
Dr Amy McTague is a consultant pediatric neurologist and a NIHR Great Ormond Street BRC Catalyst Fellow who has recently completed a PhD investigating the molecular genetics of EIMFS in the Kurian group at the UCL Great Ormond Street Institute of Child Health.
Dr Manju Kurian is a NIHR Research Professor and group leader in the Developmental Neurosciences programme at the UCL Great Ormond Street Institute of Child Health and a consultant pediatric neurologist at Great Ormond Street Hospital.
## Revision History
14 February 2019 (bp) Review posted live
13 November 2017 (am) Original submission
• 14 February 2019 (bp) Review posted live
• 13 November 2017 (am) Original submission
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] |
14/2/2019
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
slc19a1-ft-def
|
slc19a1-ft-def
|
[
"Reduced folate transporter",
"SLC19A1",
"SLC19A1-Related Folate Transport Deficiency"
] |
I David Goldman
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Birth weight and head circumference that are in the lower ranges of the typical growth chart for age and sex
Poor postnatal growth
Developmental delay, including gross motor (gait), speech/language, and cognitive skills
Seizures
Recurrent infections, particularly respiratory
Mucositis with oral lesions
Diarrhea
Anemia, typically megaloblastic, that may be accompanied by leukopenia and/or thrombocytopenia
Normal blood folate with low red blood cell folate
Note: Serum folate should be normal if intake and intestinal absorption are normal; however, red blood cell folate will be depressed in affected individuals.
Low cerebrospinal fluid (CSF) folate concentration
Note: Normal CSF folate concentrations are higher in infants and toddlers and decrease with age.
Elevated blood total homocysteine concentration
Hypoimmunoglobulinemia
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 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 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.
No large intragenic deletions/duplications have been reported to date in individuals with
• Birth weight and head circumference that are in the lower ranges of the typical growth chart for age and sex
• Poor postnatal growth
• Developmental delay, including gross motor (gait), speech/language, and cognitive skills
• Seizures
• Recurrent infections, particularly respiratory
• Mucositis with oral lesions
• Diarrhea
• Anemia, typically megaloblastic, that may be accompanied by leukopenia and/or thrombocytopenia
• Normal blood folate with low red blood cell folate
• Note: Serum folate should be normal if intake and intestinal absorption are normal; however, red blood cell folate will be depressed in affected individuals.
• Low cerebrospinal fluid (CSF) folate concentration
• Note: Normal CSF folate concentrations are higher in infants and toddlers and decrease with age.
• Elevated blood total homocysteine concentration
• Hypoimmunoglobulinemia
• For an introduction to multigene panels click
## Suggestive Findings
Birth weight and head circumference that are in the lower ranges of the typical growth chart for age and sex
Poor postnatal growth
Developmental delay, including gross motor (gait), speech/language, and cognitive skills
Seizures
Recurrent infections, particularly respiratory
Mucositis with oral lesions
Diarrhea
Anemia, typically megaloblastic, that may be accompanied by leukopenia and/or thrombocytopenia
Normal blood folate with low red blood cell folate
Note: Serum folate should be normal if intake and intestinal absorption are normal; however, red blood cell folate will be depressed in affected individuals.
Low cerebrospinal fluid (CSF) folate concentration
Note: Normal CSF folate concentrations are higher in infants and toddlers and decrease with age.
Elevated blood total homocysteine concentration
Hypoimmunoglobulinemia
• Birth weight and head circumference that are in the lower ranges of the typical growth chart for age and sex
• Poor postnatal growth
• Developmental delay, including gross motor (gait), speech/language, and cognitive skills
• Seizures
• Recurrent infections, particularly respiratory
• Mucositis with oral lesions
• Diarrhea
• Anemia, typically megaloblastic, that may be accompanied by leukopenia and/or thrombocytopenia
• Normal blood folate with low red blood cell folate
• Note: Serum folate should be normal if intake and intestinal absorption are normal; however, red blood cell folate will be depressed in affected individuals.
• Low cerebrospinal fluid (CSF) folate concentration
• Note: Normal CSF folate concentrations are higher in infants and toddlers and decrease with age.
• Elevated blood total homocysteine concentration
• Hypoimmunoglobulinemia
## 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 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 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.
No large intragenic deletions/duplications have been reported to date in individuals with
• 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 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.
No large intragenic deletions/duplications have been reported to date in individuals with
## Clinical Characteristics
To date, five individuals from three families have been identified with biallelic pathogenic variants in
Four of the five affected individuals had pathogenic variants predicted to cause a marked loss of RFC function. One affected individual, for whom the only manifestation was late-onset anemia, had a pathogenic variant predicted to cause only mild loss of protein function.
The prevalence of this condition is likely to be underestimated since pathogenic variants with only modest reduction in function may go undiagnosed unless there is secondary dietary folate deficiency and/or intestinal disease with folate malabsorption.
Note: Mice with total absence of RFC protein die in utero; unrecognized embryonic loss in humans is likely when there are biallelic pathogenic variants that result in complete loss of transport function [
## Clinical Description
To date, five individuals from three families have been identified with biallelic pathogenic variants in
Four of the five affected individuals had pathogenic variants predicted to cause a marked loss of RFC function. One affected individual, for whom the only manifestation was late-onset anemia, had a pathogenic variant predicted to cause only mild loss of protein function.
## Genotype-Phenotype Correlations
## Prevalence
The prevalence of this condition is likely to be underestimated since pathogenic variants with only modest reduction in function may go undiagnosed unless there is secondary dietary folate deficiency and/or intestinal disease with folate malabsorption.
Note: Mice with total absence of RFC protein die in utero; unrecognized embryonic loss in humans is likely when there are biallelic pathogenic variants that result in complete loss of transport function [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Infants with HFM are clinically asymptomatic at birth. Hematologic and immunologic/infectious signs appear within a few months; developmental and neurologic signs evolve later in the first year. In
In contrast to
Genetic Disorders in the Differential Diagnosis of
Very low blood & CSF folate concentrations
Anemia, pancytopenia, immune deficiency, mucositis, DD, & neurologic & cognitive defects
Very low CSF folate concentrations. Generally, normal blood folate concentrations & hemograms.
Neurologic & cognitive signs recognized by age 1-2 yrs, although milder signs likely appear earlier.
No response to folic acid
Corrects w/5-formylTHF or 5-methylTHF
Defect in 5-formylTHF metabolism
Treated w/5-methylTHF
Neurocognitive & motor impairment, DD w/seizures
Clinical phenotype correlates w/extent of residual enzyme activity
Megaloblastic anemia, DD, & cognitive & other neurologic deficits
Age of appearance ranges from infancy to adulthood depending on pathogenic variant
Serum folate normal
MTR & MTRR are enzymes required for methionine synthesis from homocysteine.
Responds to cobalamin.
Frequent infections w/opportunistic organisms (e.g.,
Secondary anemias & vitamin deficiencies may result in confusion w/folate transport deficiency disorders.
AR = autosomal recessive; CSF = cerebrospinal fluid; DD = developmental delay; FTD = folate transport deficiency; MOI = mode of inheritance; SCID = severe combined immunodeficiency; THF = tetrahydrofolate
Genes are ordered by relevance to the differential diagnosis of
• Infants with HFM are clinically asymptomatic at birth. Hematologic and immunologic/infectious signs appear within a few months; developmental and neurologic signs evolve later in the first year. In
• In contrast to
• Very low blood & CSF folate concentrations
• Anemia, pancytopenia, immune deficiency, mucositis, DD, & neurologic & cognitive defects
• Very low CSF folate concentrations. Generally, normal blood folate concentrations & hemograms.
• Neurologic & cognitive signs recognized by age 1-2 yrs, although milder signs likely appear earlier.
• No response to folic acid
• Corrects w/5-formylTHF or 5-methylTHF
• Defect in 5-formylTHF metabolism
• Treated w/5-methylTHF
• Neurocognitive & motor impairment, DD w/seizures
• Clinical phenotype correlates w/extent of residual enzyme activity
• Megaloblastic anemia, DD, & cognitive & other neurologic deficits
• Age of appearance ranges from infancy to adulthood depending on pathogenic variant
• Serum folate normal
• MTR & MTRR are enzymes required for methionine synthesis from homocysteine.
• Responds to cobalamin.
• Frequent infections w/opportunistic organisms (e.g.,
• Secondary anemias & vitamin deficiencies may result in confusion w/folate transport deficiency disorders.
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with
Serum & RBC folate concentrations
Serum total homocysteine concentration
To delineate if there are any brain abnormalities incl delayed myelination & cerebral & cerebellar calcifications
May be used over time as indication of adequacy of CSF folate concentrations achieved
Clinical assessment for mucositis (oral lesions)
Assessment for chronic diarrhea & nutritional status
To include motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support
Home nursing referral
CBC = complete blood count; CSF = cerebrospinal fluid; FTD = folate transporter deficiency; MOI = mode of inheritance; RBC = red blood cell
The protein product of
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
There is no cure for
A therapeutic folate dose achieves supranormal levels of CSF folate for the age of the individual.
The only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 [
Normalization of anemia, immunoglobulin levels, red blood cell folate levels, and intestinal mucosal integrity alone do
In folate transport deficiency disorders,
A reasonable oral starting dose is 2.5-5.0 mg/kg/day. The available 5-formylTHF oral formulation is racemic; only half the dose is the biologically active isomer.
If CSF monitoring is not possible, see footnote 1 for dosing suggestions.
A reasonable oral starting dose is 1.5-3.0 mg/kg/day. This is the active "S" isomer, so the entire dose is the biologically active form.
If CSF monitoring is not possible, see footnote 1.
FTD = folate transporter deficiency; THF = tetrahydrofolate
Oral dosing may be sufficient for the treatment of this condition, since intestinal folate absorption is normal in the absence of secondary intestinal disease. The oral dose required to achieve therapeutic CSF folate levels is not yet clear; it is likely that the required dose may be much higher than the recommended starting dose. A starting daily dose of 40-50 mg of 5-formylTHF has been used for the treatment of
Leucovorin has been the major folate used in the treatment of these conditions and requires enzymatic interconversion to other folate forms for utilization in folate-dependent reactions.
Delivery of folates to cerebral tissues requires (1) passage across the vascular blood-brain barrier that supplies the entire brain parenchyma and (2) transport across the choroid plexus, which mediates transfer of folates from blood to the CSF that bathes the cerebral ventricular system and the tissues most proximal to the ventricular membranes. RFC is produced in both tissues and likely plays a role in delivery across these barriers. Once across these barriers, RFC is then required for transport of folates into neural cells.
5-methylTHF is the major physiologic blood folate.
Most systemic manifestations will correct rapidly after folate repletion (see
Mucositis (oral lesions)
Diarrhea
Immunodeficiency/infections
Anemia. If anemia is severe, red blood cell transfusion may be required for partial initial correction to allow for onset of adequate endogenous erythropoiesis.
However, depending on the severity of the deficiency, the time to diagnosis, and the adequacy of the cerebral folate concentrations achieved, cognitive and neurologic deficits may remain. There is no information to date on whether treatment with folate will reduce or eliminate seizures in those who have developed a seizure disorder.
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.
To monitor existing manifestations, the individual's response to targeted therapy and supportive care, and the emergence of new manifestations, the evaluations summarized in
CSF folate determinations will be required until levels are above those normal for age.
Monitor periodically thereafter, if possible, for the 1st 5 yrs, & if there are progressive developmental or neurologic signs or concerns about adherence.
CBC = complete blood count; RBC = red blood cell
Folate blood levels must be supranormal to compensate for
Normal CSF folate levels are considerably higher during infancy and childhood than in adults and are critical for normal brain development. CSF folate levels are ~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 [
It is unclear what role, if any, deficiency in the STING pathway plays in the immunologic aspects of this condition. Clinically, correction of the systemic folate deficiency corrects the immunoglobulin and infectious deficits; however, folate will not correct the deficiency in exogenous STING activation.
A variety of anionic compounds are potential inhibitors of RFC-mediated folate transport [
Folic acid is not recommended for treatment of this condition since it may interfere with physiologic folate transport into the CSF at the choroid plexus and it has a very low affinity for RFC.
RFC is also the major route of transport of the folate analog methotrexate into normal and malignant cells; therefore, methotrexate should not be used to treat cancer or leukemia in people with
Clarification of the genetic status of newborn sibs and apparently asymptomatic younger and older sibs of a proband is recommended to identify as early as possible those who would benefit from prompt initiation of folate treatment. There is very limited experience in the early treatment of this disorder; however, it is expected that the hematologic, gastrointestinal, and immunologic manifestations of
Molecular genetic testing of younger or older at-risk sibs who have not undergone prenatal testing should be performed immediately after birth.
If genetic testing is not possible, complete blood count, serum and red blood cell folate concentrations, total homocysteine concentration, and serum immunoglobulin levels should be assessed in at-risk sibs immediately after birth or as soon as the diagnosis is confirmed in the proband.
See
Based upon available information, folic acid should not be taken by a pregnant woman carrying a fetus with
Search
• Serum & RBC folate concentrations
• Serum total homocysteine concentration
• To delineate if there are any brain abnormalities incl delayed myelination & cerebral & cerebellar calcifications
• May be used over time as indication of adequacy of CSF folate concentrations achieved
• Clinical assessment for mucositis (oral lesions)
• Assessment for chronic diarrhea & nutritional status
• To include motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Community or
• Social work involvement for parental support
• Home nursing referral
• A therapeutic folate dose achieves supranormal levels of CSF folate for the age of the individual.
• The only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
• Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
• Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 [
• Normalization of anemia, immunoglobulin levels, red blood cell folate levels, and intestinal mucosal integrity alone do
• In folate transport deficiency disorders,
• The only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
• Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 [
• A reasonable oral starting dose is 2.5-5.0 mg/kg/day. The available 5-formylTHF oral formulation is racemic; only half the dose is the biologically active isomer.
• If CSF monitoring is not possible, see footnote 1 for dosing suggestions.
• A reasonable oral starting dose is 1.5-3.0 mg/kg/day. This is the active "S" isomer, so the entire dose is the biologically active form.
• If CSF monitoring is not possible, see footnote 1.
• Mucositis (oral lesions)
• Diarrhea
• Immunodeficiency/infections
• Anemia. If anemia is severe, red blood cell transfusion may be required for partial initial correction to allow for onset of adequate endogenous erythropoiesis.
• 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
• CSF folate determinations will be required until levels are above those normal for age.
• Monitor periodically thereafter, if possible, for the 1st 5 yrs, & if there are progressive developmental or neurologic signs or concerns about adherence.
• Molecular genetic testing of younger or older at-risk sibs who have not undergone prenatal testing should be performed immediately after birth.
• If genetic testing is not possible, complete blood count, serum and red blood cell folate concentrations, total homocysteine concentration, and serum immunoglobulin levels should be assessed in at-risk sibs 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 an individual diagnosed with
Serum & RBC folate concentrations
Serum total homocysteine concentration
To delineate if there are any brain abnormalities incl delayed myelination & cerebral & cerebellar calcifications
May be used over time as indication of adequacy of CSF folate concentrations achieved
Clinical assessment for mucositis (oral lesions)
Assessment for chronic diarrhea & nutritional status
To include motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Community or
Social work involvement for parental support
Home nursing referral
CBC = complete blood count; CSF = cerebrospinal fluid; FTD = folate transporter deficiency; MOI = mode of inheritance; RBC = red blood cell
The protein product of
Clinical geneticist, certified genetic counselor, certified genetic nurse, genetics advanced practice provider (nurse practitioner or physician assistant)
• Serum & RBC folate concentrations
• Serum total homocysteine concentration
• To delineate if there are any brain abnormalities incl delayed myelination & cerebral & cerebellar calcifications
• May be used over time as indication of adequacy of CSF folate concentrations achieved
• Clinical assessment for mucositis (oral lesions)
• Assessment for chronic diarrhea & nutritional status
• To include 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
A therapeutic folate dose achieves supranormal levels of CSF folate for the age of the individual.
The only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 [
Normalization of anemia, immunoglobulin levels, red blood cell folate levels, and intestinal mucosal integrity alone do
In folate transport deficiency disorders,
A reasonable oral starting dose is 2.5-5.0 mg/kg/day. The available 5-formylTHF oral formulation is racemic; only half the dose is the biologically active isomer.
If CSF monitoring is not possible, see footnote 1 for dosing suggestions.
A reasonable oral starting dose is 1.5-3.0 mg/kg/day. This is the active "S" isomer, so the entire dose is the biologically active form.
If CSF monitoring is not possible, see footnote 1.
FTD = folate transporter deficiency; THF = tetrahydrofolate
Oral dosing may be sufficient for the treatment of this condition, since intestinal folate absorption is normal in the absence of secondary intestinal disease. The oral dose required to achieve therapeutic CSF folate levels is not yet clear; it is likely that the required dose may be much higher than the recommended starting dose. A starting daily dose of 40-50 mg of 5-formylTHF has been used for the treatment of
Leucovorin has been the major folate used in the treatment of these conditions and requires enzymatic interconversion to other folate forms for utilization in folate-dependent reactions.
Delivery of folates to cerebral tissues requires (1) passage across the vascular blood-brain barrier that supplies the entire brain parenchyma and (2) transport across the choroid plexus, which mediates transfer of folates from blood to the CSF that bathes the cerebral ventricular system and the tissues most proximal to the ventricular membranes. RFC is produced in both tissues and likely plays a role in delivery across these barriers. Once across these barriers, RFC is then required for transport of folates into neural cells.
5-methylTHF is the major physiologic blood folate.
Most systemic manifestations will correct rapidly after folate repletion (see
Mucositis (oral lesions)
Diarrhea
Immunodeficiency/infections
Anemia. If anemia is severe, red blood cell transfusion may be required for partial initial correction to allow for onset of adequate endogenous erythropoiesis.
However, depending on the severity of the deficiency, the time to diagnosis, and the adequacy of the cerebral folate concentrations achieved, cognitive and neurologic deficits may remain. There is no information to date on whether treatment with folate will reduce or eliminate seizures in those who have developed a seizure disorder.
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.
• A therapeutic folate dose achieves supranormal levels of CSF folate for the age of the individual.
• The only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
• Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
• Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 [
• Normalization of anemia, immunoglobulin levels, red blood cell folate levels, and intestinal mucosal integrity alone do
• In folate transport deficiency disorders,
• The only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
• Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 [
• A reasonable oral starting dose is 2.5-5.0 mg/kg/day. The available 5-formylTHF oral formulation is racemic; only half the dose is the biologically active isomer.
• If CSF monitoring is not possible, see footnote 1 for dosing suggestions.
• A reasonable oral starting dose is 1.5-3.0 mg/kg/day. This is the active "S" isomer, so the entire dose is the biologically active form.
• If CSF monitoring is not possible, see footnote 1.
• Mucositis (oral lesions)
• Diarrhea
• Immunodeficiency/infections
• Anemia. If anemia is severe, red blood cell transfusion may be required for partial initial correction to allow for onset of adequate endogenous erythropoiesis.
• 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 Therapies
A therapeutic folate dose achieves supranormal levels of CSF folate for the age of the individual.
The only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 [
Normalization of anemia, immunoglobulin levels, red blood cell folate levels, and intestinal mucosal integrity alone do
In folate transport deficiency disorders,
A reasonable oral starting dose is 2.5-5.0 mg/kg/day. The available 5-formylTHF oral formulation is racemic; only half the dose is the biologically active isomer.
If CSF monitoring is not possible, see footnote 1 for dosing suggestions.
A reasonable oral starting dose is 1.5-3.0 mg/kg/day. This is the active "S" isomer, so the entire dose is the biologically active form.
If CSF monitoring is not possible, see footnote 1.
FTD = folate transporter deficiency; THF = tetrahydrofolate
Oral dosing may be sufficient for the treatment of this condition, since intestinal folate absorption is normal in the absence of secondary intestinal disease. The oral dose required to achieve therapeutic CSF folate levels is not yet clear; it is likely that the required dose may be much higher than the recommended starting dose. A starting daily dose of 40-50 mg of 5-formylTHF has been used for the treatment of
Leucovorin has been the major folate used in the treatment of these conditions and requires enzymatic interconversion to other folate forms for utilization in folate-dependent reactions.
Delivery of folates to cerebral tissues requires (1) passage across the vascular blood-brain barrier that supplies the entire brain parenchyma and (2) transport across the choroid plexus, which mediates transfer of folates from blood to the CSF that bathes the cerebral ventricular system and the tissues most proximal to the ventricular membranes. RFC is produced in both tissues and likely plays a role in delivery across these barriers. Once across these barriers, RFC is then required for transport of folates into neural cells.
5-methylTHF is the major physiologic blood folate.
• A therapeutic folate dose achieves supranormal levels of CSF folate for the age of the individual.
• The only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
• Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
• Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 [
• Normalization of anemia, immunoglobulin levels, red blood cell folate levels, and intestinal mucosal integrity alone do
• In folate transport deficiency disorders,
• The only feasible and rapid way to evaluate the extent to which brain folate requirements may be met is to assess the CSF folate concentration.
• Normal CSF folate levels are considerably higher in infants and children than in adults and are critical for normal brain development. CSF folate levels are ~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 [
• A reasonable oral starting dose is 2.5-5.0 mg/kg/day. The available 5-formylTHF oral formulation is racemic; only half the dose is the biologically active isomer.
• If CSF monitoring is not possible, see footnote 1 for dosing suggestions.
• A reasonable oral starting dose is 1.5-3.0 mg/kg/day. This is the active "S" isomer, so the entire dose is the biologically active form.
• If CSF monitoring is not possible, see footnote 1.
## Supportive Care of Systemic Manifestations
Most systemic manifestations will correct rapidly after folate repletion (see
Mucositis (oral lesions)
Diarrhea
Immunodeficiency/infections
Anemia. If anemia is severe, red blood cell transfusion may be required for partial initial correction to allow for onset of adequate endogenous erythropoiesis.
However, depending on the severity of the deficiency, the time to diagnosis, and the adequacy of the cerebral folate concentrations achieved, cognitive and neurologic deficits may remain. There is no information to date on whether treatment with folate will reduce or eliminate seizures in those who have developed a seizure disorder.
• Mucositis (oral lesions)
• Diarrhea
• Immunodeficiency/infections
• Anemia. If anemia is severe, red blood cell transfusion may be required for partial initial correction to allow for onset of adequate endogenous erythropoiesis.
## 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
## 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 targeted therapy and supportive care, and the emergence of new manifestations, the evaluations summarized in
CSF folate determinations will be required until levels are above those normal for age.
Monitor periodically thereafter, if possible, for the 1st 5 yrs, & if there are progressive developmental or neurologic signs or concerns about adherence.
CBC = complete blood count; RBC = red blood cell
Folate blood levels must be supranormal to compensate for
Normal CSF folate levels are considerably higher during infancy and childhood than in adults and are critical for normal brain development. CSF folate levels are ~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 [
It is unclear what role, if any, deficiency in the STING pathway plays in the immunologic aspects of this condition. Clinically, correction of the systemic folate deficiency corrects the immunoglobulin and infectious deficits; however, folate will not correct the deficiency in exogenous STING activation.
• CSF folate determinations will be required until levels are above those normal for age.
• Monitor periodically thereafter, if possible, for the 1st 5 yrs, & if there are progressive developmental or neurologic signs or concerns about adherence.
## Agents/Circumstances to Avoid
A variety of anionic compounds are potential inhibitors of RFC-mediated folate transport [
Folic acid is not recommended for treatment of this condition since it may interfere with physiologic folate transport into the CSF at the choroid plexus and it has a very low affinity for RFC.
RFC is also the major route of transport of the folate analog methotrexate into normal and malignant cells; therefore, methotrexate should not be used to treat cancer or leukemia in people with
## Evaluation of Relatives at Risk
Clarification of the genetic status of newborn sibs and apparently asymptomatic younger and older sibs of a proband is recommended to identify as early as possible those who would benefit from prompt initiation of folate treatment. There is very limited experience in the early treatment of this disorder; however, it is expected that the hematologic, gastrointestinal, and immunologic manifestations of
Molecular genetic testing of younger or older at-risk sibs who have not undergone prenatal testing should be performed immediately after birth.
If genetic testing is not possible, complete blood count, serum and red blood cell folate concentrations, total homocysteine concentration, and serum immunoglobulin levels should be assessed in at-risk sibs immediately after birth or as soon as the diagnosis is confirmed in the proband.
See
• Molecular genetic testing of younger or older at-risk sibs who have not undergone prenatal testing should be performed immediately after birth.
• If genetic testing is not possible, complete blood count, serum and red blood cell folate concentrations, total homocysteine concentration, and serum immunoglobulin levels should be assessed in at-risk sibs immediately after birth or as soon as the diagnosis is confirmed in the proband.
## Pregnancy Management
Based upon available information, folic acid should not be taken by a pregnant woman carrying a fetus with
## 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 likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a modest decrease in folate intake. No data on heterozygotes are currently available.
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 likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a decrease in folate intake or folate malabsorption. No data on heterozygotes are currently available.
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 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 likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a modest decrease in folate intake. No data on heterozygotes are currently available.
• 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 likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a decrease in folate intake or folate malabsorption. No data on heterozygotes are currently available.
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 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 likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a modest decrease in folate intake. No data on heterozygotes are currently available.
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 likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a decrease in folate intake or folate malabsorption. No data on heterozygotes are currently available.
• 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 likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a modest decrease in folate intake. No data on heterozygotes are currently available.
• 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 likely to be asymptomatic but may be at greater risk for clinical signs of folate deficiency when there is a decrease in folate intake or folate malabsorption. No data on heterozygotes are currently available.
## 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 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
SLC19A1-Related Folate Transport Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SLC19A1-Related Folate Transport Deficiency (
"Folates" refers to a family of B
The protein product of
RFC is also a low-affinity transporter of a variety of organic anions [
The role of the RFC protein in folate transport across the blood-brain barrier into the central nervous system is not understood. RFC is produced at the choroid plexus, but its role in transport of folate into the CSF is uncertain [
Variants listed in the table have been provided by the author.
The transport function of this pathogenic variant has not been directly assessed.
## Molecular Pathogenesis
"Folates" refers to a family of B
The protein product of
RFC is also a low-affinity transporter of a variety of organic anions [
The role of the RFC protein in folate transport across the blood-brain barrier into the central nervous system is not understood. RFC is produced at the choroid plexus, but its role in transport of folate into the CSF is uncertain [
Variants listed in the table have been provided by the author.
The transport function of this pathogenic variant has not been directly assessed.
## Chapter Notes
Dr I David 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 provided the first comprehensive characterization of the reduced folate carrier (RFC) protein, established RFC as an organic anion antiporter, and defined the role organic phosphates play in concentrative folate transport [
Faculty profile web page:
Complete PubMed publications:
Dr Goldman is interested in hearing from clinicians treating, and families affected by, hereditary folate malabsorption,
Dr Goldman's research has been supported by grants from the National Institutes of Health.
14 August 2025 (ma) Review posted live
28 March 2024 (idg) Original submission
• 14 August 2025 (ma) Review posted live
• 28 March 2024 (idg) Original submission
## Author Notes
Dr I David 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 provided the first comprehensive characterization of the reduced folate carrier (RFC) protein, established RFC as an organic anion antiporter, and defined the role organic phosphates play in concentrative folate transport [
Faculty profile web page:
Complete PubMed publications:
Dr Goldman is interested in hearing from clinicians treating, and families affected by, hereditary folate malabsorption,
## Acknowledgments
Dr Goldman's research has been supported by grants from the National Institutes of Health.
## Revision History
14 August 2025 (ma) Review posted live
28 March 2024 (idg) Original submission
• 14 August 2025 (ma) Review posted live
• 28 March 2024 (idg) Original submission
## Key Sections in This
## References
## Literature Cited
|
[] |
14/8/2025
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
slc25a24-fps
|
slc25a24-fps
|
[
"Hutchinson-Gilford Progeria-Like Syndrome",
"Fontaine-Farriaux Syndrome",
"Gorlin-Chaudhry-Moss Syndrome (GCMS)",
"Mitochondrial adenyl nucleotide antiporter SLC25A24",
"SLC25A24",
"SLC25A24 Fontaine Progeroid Syndrome"
] |
Danita Velasco, Ann Haskins Olney, Lois Starr
|
Summary The diagnosis of
|
## Diagnosis
No consensus clinical diagnostic criteria for
Pre- and postnatal growth failure
Sagging, thin, and translucent skin with decreased subcutaneous fat, contributing to a progeroid appearance, most pronounced in infancy
Distinctive craniofacial features (
Cranial underossification with large anterior fontanelle (
Sparse scalp hair in infancy with low anterior and posterior hairlines transitioning to coarse, unruly hair with multiple hair whorls (see
Hypertrichosis of face, back, and extensor surfaces
Umbilical hernia and underdeveloped abdominal wall musculature (
Digital anomalies including short distal phalanges, cutaneous syndactyly of fingers or toes, and abnormal nail development (see
Hypoplastic labia majora in females or cryptorchidism in males
Poorly ossified calvarium (see
Short distal phalanges, with or without cutaneous syndactyly
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
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
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.
No data on detection rate of gene-targeted deletion/duplication analysis are available.
• Pre- and postnatal growth failure
• Sagging, thin, and translucent skin with decreased subcutaneous fat, contributing to a progeroid appearance, most pronounced in infancy
• Distinctive craniofacial features (
• Cranial underossification with large anterior fontanelle (
• Sparse scalp hair in infancy with low anterior and posterior hairlines transitioning to coarse, unruly hair with multiple hair whorls (see
• Hypertrichosis of face, back, and extensor surfaces
• Umbilical hernia and underdeveloped abdominal wall musculature (
• Digital anomalies including short distal phalanges, cutaneous syndactyly of fingers or toes, and abnormal nail development (see
• Hypoplastic labia majora in females or cryptorchidism in males
• Poorly ossified calvarium (see
• Short distal phalanges, with or without cutaneous syndactyly
• For an introduction to multigene panels click
## Suggestive Findings
Pre- and postnatal growth failure
Sagging, thin, and translucent skin with decreased subcutaneous fat, contributing to a progeroid appearance, most pronounced in infancy
Distinctive craniofacial features (
Cranial underossification with large anterior fontanelle (
Sparse scalp hair in infancy with low anterior and posterior hairlines transitioning to coarse, unruly hair with multiple hair whorls (see
Hypertrichosis of face, back, and extensor surfaces
Umbilical hernia and underdeveloped abdominal wall musculature (
Digital anomalies including short distal phalanges, cutaneous syndactyly of fingers or toes, and abnormal nail development (see
Hypoplastic labia majora in females or cryptorchidism in males
Poorly ossified calvarium (see
Short distal phalanges, with or without cutaneous syndactyly
• Pre- and postnatal growth failure
• Sagging, thin, and translucent skin with decreased subcutaneous fat, contributing to a progeroid appearance, most pronounced in infancy
• Distinctive craniofacial features (
• Cranial underossification with large anterior fontanelle (
• Sparse scalp hair in infancy with low anterior and posterior hairlines transitioning to coarse, unruly hair with multiple hair whorls (see
• Hypertrichosis of face, back, and extensor surfaces
• Umbilical hernia and underdeveloped abdominal wall musculature (
• Digital anomalies including short distal phalanges, cutaneous syndactyly of fingers or toes, and abnormal nail development (see
• Hypoplastic labia majora in females or cryptorchidism in males
• Poorly ossified calvarium (see
• Short distal phalanges, with or without cutaneous syndactyly
## 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
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
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.
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 imaging 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
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
Prior to identification of the molecular basis of this disorder, clinical findings were published by
Note: (1) Of the four individuals with an
Select Features of
Turribrachycephaly or brachycephaly (12/12)
Large anterior fontanelle (10/12)
Craniosynostosis (9/10)
Short distal phalanges (11/13)
Syndactyly (7/13)
Nail aplasia/hypoplasia (12/13)
Platyspondyly (2/13)
Hip dysplasia (1/13)
Delayed bone age (1/13)
Structural abnormalities (5/11)
Pulmonary hypertension (4/10)
Aortic dilatation (6/11)
Type A aortic dissection (1/11)
8/9 females w/labial hypoplasia
3/3 males w/cryptorchidism
Delayed acquisition of milestones, particularly motor skills, is common.
In school-aged children, normal academic progress was reported in 7/8.
11 survived >24 hours.
Z scores for birth weight ranged from -1 to -4.7, for birth length from +0.1 to -4, and for head circumference from -1.4 to -5.
Feeding problems in infancy with poor growth are common. Three individuals have required gastrostomy feeds for poor feeding and/or reflux with aspiration [
Short stature was present in nine of 11 individuals who lived more than 24 hours, showing poor linear growth with Z scores ranging from -1.2 to -6.
Microcephaly, proportionate to height, is frequently present.
Turribrachycephaly or brachycephaly is apparent at birth in most individuals and may be noted prenatally. In all but two individuals for whom there are detailed infant records, large anterior fontanelle is present. In the 11 individuals who lived longer than the neonatal period, craniosynostosis (most often involving the coronal sutures) was confirmed in nine and suspected in another.
Excessively wrinkled, sagging, and thin skin is typically noted at birth. Dermal translucence with prominent vasculature and decreased subcutaneous fat is common. In combination these skin findings (reflecting an apparent lipodystrophy) contribute to a progeroid appearance in infancy that improves with time.
The hair pattern is distinctive. Hypertrichosis, most frequently over the back, neck, and face, is present at birth and persists at least through childhood. In neonates, sparse frontotemporal scalp hair with low anterior and posterior hairlines are frequently noted. With age, scalp hair becomes coarse and abnormal hair whorls and growth patterns are common (see
Digital abnormalities, present in all reported individuals, include a mix of short distal phalanges (11/13), cutaneous syndactyly (7/13), and nail aplasia or hypoplasia (12/13) [
Mixed nail hypoplasia and aplasia may be present on some digits; normal nails may be present on other digits. Postaxial digits of hands and feet tend to be more severely affected than preaxial digits.
Cutaneous syndactyly of hands or feet was present in seven individuals; in the six for whom it was specified, syndactyly involved toes 2-3 and 4-5 (in 2 individuals) [
Other skeletal findings have been variably reported and include the following:
Platyspondyly in two infants [
Nonspecific long bone diaphyseal and ossification abnormalities in one infant [
Congenital hip dysplasia in one individual [
Delayed bone age in one individual [
Two had normal neonatal echocardiograms and developed pulmonary hypertension before age six months [
Gastroesophageal reflux and aspiration requiring fundoplication and gastrostomy tube occurred in at least two individuals who also developed pulmonary hypertension [
Delayed acquisition of milestones in infancy is common. Normal cognition has been described in individuals living beyond early childhood.
Specific details regarding acquisition of developmental milestones are limited to four individuals in whom independent sitting was achieved at 12-18 months, walking at 19-36 months, and speech at 16-24 months [
Two individuals had hydrocephalus requiring shunt placement [
Two individuals had brain malformations: one with thin corpus callosum, ventriculomegaly, dysplastic cerebella vermis, pineal gland cyst, and large retrocerebellar area [
Five others had no abnormalities on brain imaging (MRI or CT) [
Hyperopia is common in individuals older than age one year [
Microphthalmia was present in several individuals [
One infant had iridocorneal adhesions and corneal clouding at birth [
Oligodontia, microdontia, and hypodontia have been reported.
Primary dentition may be normal despite subsequent abnormalities of the permanent teeth [
Umbilical hernia with diastasis recti or hypoplasia of abdominal musculature was present in 11 of 13 individuals [
Intestinal malrotation was identified at autopsy in one infant [
Hypoplastic labia were reported in 8 of 10 females [
Cryptorchidism was present in all three reported males. One also had micropenis [
It is unknown whether life span in
Additionally, earlier reports of individuals clinically diagnosed with Gorlin-Chaudhry-Moss syndrome and Petty syndrome included individuals in their 30s and 40s [
No genotype-phenotype correlations have been identified. All individuals have a similar substitution at residue 217 (
The following designations, previously thought to represent discrete phenotypes, were consolidated under the name "
Hutchinson-Gilford progeria-like syndrome [
Fontaine-Farriaux syndrome [
Gorlin-Chaudhry-Moss syndrome [
Although to date no individual with a clinical diagnosis of Petty syndrome has been confirmed to have a pathogenic variant in
The prevalence is unknown. To date, 13 individuals with molecularly confirmed
• Turribrachycephaly or brachycephaly (12/12)
• Large anterior fontanelle (10/12)
• Craniosynostosis (9/10)
• Short distal phalanges (11/13)
• Syndactyly (7/13)
• Nail aplasia/hypoplasia (12/13)
• Platyspondyly (2/13)
• Hip dysplasia (1/13)
• Delayed bone age (1/13)
• Structural abnormalities (5/11)
• Pulmonary hypertension (4/10)
• Aortic dilatation (6/11)
• Type A aortic dissection (1/11)
• 8/9 females w/labial hypoplasia
• 3/3 males w/cryptorchidism
• Delayed acquisition of milestones, particularly motor skills, is common.
• In school-aged children, normal academic progress was reported in 7/8.
• Platyspondyly in two infants [
• Nonspecific long bone diaphyseal and ossification abnormalities in one infant [
• Congenital hip dysplasia in one individual [
• Delayed bone age in one individual [
• Two individuals had hydrocephalus requiring shunt placement [
• Two individuals had brain malformations: one with thin corpus callosum, ventriculomegaly, dysplastic cerebella vermis, pineal gland cyst, and large retrocerebellar area [
• Five others had no abnormalities on brain imaging (MRI or CT) [
• Hyperopia is common in individuals older than age one year [
• Microphthalmia was present in several individuals [
• One infant had iridocorneal adhesions and corneal clouding at birth [
• Oligodontia, microdontia, and hypodontia have been reported.
• Primary dentition may be normal despite subsequent abnormalities of the permanent teeth [
• Umbilical hernia with diastasis recti or hypoplasia of abdominal musculature was present in 11 of 13 individuals [
• Intestinal malrotation was identified at autopsy in one infant [
• Hypoplastic labia were reported in 8 of 10 females [
• Cryptorchidism was present in all three reported males. One also had micropenis [
• Hutchinson-Gilford progeria-like syndrome [
• Fontaine-Farriaux syndrome [
• Gorlin-Chaudhry-Moss syndrome [
## Clinical Description
Prior to identification of the molecular basis of this disorder, clinical findings were published by
Note: (1) Of the four individuals with an
Select Features of
Turribrachycephaly or brachycephaly (12/12)
Large anterior fontanelle (10/12)
Craniosynostosis (9/10)
Short distal phalanges (11/13)
Syndactyly (7/13)
Nail aplasia/hypoplasia (12/13)
Platyspondyly (2/13)
Hip dysplasia (1/13)
Delayed bone age (1/13)
Structural abnormalities (5/11)
Pulmonary hypertension (4/10)
Aortic dilatation (6/11)
Type A aortic dissection (1/11)
8/9 females w/labial hypoplasia
3/3 males w/cryptorchidism
Delayed acquisition of milestones, particularly motor skills, is common.
In school-aged children, normal academic progress was reported in 7/8.
11 survived >24 hours.
Z scores for birth weight ranged from -1 to -4.7, for birth length from +0.1 to -4, and for head circumference from -1.4 to -5.
Feeding problems in infancy with poor growth are common. Three individuals have required gastrostomy feeds for poor feeding and/or reflux with aspiration [
Short stature was present in nine of 11 individuals who lived more than 24 hours, showing poor linear growth with Z scores ranging from -1.2 to -6.
Microcephaly, proportionate to height, is frequently present.
Turribrachycephaly or brachycephaly is apparent at birth in most individuals and may be noted prenatally. In all but two individuals for whom there are detailed infant records, large anterior fontanelle is present. In the 11 individuals who lived longer than the neonatal period, craniosynostosis (most often involving the coronal sutures) was confirmed in nine and suspected in another.
Excessively wrinkled, sagging, and thin skin is typically noted at birth. Dermal translucence with prominent vasculature and decreased subcutaneous fat is common. In combination these skin findings (reflecting an apparent lipodystrophy) contribute to a progeroid appearance in infancy that improves with time.
The hair pattern is distinctive. Hypertrichosis, most frequently over the back, neck, and face, is present at birth and persists at least through childhood. In neonates, sparse frontotemporal scalp hair with low anterior and posterior hairlines are frequently noted. With age, scalp hair becomes coarse and abnormal hair whorls and growth patterns are common (see
Digital abnormalities, present in all reported individuals, include a mix of short distal phalanges (11/13), cutaneous syndactyly (7/13), and nail aplasia or hypoplasia (12/13) [
Mixed nail hypoplasia and aplasia may be present on some digits; normal nails may be present on other digits. Postaxial digits of hands and feet tend to be more severely affected than preaxial digits.
Cutaneous syndactyly of hands or feet was present in seven individuals; in the six for whom it was specified, syndactyly involved toes 2-3 and 4-5 (in 2 individuals) [
Other skeletal findings have been variably reported and include the following:
Platyspondyly in two infants [
Nonspecific long bone diaphyseal and ossification abnormalities in one infant [
Congenital hip dysplasia in one individual [
Delayed bone age in one individual [
Two had normal neonatal echocardiograms and developed pulmonary hypertension before age six months [
Gastroesophageal reflux and aspiration requiring fundoplication and gastrostomy tube occurred in at least two individuals who also developed pulmonary hypertension [
Delayed acquisition of milestones in infancy is common. Normal cognition has been described in individuals living beyond early childhood.
Specific details regarding acquisition of developmental milestones are limited to four individuals in whom independent sitting was achieved at 12-18 months, walking at 19-36 months, and speech at 16-24 months [
Two individuals had hydrocephalus requiring shunt placement [
Two individuals had brain malformations: one with thin corpus callosum, ventriculomegaly, dysplastic cerebella vermis, pineal gland cyst, and large retrocerebellar area [
Five others had no abnormalities on brain imaging (MRI or CT) [
Hyperopia is common in individuals older than age one year [
Microphthalmia was present in several individuals [
One infant had iridocorneal adhesions and corneal clouding at birth [
Oligodontia, microdontia, and hypodontia have been reported.
Primary dentition may be normal despite subsequent abnormalities of the permanent teeth [
Umbilical hernia with diastasis recti or hypoplasia of abdominal musculature was present in 11 of 13 individuals [
Intestinal malrotation was identified at autopsy in one infant [
Hypoplastic labia were reported in 8 of 10 females [
Cryptorchidism was present in all three reported males. One also had micropenis [
It is unknown whether life span in
Additionally, earlier reports of individuals clinically diagnosed with Gorlin-Chaudhry-Moss syndrome and Petty syndrome included individuals in their 30s and 40s [
• Turribrachycephaly or brachycephaly (12/12)
• Large anterior fontanelle (10/12)
• Craniosynostosis (9/10)
• Short distal phalanges (11/13)
• Syndactyly (7/13)
• Nail aplasia/hypoplasia (12/13)
• Platyspondyly (2/13)
• Hip dysplasia (1/13)
• Delayed bone age (1/13)
• Structural abnormalities (5/11)
• Pulmonary hypertension (4/10)
• Aortic dilatation (6/11)
• Type A aortic dissection (1/11)
• 8/9 females w/labial hypoplasia
• 3/3 males w/cryptorchidism
• Delayed acquisition of milestones, particularly motor skills, is common.
• In school-aged children, normal academic progress was reported in 7/8.
• Platyspondyly in two infants [
• Nonspecific long bone diaphyseal and ossification abnormalities in one infant [
• Congenital hip dysplasia in one individual [
• Delayed bone age in one individual [
• Two individuals had hydrocephalus requiring shunt placement [
• Two individuals had brain malformations: one with thin corpus callosum, ventriculomegaly, dysplastic cerebella vermis, pineal gland cyst, and large retrocerebellar area [
• Five others had no abnormalities on brain imaging (MRI or CT) [
• Hyperopia is common in individuals older than age one year [
• Microphthalmia was present in several individuals [
• One infant had iridocorneal adhesions and corneal clouding at birth [
• Oligodontia, microdontia, and hypodontia have been reported.
• Primary dentition may be normal despite subsequent abnormalities of the permanent teeth [
• Umbilical hernia with diastasis recti or hypoplasia of abdominal musculature was present in 11 of 13 individuals [
• Intestinal malrotation was identified at autopsy in one infant [
• Hypoplastic labia were reported in 8 of 10 females [
• Cryptorchidism was present in all three reported males. One also had micropenis [
## Growth
Z scores for birth weight ranged from -1 to -4.7, for birth length from +0.1 to -4, and for head circumference from -1.4 to -5.
Feeding problems in infancy with poor growth are common. Three individuals have required gastrostomy feeds for poor feeding and/or reflux with aspiration [
Short stature was present in nine of 11 individuals who lived more than 24 hours, showing poor linear growth with Z scores ranging from -1.2 to -6.
Microcephaly, proportionate to height, is frequently present.
## Craniofacial Features
Turribrachycephaly or brachycephaly is apparent at birth in most individuals and may be noted prenatally. In all but two individuals for whom there are detailed infant records, large anterior fontanelle is present. In the 11 individuals who lived longer than the neonatal period, craniosynostosis (most often involving the coronal sutures) was confirmed in nine and suspected in another.
## Skin and Hair
Excessively wrinkled, sagging, and thin skin is typically noted at birth. Dermal translucence with prominent vasculature and decreased subcutaneous fat is common. In combination these skin findings (reflecting an apparent lipodystrophy) contribute to a progeroid appearance in infancy that improves with time.
The hair pattern is distinctive. Hypertrichosis, most frequently over the back, neck, and face, is present at birth and persists at least through childhood. In neonates, sparse frontotemporal scalp hair with low anterior and posterior hairlines are frequently noted. With age, scalp hair becomes coarse and abnormal hair whorls and growth patterns are common (see
## Skeletal
Digital abnormalities, present in all reported individuals, include a mix of short distal phalanges (11/13), cutaneous syndactyly (7/13), and nail aplasia or hypoplasia (12/13) [
Mixed nail hypoplasia and aplasia may be present on some digits; normal nails may be present on other digits. Postaxial digits of hands and feet tend to be more severely affected than preaxial digits.
Cutaneous syndactyly of hands or feet was present in seven individuals; in the six for whom it was specified, syndactyly involved toes 2-3 and 4-5 (in 2 individuals) [
Other skeletal findings have been variably reported and include the following:
Platyspondyly in two infants [
Nonspecific long bone diaphyseal and ossification abnormalities in one infant [
Congenital hip dysplasia in one individual [
Delayed bone age in one individual [
• Platyspondyly in two infants [
• Nonspecific long bone diaphyseal and ossification abnormalities in one infant [
• Congenital hip dysplasia in one individual [
• Delayed bone age in one individual [
## Cardiovascular
Two had normal neonatal echocardiograms and developed pulmonary hypertension before age six months [
Gastroesophageal reflux and aspiration requiring fundoplication and gastrostomy tube occurred in at least two individuals who also developed pulmonary hypertension [
## Development
Delayed acquisition of milestones in infancy is common. Normal cognition has been described in individuals living beyond early childhood.
Specific details regarding acquisition of developmental milestones are limited to four individuals in whom independent sitting was achieved at 12-18 months, walking at 19-36 months, and speech at 16-24 months [
## Other
Two individuals had hydrocephalus requiring shunt placement [
Two individuals had brain malformations: one with thin corpus callosum, ventriculomegaly, dysplastic cerebella vermis, pineal gland cyst, and large retrocerebellar area [
Five others had no abnormalities on brain imaging (MRI or CT) [
Hyperopia is common in individuals older than age one year [
Microphthalmia was present in several individuals [
One infant had iridocorneal adhesions and corneal clouding at birth [
Oligodontia, microdontia, and hypodontia have been reported.
Primary dentition may be normal despite subsequent abnormalities of the permanent teeth [
Umbilical hernia with diastasis recti or hypoplasia of abdominal musculature was present in 11 of 13 individuals [
Intestinal malrotation was identified at autopsy in one infant [
Hypoplastic labia were reported in 8 of 10 females [
Cryptorchidism was present in all three reported males. One also had micropenis [
• Two individuals had hydrocephalus requiring shunt placement [
• Two individuals had brain malformations: one with thin corpus callosum, ventriculomegaly, dysplastic cerebella vermis, pineal gland cyst, and large retrocerebellar area [
• Five others had no abnormalities on brain imaging (MRI or CT) [
• Hyperopia is common in individuals older than age one year [
• Microphthalmia was present in several individuals [
• One infant had iridocorneal adhesions and corneal clouding at birth [
• Oligodontia, microdontia, and hypodontia have been reported.
• Primary dentition may be normal despite subsequent abnormalities of the permanent teeth [
• Umbilical hernia with diastasis recti or hypoplasia of abdominal musculature was present in 11 of 13 individuals [
• Intestinal malrotation was identified at autopsy in one infant [
• Hypoplastic labia were reported in 8 of 10 females [
• Cryptorchidism was present in all three reported males. One also had micropenis [
## Prognosis
It is unknown whether life span in
Additionally, earlier reports of individuals clinically diagnosed with Gorlin-Chaudhry-Moss syndrome and Petty syndrome included individuals in their 30s and 40s [
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified. All individuals have a similar substitution at residue 217 (
## Nomenclature
The following designations, previously thought to represent discrete phenotypes, were consolidated under the name "
Hutchinson-Gilford progeria-like syndrome [
Fontaine-Farriaux syndrome [
Gorlin-Chaudhry-Moss syndrome [
Although to date no individual with a clinical diagnosis of Petty syndrome has been confirmed to have a pathogenic variant in
• Hutchinson-Gilford progeria-like syndrome [
• Fontaine-Farriaux syndrome [
• Gorlin-Chaudhry-Moss syndrome [
## Prevalence
The prevalence is unknown. To date, 13 individuals with molecularly confirmed
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Genes of Interest in the Differential Diagnosis of
AD = autosomal dominant; apoC-III = apolipoprotein C-III; AR = autosomal recessive; CDG = congenital disorders of glycosylation; DD = developmental delay; DiffDx = differential diagnosis; ID = intellectual disability; MOI = mode of inheritance; TIEF = transferrin isoelectrofocusing
## 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
Consider eval for gastric tube & fundoplication in persons w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / need for IEP
Community or
Social work involvement for parental support;
Home nursing referral.
IEP = individualized education plan; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Management, which is largely symptomatic, may be performed by specialists in multiple disciplines, including a craniofacial clinic (involving plastic surgery, neurosurgery, and otolaryngology), cardiology, pulmonology, gastroenterology, and clinical genetics. Some students may benefit from an individualized education plan (IEP) through their school.
Treatment of Manifestations in Individuals with
W/ossification of skull, craniosynostosis may become apparent.
Protective helmet may be considered w/delayed ossification.
Mgmt of microaspiration & oxygen therapy help.
Consider sleep study (particularly in persons w/midfacial retrusion).
Aneurysm w/dissection has been reported at aortic root & not elsewhere in arterial tree.
Dissection may occur at smaller aortic diameters.
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
Recommended Surveillance for Individuals with
Echocardiogram & eval by cardiologist
Angiography may be indicated.
At diagnosis & then based on individual findings
Echocardiography at least every 3 yrs
Contact sports and isometric exercise may need to be restricted if cranial anomalies and/or aortic dilatation are present. Note, in the absence of severe aortic dilatation or other clinical restriction, aerobic activity is encouraged.
See
Search
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube & fundoplication in persons w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / need for IEP
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• W/ossification of skull, craniosynostosis may become apparent.
• Protective helmet may be considered w/delayed ossification.
• Mgmt of microaspiration & oxygen therapy help.
• Consider sleep study (particularly in persons w/midfacial retrusion).
• Aneurysm w/dissection has been reported at aortic root & not elsewhere in arterial tree.
• Dissection may occur at smaller aortic diameters.
• 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
• Echocardiogram & eval by cardiologist
• Angiography may be indicated.
• At diagnosis & then based on individual findings
• Echocardiography at least every 3 yrs
## 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
Consider eval for gastric tube & fundoplication in persons w/dysphagia &/or aspiration risk.
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / need for IEP
Community or
Social work involvement for parental support;
Home nursing referral.
IEP = individualized education plan; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastric tube & fundoplication in persons w/dysphagia &/or aspiration risk.
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / need for IEP
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Management, which is largely symptomatic, may be performed by specialists in multiple disciplines, including a craniofacial clinic (involving plastic surgery, neurosurgery, and otolaryngology), cardiology, pulmonology, gastroenterology, and clinical genetics. Some students may benefit from an individualized education plan (IEP) through their school.
Treatment of Manifestations in Individuals with
W/ossification of skull, craniosynostosis may become apparent.
Protective helmet may be considered w/delayed ossification.
Mgmt of microaspiration & oxygen therapy help.
Consider sleep study (particularly in persons w/midfacial retrusion).
Aneurysm w/dissection has been reported at aortic root & not elsewhere in arterial tree.
Dissection may occur at smaller aortic diameters.
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
• W/ossification of skull, craniosynostosis may become apparent.
• Protective helmet may be considered w/delayed ossification.
• Mgmt of microaspiration & oxygen therapy help.
• Consider sleep study (particularly in persons w/midfacial retrusion).
• Aneurysm w/dissection has been reported at aortic root & not elsewhere in arterial tree.
• Dissection may occur at smaller aortic diameters.
• 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 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
## Surveillance
Recommended Surveillance for Individuals with
Echocardiogram & eval by cardiologist
Angiography may be indicated.
At diagnosis & then based on individual findings
Echocardiography at least every 3 yrs
• Echocardiogram & eval by cardiologist
• Angiography may be indicated.
• At diagnosis & then based on individual findings
• Echocardiography at least every 3 yrs
## Agents/Circumstances to Avoid
Contact sports and isometric exercise may need to be restricted if cranial anomalies and/or aortic dilatation are present. Note, in the absence of severe aortic dilatation or other clinical restriction, aerobic activity is encouraged.
## 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 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 only in the germ cells.
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 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 only in the germ cells.
• 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 only in the germ cells.
• 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 only in the germ cells.
• 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 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 only in the germ cells.
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 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 only in the germ cells.
• 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 only in the germ cells.
• 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 only in the germ cells.
• 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
•
•
•
•
## Molecular Genetics
SLC25A24 Fontaine Progeroid Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SLC25A24 Fontaine Progeroid Syndrome (
Knockdown of SLC25A24 contributes to the oxidative stress and calcium overload and increases susceptibility to mitochondrial permeability transition pore-dependent cell death [
Pathogenic variants causative of Fontaine progeroid syndrome have been restricted to codon 217 in exon 5 of
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Knockdown of SLC25A24 contributes to the oxidative stress and calcium overload and increases susceptibility to mitochondrial permeability transition pore-dependent cell death [
Pathogenic variants causative of Fontaine progeroid syndrome have been restricted to codon 217 in exon 5 of
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
9 June 2022 (bp) Review posted live
1 March 2022 (dv) Original submission
• 9 June 2022 (bp) Review posted live
• 1 March 2022 (dv) Original submission
## Revision History
9 June 2022 (bp) Review posted live
1 March 2022 (dv) Original submission
• 9 June 2022 (bp) Review posted live
• 1 March 2022 (dv) Original submission
## References
## Literature Cited
Facial features of female at age six weeks, six months, one year, and 2.5 years. Note turribrachycephaly with broad forehead tapering to a narrower chin and triangular-shaped face. The supraorbital ridges are underdeveloped, and palpebral fissures are typically short and downslanted. Blue or gray sclera have been noted in several individuals. The nasal root is depressed with convex nasal ridge and midface retrusion. Micrognathia in infancy typically develops into relative prognathia with age, and the lower lip and tongue may protrude. Ears are consistently low set and posteriorly rotated with small, dysplastic pinnae. Note evolution of hair pattern, and improved skin appearance over time.
Skull radiographs from the same child at age two weeks. Note nearly absent calvarial ossification.
In the same individual at age six weeks (A, B) and six months (C), there is mixed nail dysplasia and aplasia affecting hands and feet (A, B) with syndactyly of the toes and shortened distal phalanges (A, B). Note thin, translucent skin with prominent vessels, lack of subcutaneous fat, and umbilical hernia (C).
|
[
"N Adolphs, M Klein, EJ Haberl, L Graul-Neumann, H Menneking, B Hoffmeister. Necrotizing soft tissue infection of the scalp after fronto-facial advancement by internal distraction in a 7-year old girl with Gorlin-Chaudhry-Moss syndrome--a case report.. J Craniomaxillofac Surg. 2011;39:554-61",
"SR Braddock, HH Ardinger, CS Yang, BM Paschal, BD Hall. Petty syndrome and Fontaine-Farriaux syndrome: delineation of a single syndrome.. Am J Med Genet A. 2010;152A:1718-23",
"M Castori, E Silvestri, L Pedace, G Marseglia, A Tempera, I Antigoni, F Torricelli, S Majore, P. Grammatico. Fontaine-Farriaux syndrome: a recognizable craniosynostosis syndrome with nail, skeletal, abdominal, and central nervous system anomalies.. Am J Med Genet A. 2009;149A:2193-9",
"N Ehmke, L Graul-Neumann, L Smorag, R Koenig, L Segebrecht, P Magoulas, F Scaglia, E Kilic, AF Hennig, N Adolphs, N Saha, B Fauler, VM Kalscheuer, F Hennig, J Altmuller, C Netzer, H Thiele, P Nurnberg, G Yigit, M Jager, J Hecht, U Kruger, T Mielke, PM Krawitz, D Horn, M Schuelke, S Mundlos, CA Bacino, PE Bonnen, B Wollnik, B Fischer-Zirnsak, U Kornak. De novo mutations in SLC25A24 cause a craniosynostosis syndrome with hypertrichosis, progeroid appearance, and mitochondrial dysfunction.. Am J Hum Genet. 2017;101:833-43",
"L Faivre, P Khau Van Kien, N Madinier-Chappat, A Nivelon-Chevallier, F Beer, M. LeMerrer. Can Hutchinson-Gilford progeria syndrome be a neonatal condition?. Am J Med Genet. 1999;87:450-2",
"G Fontaine, JP Farriaux, D Blanckaert, C Lefebvre. Un nouveau syndrome polymalformatif complexe.. J Genet Hum. 1977;25:109-19",
"RJ Gorlin, AP Chaudhry, ML Moss. Craniofacial dysostosis, patent ductus arteriosus, hypertrichosis, hypoplasia of labia majora, dental and eye anomalies-a new syndrome?. J Pediatr. 1960;56:778-85",
"PF Ippel, RJ Gorlin, W Lenz, JM van Doorne, JB Bijlsma. Craniofacial dysostosis, hypertrichosis, genital hypoplasia, ocular, dental, and digital defects: confirmation of the Gorlin-Chaudhry-Moss syndrome.. Am J Med Genet. 1992;44:518-22",
"J Legué, JHM François, CSP van Rijswijk, TJ van Brakel. Is Gorlin-Chaudhry-Moss syndrome associated with aortopathy?. Eur J Cardiothorac Surg. 2020;58:654-5",
"F Palmieri, P Scarcia, M Monné. Diseases caused by mutations in mitochondrial carrier genes SLC25: a review.. Biomolecules. 2020;10:655",
"EM Petty, R Laxova, HR Wiedemann. Previously unrecognized congenital progeroid disorder.. Am J Med Genet. 1990;35:383-7",
"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",
"JI Rodríguez, P Pérez-Alonso, R Funes, J Pérez-Rodríguez. Lethal neonatal Hutchinson-Gilford progeria syndrome.. Am J Med Genet. 1999;82:242-8",
"ME Rodríguez-García, FJ Cotrina-Vinagre, J Cruz-Rojo, L Garzón-Lorenzo, P Carnicero-Rodríguez, JS Pozo, F Martínez-Azorín. A rare male patient with Fontaine progeroid syndrome caused by p.R217H de novo mutation in SLC25A24.. Am J Med Genet A. 2018;176:2479-86",
"J Ryu, JM Ko, CH. A Shin. 9-year-old Korean girl with Fontaine progeroid syndrome: a case report with further phenotypical delineation and description of clinical course during long-term follow-up.. BMC Med Genet. 2019;20:188",
"J Traba, A Del Arco, MR Duchen, G Szabadkai, J Satrústegui. SCaMC-1 promotes cancer cell survival by desensitizing mitochondrial permeability transition via ATP/ADP-mediated matrix Ca(2+) buffering.. Cell Death Differ. 2012;19:650-60",
"K Writzl, A Maver, L Kovacic, P Martinez-Valero, L Contreras, J Satrustegui, M Castori, L Faivre, P Lapunzina, ABP van Kuilenburg, S Radovic, C Thauvin-Robinet, B Peterlin, A Del Arco, RC Hennekam. De novo mutations in SLC25A24 cause a disorder characterized by early aging, bone dysplasia, characteristic face, and early demise.. Am J Hum Genet. 2017;101:844-55"
] |
9/6/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
slc39a14-def
|
slc39a14-def
|
[
"Hypermanganesemia with Dystonia 2 (HMNDYT2)",
"SLC39A14-Related Early-Onset Dystonia-Parkinsonism",
"SLC39A14-Related Early-Onset Dystonia-Parkinsonism",
"Hypermanganesemia with Dystonia 2 (HMNDYT2)",
"Metal cation symporter ZIP14",
"SLC39A14",
"SLC39A14 Deficiency"
] |
SLC39A14 Deficiency
|
Karin Tuschl, Allison Gregory, Esther Meyer, Peter T Clayton, Susan J Hayflick, Philippa B Mills, Manju A Kurian
|
Summary SLC39A14 deficiency is typically characterized by evidence of delay or loss of motor developmental milestones (e.g., delayed walking, gait disturbance) between ages six months and three years. Early in the disease course, children show axial hypotonia followed by dystonia, spasticity, dysarthria, bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor. By the end of the first decade, they develop severe, generalized, pharmaco-resistant dystonia, limb contractures, and scoliosis, and lose independent ambulation. Cognitive impairment appears to be less prominent than motor disability. Some affected children have died in their first decade due to secondary complications such as respiratory infections. One individual with disease onset during the late teens has been reported, suggesting that milder adult presentation can occur. The diagnosis of SLC39A14 deficiency is established in a proband with progressive dystonia-parkinsonism (often combined with other signs such as spasticity and parkinsonian features), characteristic neuroimaging findings, hypermanganesemia, and biallelic pathogenic (or likely pathogenic) variants in Environmental manganese exposure (i.e., contaminated drinking water, occupational manganese exposure in welding/mining industries, contaminated ephedrone preparations) High manganese content of total parenteral nutrition Foods very high in manganese including: cloves; saffron; nuts; mussels; dark chocolate; pumpkin, sesame, and sunflower seeds SLC39A14 deficiency is inherited in an autosomal recessive manner. 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 the
|
## Diagnosis
SLC39A14 deficiency
Delay in acquisition of developmental motor milestones or loss of developmental motor milestones
Progressive pharmaco-resistant dystonia
Parkinsonism signs (tremor, bradykinesia, hypomimia)
Bulbar dysfunction
Dysarthria
Note: One individual with onset of dystonia during the second decade has been reported, suggesting that milder presentations with juvenile or adult onset may also occur [
Globus pallidus and striatum, with thalamic sparing
Note: Basal ganglia changes on T
White matter including the cerebellum, spinal cord, and dorsal pons, with sparing of the ventral pons
Anterior pituitary gland
The diagnosis of SLC39A14 deficiency
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 the clinician to determine which gene(s) are likely involved, whereas genomic testing does 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 SLC39A14 deficiency, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from other movement disorders,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SLC39A14 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.
• Delay in acquisition of developmental motor milestones or loss of developmental motor milestones
• Progressive pharmaco-resistant dystonia
• Parkinsonism signs (tremor, bradykinesia, hypomimia)
• Bulbar dysfunction
• Dysarthria
• Globus pallidus and striatum, with thalamic sparing
• Note: Basal ganglia changes on T
• White matter including the cerebellum, spinal cord, and dorsal pons, with sparing of the ventral pons
• Anterior pituitary gland
• For an introduction to multigene panels click
## Suggestive Findings
SLC39A14 deficiency
Delay in acquisition of developmental motor milestones or loss of developmental motor milestones
Progressive pharmaco-resistant dystonia
Parkinsonism signs (tremor, bradykinesia, hypomimia)
Bulbar dysfunction
Dysarthria
Note: One individual with onset of dystonia during the second decade has been reported, suggesting that milder presentations with juvenile or adult onset may also occur [
Globus pallidus and striatum, with thalamic sparing
Note: Basal ganglia changes on T
White matter including the cerebellum, spinal cord, and dorsal pons, with sparing of the ventral pons
Anterior pituitary gland
• Delay in acquisition of developmental motor milestones or loss of developmental motor milestones
• Progressive pharmaco-resistant dystonia
• Parkinsonism signs (tremor, bradykinesia, hypomimia)
• Bulbar dysfunction
• Dysarthria
• Globus pallidus and striatum, with thalamic sparing
• Note: Basal ganglia changes on T
• White matter including the cerebellum, spinal cord, and dorsal pons, with sparing of the ventral pons
• Anterior pituitary gland
## Establishing the Diagnosis
The diagnosis of SLC39A14 deficiency
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 the clinician to determine which gene(s) are likely involved, whereas genomic testing does 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 SLC39A14 deficiency, molecular genetic testing approaches can include
For an introduction to multigene panels click
When the phenotype is indistinguishable from other movement disorders,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SLC39A14 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.
• For an introduction to multigene panels click
## Option 1
When the clinical, laboratory, and brain MRI findings suggest the diagnosis of SLC39A14 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 other movement disorders,
For an introduction to comprehensive genomic testing click
Molecular Genetic Testing Used in SLC39A14 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.
## Clinical Characteristics
SLC39A14 deficiency has only recently been identified in 30 individuals from 23 families [
Onset occurs typically between ages six months and three years. Affected children present with delay or loss of motor developmental milestones (e.g., delayed walking, gait disturbance) [
Early in the disease course, children show axial hypotonia followed by dystonia, spasticity, dysarthria, bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor.
By the end of the first decade, children develop severe, generalized, pharmaco-resistant dystonia, limb contractures, scoliosis, and loss of independent ambulation.
Although there appears to be relative cognitive sparing (psychometric testing has not been possible), a degree of learning disability is present in all children.
Some affected children die in their first decade due to secondary complications such as respiratory infections.
More recently, one affected individual with a milder phenotype has been described with onset of movement disorder at age 18 years and independent ambulation and survival into late adulthood [
Extensive gliosis and neuronal loss in the globus pallidus and dentate nucleus;
Preservation of neurons in the cerebral and cerebellar cortex as well as the caudate, putamen, and thalamus;
A vacuolated myelinopathy with patchy axonal loss in the cerebral and cerebellar white matter.
No genotype-phenotype correlations are known.
The disease prevalence is not established. To date only 30 individuals with SLC39A14 deficiency from 23 families have been identified. These 23 families are from different ethnic backgrounds and the majority are consanguineous [
• Extensive gliosis and neuronal loss in the globus pallidus and dentate nucleus;
• Preservation of neurons in the cerebral and cerebellar cortex as well as the caudate, putamen, and thalamus;
• A vacuolated myelinopathy with patchy axonal loss in the cerebral and cerebellar white matter.
## Clinical Description
SLC39A14 deficiency has only recently been identified in 30 individuals from 23 families [
Onset occurs typically between ages six months and three years. Affected children present with delay or loss of motor developmental milestones (e.g., delayed walking, gait disturbance) [
Early in the disease course, children show axial hypotonia followed by dystonia, spasticity, dysarthria, bulbar dysfunction, and signs of parkinsonism including bradykinesia, hypomimia, and tremor.
By the end of the first decade, children develop severe, generalized, pharmaco-resistant dystonia, limb contractures, scoliosis, and loss of independent ambulation.
Although there appears to be relative cognitive sparing (psychometric testing has not been possible), a degree of learning disability is present in all children.
Some affected children die in their first decade due to secondary complications such as respiratory infections.
More recently, one affected individual with a milder phenotype has been described with onset of movement disorder at age 18 years and independent ambulation and survival into late adulthood [
Extensive gliosis and neuronal loss in the globus pallidus and dentate nucleus;
Preservation of neurons in the cerebral and cerebellar cortex as well as the caudate, putamen, and thalamus;
A vacuolated myelinopathy with patchy axonal loss in the cerebral and cerebellar white matter.
• Extensive gliosis and neuronal loss in the globus pallidus and dentate nucleus;
• Preservation of neurons in the cerebral and cerebellar cortex as well as the caudate, putamen, and thalamus;
• A vacuolated myelinopathy with patchy axonal loss in the cerebral and cerebellar white matter.
## Genotype-Phenotype Correlations
No genotype-phenotype correlations are known.
## Prevalence
The disease prevalence is not established. To date only 30 individuals with SLC39A14 deficiency from 23 families have been identified. These 23 families are from different ethnic backgrounds and the majority are consanguineous [
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Hereditary Disorders of Interest in the Differential Diagnosis of SLC39A14 Deficiency
AD = autosomal dominant; AR = autosomal recessive; BPAN = beta-propeller protein-associated neurodegeneration; CoPAN = COASY protein-associated neurodegeneration; DYT = dystonia; DRD = dopa-responsive dystonia; FAHN = fatty acid hydroxylase-associated neurodegeneration. Mn = manganese; MOI = mode of inheritance; MPAN = mitochondrial membrane protein-associated neurodegeneration; NBIA = neurodegeneration with brain iron accumulation; PKAN = pantothenate kinase-associated neurodegeneration; PLAN =
Additional hereditary disorders in the differential diagnosis of SLC39A14 deficiency include
Acquired conditions in the differential diagnosis of SLC39A14 deficiency include
Unlike SLC39A14 deficiency, acquired hypermanganesemia often presents with psychiatric symptoms and a history of Mn exposure from environmental sources, parenteral nutrition, or contaminated ephedrone preparations [
Unlike SLC39A14 deficiency, liver disease is the predominant feature in acquired hepatocerebral degeneration and it precedes development of neurologic symptoms [
• Unlike SLC39A14 deficiency, acquired hypermanganesemia often presents with psychiatric symptoms and a history of Mn exposure from environmental sources, parenteral nutrition, or contaminated ephedrone preparations [
• Unlike SLC39A14 deficiency, liver disease is the predominant feature in acquired hepatocerebral degeneration and it precedes development of neurologic symptoms [
## Management
To establish the extent of disease and needs in an individual diagnosed with SLC39A14 deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SLC39A14 Deficiency
Neurologic exam for dystonia, parkinsonism, & spasticity
Brain MRI
Assessment of whole-blood manganese levels
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
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 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; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
Early initiation of physical therapy and orthopedic management aims to prevent contractures and maintain ambulation. As needed, individuals should be referred for adaptive aids (e.g., a walker or wheelchair for gait abnormalities) and assistive communication devices.
Support by a speech-language pathologist, feeding specialist, and nutritionist is indicated to assure adequate nutrition and to reduce the risk of aspiration. When an adequate oral diet can no longer be maintained, gastrostomy tube placement should be considered. Gastric feeding tube and/or tracheostomy may be required to prevent aspiration pneumonia.
Note that symptomatic treatment with L-dopa and antispasticity medications including benzodiazepines, baclofen, and botulinum toxin has been attempted with limited success. There has been partial but poorly sustained response to trihexyphenidyl at high doses of 20 mg/day and intrathecal baclofen of 1,500-2,000 µg/day in two older sibs reported by
There is evidence that disodium calcium edetate, which primarily promotes the urinary excretion of manganese, can improve neurologic symptoms and slow the disease progression [
A female age five years with SLC39A14 deficiency showed improvement of neurologic manifestations with regain of her ability to walk after six months of disodium calcium edetate treatment [
It is anticipated that chelation therapy will need to be lifelong.
Potential adverse effects of disodium calcium edetate chelation therapy include thrombocytopenia and leukopenia, nephrotoxicity, hepatoxicity, hypocalcemia, and trace metal and vitamin deficiencies [
Complete blood count
Assessment of renal function including urinalysis assessed at baseline and monthly thereafter. Monitoring may be extended to every other month once on a stable dose.
Assessment of liver function
Measurement of the concentrations of electrolytes, calcium, magnesium, and phosphate
Measurement of the concentrations of trace metals (manganese, zinc, copper, and selenium)
Assessment of iron status
Treatment may need to be discontinued if:
White blood count is <3.5x10
Neutrophil count is <2.0x10
Platelet count is <150x10
>2+ proteinuria is detected on more than one occasion (with no evidence of infection)
The above cut-off values are based on guidelines for D-penicillamine treatment [
Chelation therapy with disodium calcium edetate may prevent primary disease manifestations in affected sibs who are asymptomatic (see Treatment of Manifestations,
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.
Recommended Surveillance for Individuals with SLC39A14 Deficiency
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor development incl ambulation & speech.
Neurologic exam (scoring of mvmt disorder severity)
Whole-blood manganese levels
Brain MRI
The following should be avoided:
Environmental manganese exposure (i.e., contaminated drinking water, occupational manganese exposure in welding/mining industries, contaminated ephedrone preparations)
High manganese content of total parenteral nutrition
Foods very high in manganese including: cloves; saffron; nuts; mussels; dark chocolate; and pumpkin, sesame, and sunflower seeds
It is appropriate to clarify the genetic status of apparently asymptomatic younger sibs of an affected individual in order to identified as early as possible sibs who would benefit from prompt initiation of treatment and preventive measures (see
See
Search
• Neurologic exam for dystonia, parkinsonism, & spasticity
• Brain MRI
• Assessment of whole-blood manganese levels
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• 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 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.
• Complete blood count
• Assessment of renal function including urinalysis assessed at baseline and monthly thereafter. Monitoring may be extended to every other month once on a stable dose.
• Assessment of liver function
• Measurement of the concentrations of electrolytes, calcium, magnesium, and phosphate
• Measurement of the concentrations of trace metals (manganese, zinc, copper, and selenium)
• Assessment of iron status
• White blood count is <3.5x10
• Neutrophil count is <2.0x10
• Platelet count is <150x10
• >2+ proteinuria is detected on more than one occasion (with no evidence of infection)
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor development incl ambulation & speech.
• Neurologic exam (scoring of mvmt disorder severity)
• Whole-blood manganese levels
• Brain MRI
• Environmental manganese exposure (i.e., contaminated drinking water, occupational manganese exposure in welding/mining industries, contaminated ephedrone preparations)
• High manganese content of total parenteral nutrition
• Foods very high in manganese including: cloves; saffron; nuts; mussels; dark chocolate; and pumpkin, sesame, and sunflower seeds
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SLC39A14 deficiency, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SLC39A14 Deficiency
Neurologic exam for dystonia, parkinsonism, & spasticity
Brain MRI
Assessment of whole-blood manganese levels
To incl motor, adaptive, cognitive, & speech/language eval
Eval for early intervention / special education
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 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; MOI = mode of inheritance; OT = occupational therapy; PT = physical therapy;
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Neurologic exam for dystonia, parkinsonism, & spasticity
• Brain MRI
• Assessment of whole-blood manganese levels
• To incl motor, adaptive, cognitive, & speech/language eval
• Eval for early intervention / special education
• 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 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
Early initiation of physical therapy and orthopedic management aims to prevent contractures and maintain ambulation. As needed, individuals should be referred for adaptive aids (e.g., a walker or wheelchair for gait abnormalities) and assistive communication devices.
Support by a speech-language pathologist, feeding specialist, and nutritionist is indicated to assure adequate nutrition and to reduce the risk of aspiration. When an adequate oral diet can no longer be maintained, gastrostomy tube placement should be considered. Gastric feeding tube and/or tracheostomy may be required to prevent aspiration pneumonia.
Note that symptomatic treatment with L-dopa and antispasticity medications including benzodiazepines, baclofen, and botulinum toxin has been attempted with limited success. There has been partial but poorly sustained response to trihexyphenidyl at high doses of 20 mg/day and intrathecal baclofen of 1,500-2,000 µg/day in two older sibs reported by
There is evidence that disodium calcium edetate, which primarily promotes the urinary excretion of manganese, can improve neurologic symptoms and slow the disease progression [
A female age five years with SLC39A14 deficiency showed improvement of neurologic manifestations with regain of her ability to walk after six months of disodium calcium edetate treatment [
It is anticipated that chelation therapy will need to be lifelong.
Potential adverse effects of disodium calcium edetate chelation therapy include thrombocytopenia and leukopenia, nephrotoxicity, hepatoxicity, hypocalcemia, and trace metal and vitamin deficiencies [
Complete blood count
Assessment of renal function including urinalysis assessed at baseline and monthly thereafter. Monitoring may be extended to every other month once on a stable dose.
Assessment of liver function
Measurement of the concentrations of electrolytes, calcium, magnesium, and phosphate
Measurement of the concentrations of trace metals (manganese, zinc, copper, and selenium)
Assessment of iron status
Treatment may need to be discontinued if:
White blood count is <3.5x10
Neutrophil count is <2.0x10
Platelet count is <150x10
>2+ proteinuria is detected on more than one occasion (with no evidence of infection)
The above cut-off values are based on guidelines for D-penicillamine treatment [
• Complete blood count
• Assessment of renal function including urinalysis assessed at baseline and monthly thereafter. Monitoring may be extended to every other month once on a stable dose.
• Assessment of liver function
• Measurement of the concentrations of electrolytes, calcium, magnesium, and phosphate
• Measurement of the concentrations of trace metals (manganese, zinc, copper, and selenium)
• Assessment of iron status
• White blood count is <3.5x10
• Neutrophil count is <2.0x10
• Platelet count is <150x10
• >2+ proteinuria is detected on more than one occasion (with no evidence of infection)
## Symptomatic Treatment
Early initiation of physical therapy and orthopedic management aims to prevent contractures and maintain ambulation. As needed, individuals should be referred for adaptive aids (e.g., a walker or wheelchair for gait abnormalities) and assistive communication devices.
Support by a speech-language pathologist, feeding specialist, and nutritionist is indicated to assure adequate nutrition and to reduce the risk of aspiration. When an adequate oral diet can no longer be maintained, gastrostomy tube placement should be considered. Gastric feeding tube and/or tracheostomy may be required to prevent aspiration pneumonia.
Note that symptomatic treatment with L-dopa and antispasticity medications including benzodiazepines, baclofen, and botulinum toxin has been attempted with limited success. There has been partial but poorly sustained response to trihexyphenidyl at high doses of 20 mg/day and intrathecal baclofen of 1,500-2,000 µg/day in two older sibs reported by
## Chelation Therapy
There is evidence that disodium calcium edetate, which primarily promotes the urinary excretion of manganese, can improve neurologic symptoms and slow the disease progression [
A female age five years with SLC39A14 deficiency showed improvement of neurologic manifestations with regain of her ability to walk after six months of disodium calcium edetate treatment [
It is anticipated that chelation therapy will need to be lifelong.
Potential adverse effects of disodium calcium edetate chelation therapy include thrombocytopenia and leukopenia, nephrotoxicity, hepatoxicity, hypocalcemia, and trace metal and vitamin deficiencies [
Complete blood count
Assessment of renal function including urinalysis assessed at baseline and monthly thereafter. Monitoring may be extended to every other month once on a stable dose.
Assessment of liver function
Measurement of the concentrations of electrolytes, calcium, magnesium, and phosphate
Measurement of the concentrations of trace metals (manganese, zinc, copper, and selenium)
Assessment of iron status
Treatment may need to be discontinued if:
White blood count is <3.5x10
Neutrophil count is <2.0x10
Platelet count is <150x10
>2+ proteinuria is detected on more than one occasion (with no evidence of infection)
The above cut-off values are based on guidelines for D-penicillamine treatment [
• Complete blood count
• Assessment of renal function including urinalysis assessed at baseline and monthly thereafter. Monitoring may be extended to every other month once on a stable dose.
• Assessment of liver function
• Measurement of the concentrations of electrolytes, calcium, magnesium, and phosphate
• Measurement of the concentrations of trace metals (manganese, zinc, copper, and selenium)
• Assessment of iron status
• White blood count is <3.5x10
• Neutrophil count is <2.0x10
• Platelet count is <150x10
• >2+ proteinuria is detected on more than one occasion (with no evidence of infection)
## Prevention of Primary Manifestations
Chelation therapy with disodium calcium edetate may prevent primary disease manifestations in affected sibs who are asymptomatic (see Treatment of Manifestations,
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the following evaluations are recommended.
Recommended Surveillance for Individuals with SLC39A14 Deficiency
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor development incl ambulation & speech.
Neurologic exam (scoring of mvmt disorder severity)
Whole-blood manganese levels
Brain MRI
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor development incl ambulation & speech.
• Neurologic exam (scoring of mvmt disorder severity)
• Whole-blood manganese levels
• Brain MRI
## Agents/Circumstances to Avoid
The following should be avoided:
Environmental manganese exposure (i.e., contaminated drinking water, occupational manganese exposure in welding/mining industries, contaminated ephedrone preparations)
High manganese content of total parenteral nutrition
Foods very high in manganese including: cloves; saffron; nuts; mussels; dark chocolate; and pumpkin, sesame, and sunflower seeds
• Environmental manganese exposure (i.e., contaminated drinking water, occupational manganese exposure in welding/mining industries, contaminated ephedrone preparations)
• High manganese content of total parenteral nutrition
• Foods very high in manganese including: cloves; saffron; nuts; mussels; dark chocolate; and pumpkin, sesame, and sunflower seeds
## Evaluation of Relatives at Risk
It is appropriate to clarify the genetic status of apparently asymptomatic younger sibs of an affected individual in order to identified as early as possible sibs who would benefit from prompt initiation of treatment and preventive measures (see
See
## Therapies Under Investigation
Search
## Genetic Counseling
SLC39A14 deficiency 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
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 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/preimplantation genetic testing is before 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
SLC39A14 deficiency 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.
• 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
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
•
•
•
•
•
•
•
•
## Molecular Genetics
SLC39A14 Deficiency: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SLC39A14 Deficiency (
Biallelic
## Molecular Pathogenesis
Biallelic
## Chapter Notes
Dr Karin TuschlEmail:
Web:
This work was supported by grants from Action Medical Research, the Wellcome Trust, Great Ormond Street Hospital Children's Charity, NBIA Disorders Association, Gracious Heart Charity Foundation and Rosetrees Trust, and the GOSH National Institute for Health Research/Biomedical Research Centre.
8 December 2022 (sw) Comprehensive update posted live
25 May 2017 (bp) Review posted live
29 November 2016 (kt) Original submission
• 8 December 2022 (sw) Comprehensive update posted live
• 25 May 2017 (bp) Review posted live
• 29 November 2016 (kt) Original submission
## Author Notes
Dr Karin TuschlEmail:
Web:
## Acknowledgments
This work was supported by grants from Action Medical Research, the Wellcome Trust, Great Ormond Street Hospital Children's Charity, NBIA Disorders Association, Gracious Heart Charity Foundation and Rosetrees Trust, and the GOSH National Institute for Health Research/Biomedical Research Centre.
## Revision History
8 December 2022 (sw) Comprehensive update posted live
25 May 2017 (bp) Review posted live
29 November 2016 (kt) Original submission
• 8 December 2022 (sw) Comprehensive update posted live
• 25 May 2017 (bp) Review posted live
• 29 November 2016 (kt) Original submission
## References
## Literature Cited
A. Axial T
B. Axial T
C. Sagittal T
|
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"D Garg, S Yoganathan, U Shamim, K Mankad, P Gulati, V Bonifati, A Botre, U Kalane, AG Saini, N Sankhyan, K Srivastava, VK Gowda, M Juneja, M Kamate, H Padmanabha, D Panigrahi, S Pachapure, V Udani, A Kumar, S Pandey, M Thomas, S Danda, SA Iqbalahmed, A Subramanian, H Pemde, V Singh, M Faruq, S Sharma. Clinical profile and treatment outcomes of hypermanganesemia with dystonia 1 and 2 among 27 Indian children.. Mov Disord Clin Pract. 2022;9:886-99",
"J Janocha-Litwin, K Marianska, S Serafinska, K Simon. Manganese encephalopathy among ephedron abusers.. J Neuroimaging. 2015;25:832-5",
"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 Juneja, U Shamim, A Joshi, A Mathur, B Uppili, S Sairam, S Ambawat, R Dixit, M. Faruq. A novel mutation in SLC39A14 causing hypermanganesemia associated with infantile onset dystonia.. J Gene Med. 2018;20",
"GA Lamas, C Goertz, R Boineau, DB Mark, T Rozema, RL Nahin, JA Drisko, KL Lee. Design of the trial to assess chelation therapy (TACT).. Am Heart J. 2012;163:7-12",
"JH Lee, JH Shin. Effect of chelation therapy on a Korean patient with brain manganese deposition resulting from a compound heterozygous mutation in the SLC39A14 gene.. J Mov Disord. 2022;15:171-4",
"L Marti-Sanchez, JD Ortigoza-Escobar, A Darling, M Villaronga, H Baide, M Molero-Luis, M Batllori, MI Vanegas, J Muchart, L Aquino, R Artuch, A Macaya, MA Kurian, P Dueñas. Hypermanganesemia due to mutations in SLC39A14: further insights into Mn deposition in the central nervous system.. Orphanet J Rare Dis. 2018;13:28",
"V Miletić, D Ozretić, M Relja. Parkinsonian syndrome and ataxia as a presenting finding of acquired hepatocerebral degeneration.. Metab Brain Dis. 2014;29:207-9",
"JA Mortimer, AR Borenstein, LM Nelson. Associations of welding and manganese exposure with Parkinson disease: review and meta-analysis.. Neurology. 2012;79:1174-80",
"M Namnah, M Bauer, H Mor-Shaked, SB Bressman, D Raymond, LJ Ozelius, D Arkadir. Benign SLC39A14 course of dystonia-parkinsonism secondary to inherited manganese accumulation.. Mov Disord Clin Pract. 2020;7:569-70",
"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",
"D Santos, C Batoreu, L Mateus, AP Marreilha Dos Santos, M Aschner. Manganese in human parenteral nutrition: considerations for toxicity and biomonitoring.. Neurotoxicology. 2014;43:36-45",
"K Tuschl, E Meyer, LE Valdivia, N Zhao, C Dadswell, A Abdul-Sada, CY Hung, MA Simpson, WK Chong, TS Jacques, RL Woltjer, S Eaton, A Gregory, L Sanford, E Kara, H Houlden, SM Cuno, H Prokisch, L Valletta, V Tiranti, R Younis, ER Maher, J Spencer, A Straatman-Iwanowska, P Gissen, LA Selim, G Pintos-Morell, W Coroleu-Lletget, SS Mohammad, S Yoganathan, RC Dale, M Thomas, J Rihel, OA Bodamer, CA Enns, SJ Hayflick, PT Clayton, PB Mills, MA Kurian, SW Wilson. Mutations in SLC39A14 disrupt manganese homeostasis and cause childhood-onset parkinsonism-dystonia.. Nat Commun. 2016;7:11601",
"JWW Winslow, KH Limesand, N Zhao. The functions of ZIP8, ZIP14, and ZnT10 in the regulation of systemic manganese homeostasis.. Int J Mol Sci. 2020;21:3304",
"A Zeglam, A Abugrara, M Kabuka. Autosomal-recessive iron deficiency anemia, dystonia and hypermanganesemia caused by new variant mutation of the manganese transporter gene SLC39A14.. Acta Neurol Belg. 2019;119:379-84"
] |
25/5/2017
|
8/12/2022
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|
slc39a8-cdg
|
slc39a8-cdg
|
[
"CDG-IIn",
"Congenital Disorder of Glycosylation Type IIn (CDG2N)",
"SLC39A8 Deficiency",
"CDG-IIn",
"Congenital Disorder of Glycosylation Type IIn (CDG2N)",
"SLC39A8 Deficiency",
"Metal cation symporter ZIP8",
"SLC39A8",
"SLC39A8-CDG"
] |
SLC39A8-CDG
|
Julien H Park
|
Summary SLC39A8-CDG is characterized by mild-to-profound developmental delay, intellectual disability, hypotonia, feeding difficulties with poor weight gain and growth deficiency, dystonia, spasticity, epilepsy, ophthalmologic manifestations including cortical blindness and strabismus, and sensorineural hearing impairment. The diagnosis of SLC39A8-CDG is established in a proband with characteristic clinical features and suggestive laboratory findings (decreased whole blood manganese, elevated xanthine on urinary purines/pyrimidines, and evidence of altered glycosylation) by identification of biallelic pathogenic variants in SLC39A8-CDG is inherited in an autosomal recessive manner. If both parents are known to be heterozygous for an
|
## Diagnosis
SLC39A8-CDG
Mild-to-profound developmental delay and/or intellectual disability
Generalized hypotonia of infancy
Feeding difficulties with poor weight gain and growth deficiency
Movement disorder with marked dystonia
Spasticity
Epilepsy, especially severe infantile epileptic spasms not responding to conventional treatment
Ophthalmologic manifestations including cortical blindness and strabismus
Sensorineural hearing impairment
Decreased whole blood manganese concentration
Elevated transaminases (aspartate transaminase, alanine transaminase)
Elevated xanthine (xanthine oxidase) in urinary purines/pyrimidines detected by mass spectrometry [
Altered glycosylation
A type II pattern of dysglycosylation of serum transferrin can be detected by isoelectric focusing, high-performance liquid chromatography, capillary zone electrophoresis, or mass spectrometry-based analysis of serum transferrin glycosylation.
Hypogalactosylation of glycans can be detected by glycome profiling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, especially an increase of the asialo-agalactosylated precursor N-glycan A2G1S1.
Bilateral T
Cerebral and cerebellar atrophy
Craniosynostoses
Lacunar skull
The diagnosis of SLC39A8-CDG
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
Note: Targeted analysis for the
Molecular Genetic Testing Used in SLC39A8-CDG
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.
• Mild-to-profound developmental delay and/or intellectual disability
• Generalized hypotonia of infancy
• Feeding difficulties with poor weight gain and growth deficiency
• Movement disorder with marked dystonia
• Spasticity
• Epilepsy, especially severe infantile epileptic spasms not responding to conventional treatment
• Ophthalmologic manifestations including cortical blindness and strabismus
• Sensorineural hearing impairment
• Decreased whole blood manganese concentration
• Elevated transaminases (aspartate transaminase, alanine transaminase)
• Elevated xanthine (xanthine oxidase) in urinary purines/pyrimidines detected by mass spectrometry [
• Altered glycosylation
• A type II pattern of dysglycosylation of serum transferrin can be detected by isoelectric focusing, high-performance liquid chromatography, capillary zone electrophoresis, or mass spectrometry-based analysis of serum transferrin glycosylation.
• Hypogalactosylation of glycans can be detected by glycome profiling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, especially an increase of the asialo-agalactosylated precursor N-glycan A2G1S1.
• A type II pattern of dysglycosylation of serum transferrin can be detected by isoelectric focusing, high-performance liquid chromatography, capillary zone electrophoresis, or mass spectrometry-based analysis of serum transferrin glycosylation.
• Hypogalactosylation of glycans can be detected by glycome profiling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, especially an increase of the asialo-agalactosylated precursor N-glycan A2G1S1.
• A type II pattern of dysglycosylation of serum transferrin can be detected by isoelectric focusing, high-performance liquid chromatography, capillary zone electrophoresis, or mass spectrometry-based analysis of serum transferrin glycosylation.
• Hypogalactosylation of glycans can be detected by glycome profiling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, especially an increase of the asialo-agalactosylated precursor N-glycan A2G1S1.
• Bilateral T
• Cerebral and cerebellar atrophy
• Craniosynostoses
• Lacunar skull
## Suggestive Findings
SLC39A8-CDG
Mild-to-profound developmental delay and/or intellectual disability
Generalized hypotonia of infancy
Feeding difficulties with poor weight gain and growth deficiency
Movement disorder with marked dystonia
Spasticity
Epilepsy, especially severe infantile epileptic spasms not responding to conventional treatment
Ophthalmologic manifestations including cortical blindness and strabismus
Sensorineural hearing impairment
Decreased whole blood manganese concentration
Elevated transaminases (aspartate transaminase, alanine transaminase)
Elevated xanthine (xanthine oxidase) in urinary purines/pyrimidines detected by mass spectrometry [
Altered glycosylation
A type II pattern of dysglycosylation of serum transferrin can be detected by isoelectric focusing, high-performance liquid chromatography, capillary zone electrophoresis, or mass spectrometry-based analysis of serum transferrin glycosylation.
Hypogalactosylation of glycans can be detected by glycome profiling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, especially an increase of the asialo-agalactosylated precursor N-glycan A2G1S1.
Bilateral T
Cerebral and cerebellar atrophy
Craniosynostoses
Lacunar skull
• Mild-to-profound developmental delay and/or intellectual disability
• Generalized hypotonia of infancy
• Feeding difficulties with poor weight gain and growth deficiency
• Movement disorder with marked dystonia
• Spasticity
• Epilepsy, especially severe infantile epileptic spasms not responding to conventional treatment
• Ophthalmologic manifestations including cortical blindness and strabismus
• Sensorineural hearing impairment
• Decreased whole blood manganese concentration
• Elevated transaminases (aspartate transaminase, alanine transaminase)
• Elevated xanthine (xanthine oxidase) in urinary purines/pyrimidines detected by mass spectrometry [
• Altered glycosylation
• A type II pattern of dysglycosylation of serum transferrin can be detected by isoelectric focusing, high-performance liquid chromatography, capillary zone electrophoresis, or mass spectrometry-based analysis of serum transferrin glycosylation.
• Hypogalactosylation of glycans can be detected by glycome profiling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, especially an increase of the asialo-agalactosylated precursor N-glycan A2G1S1.
• A type II pattern of dysglycosylation of serum transferrin can be detected by isoelectric focusing, high-performance liquid chromatography, capillary zone electrophoresis, or mass spectrometry-based analysis of serum transferrin glycosylation.
• Hypogalactosylation of glycans can be detected by glycome profiling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, especially an increase of the asialo-agalactosylated precursor N-glycan A2G1S1.
• A type II pattern of dysglycosylation of serum transferrin can be detected by isoelectric focusing, high-performance liquid chromatography, capillary zone electrophoresis, or mass spectrometry-based analysis of serum transferrin glycosylation.
• Hypogalactosylation of glycans can be detected by glycome profiling using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, especially an increase of the asialo-agalactosylated precursor N-glycan A2G1S1.
• Bilateral T
• Cerebral and cerebellar atrophy
• Craniosynostoses
• Lacunar skull
## Establishing the Diagnosis
The diagnosis of SLC39A8-CDG
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
Note: Targeted analysis for the
Molecular Genetic Testing Used in SLC39A8-CDG
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.
## Recommended Testing
For an introduction to comprehensive genomic testing click
## Other Testing Options
For an introduction to multigene panels click
Note: Targeted analysis for the
Molecular Genetic Testing Used in SLC39A8-CDG
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.
## Other Testing
## Clinical Characteristics
SLC39A8-CDG is characterized by a severe, primarily neurologic phenotype with developmental delay, intellectual disability, muscular hypotonia, and variable additional neurologic symptoms including dyskinetic movements and spasticity. To date, 15 individuals have been identified with pathogenic variants in
SLC39A8-CDG: Frequency of Select Features
No genotype-phenotype correlations have been identified.
In 2009 the nomenclature for all types of CDG was changed to include the official gene (not italicized) followed by "-CDG" [
The prevalence of SLC39A8-CDG is unknown. To date, 15 individuals have been described in the literature [
Of note, the founder variant
## Clinical Description
SLC39A8-CDG is characterized by a severe, primarily neurologic phenotype with developmental delay, intellectual disability, muscular hypotonia, and variable additional neurologic symptoms including dyskinetic movements and spasticity. To date, 15 individuals have been identified with pathogenic variants in
SLC39A8-CDG: Frequency of Select Features
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified.
## Nomenclature
In 2009 the nomenclature for all types of CDG was changed to include the official gene (not italicized) followed by "-CDG" [
## Prevalence
The prevalence of SLC39A8-CDG is unknown. To date, 15 individuals have been described in the literature [
Of note, the founder variant
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
Metabolic Disorders to Consider in the Differential Diagnosis of SLC39A8-CDG in Infants Who Have Not Yet Had an MRI
DD
Seizures
Liver disease
Abnormal transferrin glycosylation analysis
Commonly involve multiple organ systems
Movement disorder(s)
Unlike persons w/mitochondrial disorders, persons w/SLC39A8-CDG do not typically have episodes of metabolic decompensation or significantly ↑ acidemia (if not assoc w/hypoperfusion).
The disorders are further distinguished by the presence of abnormal transferrin glycoform analysis & deficient SLC39A8 activity in SLC39A8-CDG.
Multisystem involvement
DD/ID
Neurologic dysfunction
Liver disease
Hypotonia
Growth deficiency
Feeding intolerance
DD/ID
Spasticity
Unlike persons w/urea cycle disorders / organic acidemias, persons w/SLC39A8-CDG do not typically have episodes of metabolic decompensation or hyperammonemia.
The disorders are further distinguished by the presence of abnormal transferrin glycoform analysis & ↓ levels of manganese in SLC39A8-CDG.
CDDG = congenital disorder of deglycosylation; CDG = congenital disorder of glycosylation; DD = developmental delay; ID = intellectual disability; VLCFAs = very long-chain fatty acids
Metabolic Disorders with Overlapping MRI Findings in the Differential Diagnosis of SLC39A8-CDG
Ataxia
Cataracts
Hearing loss
Neurodegeneration
Retinitis pigmentosa
Cataracts
Cutis laxa
DD/ID
Faltering growth
Hypotonia
Joint hyperlaxity
Microcephaly
Short stature
Abnormalities of myelination
Cerebellar atrophy
Hyperintensity of T
Ataxia
DD
Epilepsy
Hyporeflexia
Hypotonia
Confluent periventricular white matter abnormalities
Iron accumulation
Profound pontocerebellar atrophy
Cognitive decline
Optic atrophy
Progressive spastic paraparesis & dysmetria
Xeroderma
Cerebellar atrophy
Cortical atrophy
Progressive disturbance of myelination
Signal changes &/or atrophy of basal ganglia
Striatal injury spreading in dorsoventral direction
Acute brain injury assoc w/infections
Choreoathetosis
Progressive dystonic cerebral palsy
↑ signal density of dentate nuclei & globi pallidi on T
Cerebellar atrophy
Leukoencephalopathy
Variety of neurologic malignancies
Progressive ataxia
DD/ID
Seizures
Spasticity
Ataxia
Autoinflammation
Dysmorphic features
Faltering growth
Hypotonia
ID
Cerebellar atrophy
Hypointensities in globus pallidus & substantial nigra
Signal hyperintensity in cerebellar cortex
Cerebellar ataxia
Chronic denervation
Hypotonia
Progression to spastic tetraplegia
Progressive motor & cognitive deterioration
Visual disturbances
DD = developmental delay; ID = intellectual disability; NBIA = neurodegeneration with brain iron accumulation; PHARC =
With the exception of delta-1-pyrroline-5-carboxylate synthetase deficiency (which can be inherited in either an autosomal dominant or autosomal recessive manner) and
Many genes (nuclear and mitochondrial) are known to be associated with
• DD
• Seizures
• Liver disease
• Abnormal transferrin glycosylation analysis
• Commonly involve multiple organ systems
• Movement disorder(s)
• Unlike persons w/mitochondrial disorders, persons w/SLC39A8-CDG do not typically have episodes of metabolic decompensation or significantly ↑ acidemia (if not assoc w/hypoperfusion).
• The disorders are further distinguished by the presence of abnormal transferrin glycoform analysis & deficient SLC39A8 activity in SLC39A8-CDG.
• Multisystem involvement
• DD/ID
• Neurologic dysfunction
• Liver disease
• Hypotonia
• Growth deficiency
• Feeding intolerance
• DD/ID
• Spasticity
• Unlike persons w/urea cycle disorders / organic acidemias, persons w/SLC39A8-CDG do not typically have episodes of metabolic decompensation or hyperammonemia.
• The disorders are further distinguished by the presence of abnormal transferrin glycoform analysis & ↓ levels of manganese in SLC39A8-CDG.
• Ataxia
• Cataracts
• Hearing loss
• Neurodegeneration
• Retinitis pigmentosa
• Cataracts
• Cutis laxa
• DD/ID
• Faltering growth
• Hypotonia
• Joint hyperlaxity
• Microcephaly
• Short stature
• Abnormalities of myelination
• Cerebellar atrophy
• Hyperintensity of T
• Ataxia
• DD
• Epilepsy
• Hyporeflexia
• Hypotonia
• Confluent periventricular white matter abnormalities
• Iron accumulation
• Profound pontocerebellar atrophy
• Cognitive decline
• Optic atrophy
• Progressive spastic paraparesis & dysmetria
• Xeroderma
• Cerebellar atrophy
• Cortical atrophy
• Progressive disturbance of myelination
• Signal changes &/or atrophy of basal ganglia
• Striatal injury spreading in dorsoventral direction
• Acute brain injury assoc w/infections
• Choreoathetosis
• Progressive dystonic cerebral palsy
• ↑ signal density of dentate nuclei & globi pallidi on T
• Cerebellar atrophy
• Leukoencephalopathy
• Variety of neurologic malignancies
• Progressive ataxia
• DD/ID
• Seizures
• Spasticity
• Ataxia
• Autoinflammation
• Dysmorphic features
• Faltering growth
• Hypotonia
• ID
• Cerebellar atrophy
• Hypointensities in globus pallidus & substantial nigra
• Signal hyperintensity in cerebellar cortex
• Cerebellar ataxia
• Chronic denervation
• Hypotonia
• Progression to spastic tetraplegia
• Progressive motor & cognitive deterioration
• Visual disturbances
## Management
No clinical practice guidelines for SLC39A8-CDG have been published.
To establish the extent of disease and needs in an individual diagnosed with SLC39A8-CDG, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SLC39A8-CDG
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.
Gastroenterology / nutrition / feeding team eval
Logotherapy eval to assess for swallowing abnormalities
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons 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)
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
Manganese sulfate is preferable to other manganese salts given its high solubility and widespread availability at pharmaceutical grade due to its use in nutritional applications.
Manganese sulfate doses of up to 20 mg/kg body weight per day have been used to treat SLC39A8-CDG.
Monitoring glycosylation using mass spectrometry-based methods is necessary to identify the appropriate manganese dose. Note: (1) Abnormal glycosylation persisted longer than other observed abnormal laboratory findings [
Regular measurement of blood manganese levels is advised with the aim of adjusting the manganese dose to achieve manganese levels similar to those observed in healthy controls.
Brain MRI every one to two years is recommend in order to detect potential manganese deposits. Note: Long-term, high-dose manganese can be neurotoxic in healthy individuals [
Titration to identify adequate manganese sulfate dose should precede introduction of galactose.
Note: Addition of galactose and subsequent normalization of glycosylation prevents the ability to identify the appropriate manganese dose based on the levels of dysglycosylation.
Galactose supplementation does not have any effect on unrelated enzyme dysfunctions caused by manganese depletion and should thus be considered only in combination with manganese supplementation.
Galactose doses of up to 3.75 g/kg body weight per day resulted in rapid normalization of glycosylation of the marker protein serum transferrin.
Supportive care to improve quality of life, maximize function, and reduce complications is also recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Treatment of Manifestations in Individuals with SLC39A8-CDG
Supplementation w/manganese to ↓ seizure frequency & severity (See
Standardized treatment w/ASM by experienced neurologist
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.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / 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
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 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
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with SLC39A8-CDG
Assess for abnormal glycosylation using mass spectrometry.
Measure blood manganese levels.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor for evidence of aspiration (e.g., respiratory insufficiency).
Assessment of visual acuity
Assessment for strabismus
Physical medicine, OT/PT assessment of mobility, self-help skills
Clinical exam for scoliosis
ALT = alanine transaminase; AST = aspartate transaminase; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
All at-risk sibs of any age should have molecular testing for the familial
For at-risk newborn sibs, analysis of blood and urine manganese levels as well as protein N-glycosylation should be performed simultaneously with molecular genetic testing, as results from these tests are potentially available earlier than results of genetic testing. Altered glycosylation and severely reduced blood manganese levels are indicative of SLC39A8-CDG.
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.
• Gastroenterology / nutrition / feeding team eval
• Logotherapy eval to assess for swallowing abnormalities
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons 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)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Manganese sulfate is preferable to other manganese salts given its high solubility and widespread availability at pharmaceutical grade due to its use in nutritional applications.
• Manganese sulfate doses of up to 20 mg/kg body weight per day have been used to treat SLC39A8-CDG.
• Monitoring glycosylation using mass spectrometry-based methods is necessary to identify the appropriate manganese dose. Note: (1) Abnormal glycosylation persisted longer than other observed abnormal laboratory findings [
• Regular measurement of blood manganese levels is advised with the aim of adjusting the manganese dose to achieve manganese levels similar to those observed in healthy controls.
• Brain MRI every one to two years is recommend in order to detect potential manganese deposits. Note: Long-term, high-dose manganese can be neurotoxic in healthy individuals [
• Titration to identify adequate manganese sulfate dose should precede introduction of galactose.
• Note: Addition of galactose and subsequent normalization of glycosylation prevents the ability to identify the appropriate manganese dose based on the levels of dysglycosylation.
• Galactose supplementation does not have any effect on unrelated enzyme dysfunctions caused by manganese depletion and should thus be considered only in combination with manganese supplementation.
• Galactose doses of up to 3.75 g/kg body weight per day resulted in rapid normalization of glycosylation of the marker protein serum transferrin.
• Supplementation w/manganese to ↓ seizure frequency & severity (See
• Standardized treatment w/ASM by experienced neurologist
• 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.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / 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).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Assess for abnormal glycosylation using mass spectrometry.
• Measure blood manganese levels.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor for evidence of aspiration (e.g., respiratory insufficiency).
• Assessment of visual acuity
• Assessment for strabismus
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Clinical exam for scoliosis
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with SLC39A8-CDG, the evaluations summarized in
Recommended Evaluations Following Initial Diagnosis in Individuals with SLC39A8-CDG
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.
Gastroenterology / nutrition / feeding team eval
Logotherapy eval to assess for swallowing abnormalities
To incl eval of aspiration risk & nutritional status
Consider eval for gastrostomy tube placement in persons 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)
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
• 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.
• Gastroenterology / nutrition / feeding team eval
• Logotherapy eval to assess for swallowing abnormalities
• To incl eval of aspiration risk & nutritional status
• Consider eval for gastrostomy tube placement in persons 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)
• Community or
• Social work involvement for parental support;
• Home nursing referral.
## Treatment of Manifestations
Manganese sulfate is preferable to other manganese salts given its high solubility and widespread availability at pharmaceutical grade due to its use in nutritional applications.
Manganese sulfate doses of up to 20 mg/kg body weight per day have been used to treat SLC39A8-CDG.
Monitoring glycosylation using mass spectrometry-based methods is necessary to identify the appropriate manganese dose. Note: (1) Abnormal glycosylation persisted longer than other observed abnormal laboratory findings [
Regular measurement of blood manganese levels is advised with the aim of adjusting the manganese dose to achieve manganese levels similar to those observed in healthy controls.
Brain MRI every one to two years is recommend in order to detect potential manganese deposits. Note: Long-term, high-dose manganese can be neurotoxic in healthy individuals [
Titration to identify adequate manganese sulfate dose should precede introduction of galactose.
Note: Addition of galactose and subsequent normalization of glycosylation prevents the ability to identify the appropriate manganese dose based on the levels of dysglycosylation.
Galactose supplementation does not have any effect on unrelated enzyme dysfunctions caused by manganese depletion and should thus be considered only in combination with manganese supplementation.
Galactose doses of up to 3.75 g/kg body weight per day resulted in rapid normalization of glycosylation of the marker protein serum transferrin.
Supportive care to improve quality of life, maximize function, and reduce complications is also recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Treatment of Manifestations in Individuals with SLC39A8-CDG
Supplementation w/manganese to ↓ seizure frequency & severity (See
Standardized treatment w/ASM by experienced neurologist
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.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / 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
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 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
• Manganese sulfate is preferable to other manganese salts given its high solubility and widespread availability at pharmaceutical grade due to its use in nutritional applications.
• Manganese sulfate doses of up to 20 mg/kg body weight per day have been used to treat SLC39A8-CDG.
• Monitoring glycosylation using mass spectrometry-based methods is necessary to identify the appropriate manganese dose. Note: (1) Abnormal glycosylation persisted longer than other observed abnormal laboratory findings [
• Regular measurement of blood manganese levels is advised with the aim of adjusting the manganese dose to achieve manganese levels similar to those observed in healthy controls.
• Brain MRI every one to two years is recommend in order to detect potential manganese deposits. Note: Long-term, high-dose manganese can be neurotoxic in healthy individuals [
• Titration to identify adequate manganese sulfate dose should precede introduction of galactose.
• Note: Addition of galactose and subsequent normalization of glycosylation prevents the ability to identify the appropriate manganese dose based on the levels of dysglycosylation.
• Galactose supplementation does not have any effect on unrelated enzyme dysfunctions caused by manganese depletion and should thus be considered only in combination with manganese supplementation.
• Galactose doses of up to 3.75 g/kg body weight per day resulted in rapid normalization of glycosylation of the marker protein serum transferrin.
• Supplementation w/manganese to ↓ seizure frequency & severity (See
• Standardized treatment w/ASM by experienced neurologist
• 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.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / 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).
• For muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
## Targeted Therapies
Manganese sulfate is preferable to other manganese salts given its high solubility and widespread availability at pharmaceutical grade due to its use in nutritional applications.
Manganese sulfate doses of up to 20 mg/kg body weight per day have been used to treat SLC39A8-CDG.
Monitoring glycosylation using mass spectrometry-based methods is necessary to identify the appropriate manganese dose. Note: (1) Abnormal glycosylation persisted longer than other observed abnormal laboratory findings [
Regular measurement of blood manganese levels is advised with the aim of adjusting the manganese dose to achieve manganese levels similar to those observed in healthy controls.
Brain MRI every one to two years is recommend in order to detect potential manganese deposits. Note: Long-term, high-dose manganese can be neurotoxic in healthy individuals [
Titration to identify adequate manganese sulfate dose should precede introduction of galactose.
Note: Addition of galactose and subsequent normalization of glycosylation prevents the ability to identify the appropriate manganese dose based on the levels of dysglycosylation.
Galactose supplementation does not have any effect on unrelated enzyme dysfunctions caused by manganese depletion and should thus be considered only in combination with manganese supplementation.
Galactose doses of up to 3.75 g/kg body weight per day resulted in rapid normalization of glycosylation of the marker protein serum transferrin.
• Manganese sulfate is preferable to other manganese salts given its high solubility and widespread availability at pharmaceutical grade due to its use in nutritional applications.
• Manganese sulfate doses of up to 20 mg/kg body weight per day have been used to treat SLC39A8-CDG.
• Monitoring glycosylation using mass spectrometry-based methods is necessary to identify the appropriate manganese dose. Note: (1) Abnormal glycosylation persisted longer than other observed abnormal laboratory findings [
• Regular measurement of blood manganese levels is advised with the aim of adjusting the manganese dose to achieve manganese levels similar to those observed in healthy controls.
• Brain MRI every one to two years is recommend in order to detect potential manganese deposits. Note: Long-term, high-dose manganese can be neurotoxic in healthy individuals [
• Titration to identify adequate manganese sulfate dose should precede introduction of galactose.
• Note: Addition of galactose and subsequent normalization of glycosylation prevents the ability to identify the appropriate manganese dose based on the levels of dysglycosylation.
• Galactose supplementation does not have any effect on unrelated enzyme dysfunctions caused by manganese depletion and should thus be considered only in combination with manganese supplementation.
• Galactose doses of up to 3.75 g/kg body weight per day resulted in rapid normalization of glycosylation of the marker protein serum transferrin.
## Supportive Care
Supportive care to improve quality of life, maximize function, and reduce complications is also recommended. This ideally involves multidisciplinary care by specialists in relevant fields (see
Treatment of Manifestations in Individuals with SLC39A8-CDG
Supplementation w/manganese to ↓ seizure frequency & severity (See
Standardized treatment w/ASM by experienced neurologist
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.
Children: through early intervention programs &/or school district
Adults: low vision clinic &/or community vision services / 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
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 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
• Supplementation w/manganese to ↓ seizure frequency & severity (See
• Standardized treatment w/ASM by experienced neurologist
• 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.
• Children: through early intervention programs &/or school district
• Adults: low vision clinic &/or community vision services / 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).
• 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 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.
##
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
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Recommended Surveillance for Individuals with SLC39A8-CDG
Assess for abnormal glycosylation using mass spectrometry.
Measure blood manganese levels.
Measurement of growth parameters
Eval of nutritional status & safety of oral intake
Monitor for evidence of aspiration (e.g., respiratory insufficiency).
Assessment of visual acuity
Assessment for strabismus
Physical medicine, OT/PT assessment of mobility, self-help skills
Clinical exam for scoliosis
ALT = alanine transaminase; AST = aspartate transaminase; DXA = dual-energy x-ray absorptiometry; OT = occupational therapy; PT = physical therapy
• Assess for abnormal glycosylation using mass spectrometry.
• Measure blood manganese levels.
• Measurement of growth parameters
• Eval of nutritional status & safety of oral intake
• Monitor for evidence of aspiration (e.g., respiratory insufficiency).
• Assessment of visual acuity
• Assessment for strabismus
• Physical medicine, OT/PT assessment of mobility, self-help skills
• Clinical exam for scoliosis
## Agents/Circumstances to Avoid
## Evaluation of Relatives at Risk
All at-risk sibs of any age should have molecular testing for the familial
For at-risk newborn sibs, analysis of blood and urine manganese levels as well as protein N-glycosylation should be performed simultaneously with molecular genetic testing, as results from these tests are potentially available earlier than results of genetic testing. Altered glycosylation and severely reduced blood manganese levels are indicative of SLC39A8-CDG.
See
## Therapies Under Investigation
Search
## Genetic Counseling
SLC39A8-CDG 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
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 carriers or are at risk of being carriers.
Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. An
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
• 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/preimplantation genetic testing is 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 for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. An
## Mode of Inheritance
SLC39A8-CDG 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
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 carriers or are at risk of being carriers.
Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. 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 carriers or are at risk of being carriers.
• Carrier testing for reproductive partners of known carriers should be considered, particularly if both partners are of the same ethnic background. 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 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
SLC39A8-CDG: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SLC39A8-CDG (
Due to its relevance as a cofactor for a plethora of enzymes [
Notable
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
Due to its relevance as a cofactor for a plethora of enzymes [
Notable
Variants listed in the table have been provided by the authors.
## Chapter Notes
Julien H Park (
They are also interested in hearing from clinicians treating families affected by
See the
The authors acknowledge the commitment of the patients and families supporting the ongoing research in the field of SLC39A8-CDG.
6 April 2023 (sw) Review posted live
22 December 2022 (jp) Original submission
• 6 April 2023 (sw) Review posted live
• 22 December 2022 (jp) Original submission
## Author Notes
Julien H Park (
They are also interested in hearing from clinicians treating families affected by
See the
## Acknowledgments
The authors acknowledge the commitment of the patients and families supporting the ongoing research in the field of SLC39A8-CDG.
## Revision History
6 April 2023 (sw) Review posted live
22 December 2022 (jp) Original submission
• 6 April 2023 (sw) Review posted live
• 22 December 2022 (jp) Original submission
## Key Sections in this
## References
## Literature Cited
Molecular pathogenesis of SLC39A8-CDG. Dysfunction of the manganese transporter SLC39A8 causes intracellular manganese depletion. (A) A reduced Mn
Reproduced from
|
[] |
6/4/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
||
slc6a1-ndd
|
slc6a1-ndd
|
[
"SLC6A1-Related Disorder",
"SLC6A1 Deficiency Disorder",
"SLC6A1-Related Disorder",
"SLC6A1 Deficiency Disorder",
"Sodium- and chloride-dependent GABA transporter 1",
"SLC6A1",
"SLC6A1-Related Neurodevelopmental Disorder"
] |
Kimberly Goodspeed, Scott Demarest, Katrine Johannesen, Jingqiong Kang, Dennis Lal, Katie Angione
|
Summary The diagnosis of
|
## Diagnosis
Mild-to-severe developmental delay (DD) and/or intellectual disability (ID)
Generalized hypotonia of infancy
Epilepsy including absence or atypical absence seizures, epilepsy with myoclonic-atonic seizures, generalized tonic-clonic seizures
Movement disorders such as tremor, stereotypies, and ataxia
Autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, anxiety, and/or sleep disturbances
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 [
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.
• Mild-to-severe developmental delay (DD) and/or intellectual disability (ID)
• Generalized hypotonia of infancy
• Epilepsy including absence or atypical absence seizures, epilepsy with myoclonic-atonic seizures, generalized tonic-clonic seizures
• Movement disorders such as tremor, stereotypies, and ataxia
• Autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, anxiety, and/or sleep disturbances
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Suggestive Findings
Mild-to-severe developmental delay (DD) and/or intellectual disability (ID)
Generalized hypotonia of infancy
Epilepsy including absence or atypical absence seizures, epilepsy with myoclonic-atonic seizures, generalized tonic-clonic seizures
Movement disorders such as tremor, stereotypies, and ataxia
Autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, anxiety, and/or sleep disturbances
• Mild-to-severe developmental delay (DD) and/or intellectual disability (ID)
• Generalized hypotonia of infancy
• Epilepsy including absence or atypical absence seizures, epilepsy with myoclonic-atonic seizures, generalized tonic-clonic seizures
• Movement disorders such as tremor, stereotypies, and ataxia
• Autism spectrum disorder, attention-deficit/hyperactivity disorder, aggression, anxiety, and/or sleep disturbances
## 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 [
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.
• For an introduction to multigene panels click
• For an introduction to comprehensive genomic testing click
## Clinical Characteristics
Select Features of
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Hypotonia is typically mild to moderate. Individuals typically sit by age nine months (range: 5-13 months) and walk by age 19 months (range: 11-33 months).
Language development is often more delayed than motor development. Children with
Some children with
No genotype-phenotype correlations have been identified to date. However, ongoing studies suggest that the level of GAT-1 function (see
Penetrance appears to be incomplete [
## Clinical Description
Select Features of
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder
Hypotonia is typically mild to moderate. Individuals typically sit by age nine months (range: 5-13 months) and walk by age 19 months (range: 11-33 months).
Language development is often more delayed than motor development. Children with
Some children with
## Genotype-Phenotype Correlations
No genotype-phenotype correlations have been identified to date. However, ongoing studies suggest that the level of GAT-1 function (see
## Penetrance
Penetrance appears to be incomplete [
## Prevalence
## Genetically Related (Allelic) Disorders
No phenotypes other than those discussed in this
## Differential Diagnosis
The phenotypic features associated with
Selected Genes of Interest in the Differential Diagnosis of
AD = autosomal dominant; ASD = autism spectrum disorder; DD = developmental delay; DEE = developmental and epileptic encephalopathy; ID = intellectual disability; LGS = Lennox-Gastaut syndrome; MOI = mode of inheritance; NDD = neurodevelopmental disorder; SUDEP = sudden unexpected death in epilepsy; XL = X-linked
Angelman syndrome (AS) is associated with deficient expression or function of the maternally inherited
Individuals with AS typically represent simplex cases and have the disorder as the result of a
•
•
•
•
•
## 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 motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI if neurologic exam is abnormal, if there is developmental regression, or if there are seizures.
Consider EEG if seizures are a concern.
Consider referral to a movement disorder specialist for severe tremor &/or ataxia.
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 eval of nutritional status
Assess for chronic constipation or diarrhea.
To inform affected persons & their families re nature, MOI, & implications of
For an online portal to aid in variant eval, click
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
Hearing impairment has not been reported in individuals with
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
Treatment of Manifestations in Individuals with
Most persons w/
ASM managed by experienced neurologist should be considered.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Standard mgmt using behavioral strategies & neuropharmacologic interventions
Stimulants could be considered for mgmt of ADHD.
Risperidone or aripiprazole are FDA-approved medications for irritability & aggression assoc w/ASD.
Standard mgmt using behavioral strategies & neuropharmacologic interventions
Treatments for sleep may incl sleep hygiene, melatonin, clonidine, or trazodone.
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
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum 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 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.
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 or neurodevelopmental disabilities neurologist 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 in
Recommended Surveillance for Individuals with
Monitor developmental progress & educational needs.
Physical medicine & OT/PT assessment of mobility & self-help skills
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
Given the high prevalence of challenging behaviors in individuals with
See
There are therapies for
Search
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI if neurologic exam is abnormal, if there is developmental regression, or if there are seizures.
• Consider EEG if seizures are a concern.
• Consider referral to a movement disorder specialist for severe tremor &/or ataxia.
• 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 eval of nutritional status
• Assess for chronic constipation or diarrhea.
• To inform affected persons & their families re nature, MOI, & implications of
• For an online portal to aid in variant eval, click
• Community or
• Social work involvement for parental support;
• Home nursing referral.
• Most persons w/
• ASM managed by experienced neurologist should be considered.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Standard mgmt using behavioral strategies & neuropharmacologic interventions
• Stimulants could be considered for mgmt of ADHD.
• Risperidone or aripiprazole are FDA-approved medications for irritability & aggression assoc w/ASD.
• Standard mgmt using behavioral strategies & neuropharmacologic interventions
• Treatments for sleep may incl sleep hygiene, melatonin, clonidine, or trazodone.
• 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 muscle tone abnormalities including hypertonia or dystonia, consider involving appropriate specialists to aid in management of baclofen, tizanidine, Botox
• Monitor developmental progress & educational needs.
• Physical medicine & OT/PT assessment of mobility & self-help skills
• 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
Recommended Evaluations Following Initial Diagnosis in Individuals with
To incl motor, adaptive, cognitive, & speech-language eval
Eval for early intervention / special education
Consider brain MRI if neurologic exam is abnormal, if there is developmental regression, or if there are seizures.
Consider EEG if seizures are a concern.
Consider referral to a movement disorder specialist for severe tremor &/or ataxia.
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 eval of nutritional status
Assess for chronic constipation or diarrhea.
To inform affected persons & their families re nature, MOI, & implications of
For an online portal to aid in variant eval, click
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
Hearing impairment has not been reported in individuals with
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• To incl motor, adaptive, cognitive, & speech-language eval
• Eval for early intervention / special education
• Consider brain MRI if neurologic exam is abnormal, if there is developmental regression, or if there are seizures.
• Consider EEG if seizures are a concern.
• Consider referral to a movement disorder specialist for severe tremor &/or ataxia.
• 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 eval of nutritional status
• Assess for chronic constipation or diarrhea.
• To inform affected persons & their families re nature, MOI, & implications of
• For an online portal to aid in variant eval, click
• 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
Treatment of Manifestations in Individuals with
Most persons w/
ASM managed by experienced neurologist should be considered.
Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
Education of parents/caregivers
Standard mgmt using behavioral strategies & neuropharmacologic interventions
Stimulants could be considered for mgmt of ADHD.
Risperidone or aripiprazole are FDA-approved medications for irritability & aggression assoc w/ASD.
Standard mgmt using behavioral strategies & neuropharmacologic interventions
Treatments for sleep may incl sleep hygiene, melatonin, clonidine, or trazodone.
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
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum 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 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.
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 or neurodevelopmental disabilities neurologist 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.
• Most persons w/
• ASM managed by experienced neurologist should be considered.
• Many ASMs may be effective; none has been demonstrated effective specifically for this disorder.
• Education of parents/caregivers
• Standard mgmt using behavioral strategies & neuropharmacologic interventions
• Stimulants could be considered for mgmt of ADHD.
• Risperidone or aripiprazole are FDA-approved medications for irritability & aggression assoc w/ASD.
• Standard mgmt using behavioral strategies & neuropharmacologic interventions
• Treatments for sleep may incl sleep hygiene, melatonin, clonidine, or trazodone.
• 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 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.
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 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 or neurodevelopmental disabilities neurologist 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 in
Recommended Surveillance for Individuals with
Monitor developmental progress & educational needs.
Physical medicine & OT/PT assessment of mobility & self-help skills
Monitor those w/seizures as clinically indicated.
Assess for new manifestations such as seizures, changes in tone, & movement disorders.
ADHD = attention-deficit/hyperactivity disorder; ASD = autism spectrum disorder; OT = occupational therapy; PT = physical therapy
• Monitor developmental progress & educational needs.
• Physical medicine & OT/PT assessment of mobility & self-help skills
• Monitor those w/seizures as clinically indicated.
• Assess for new manifestations such as seizures, changes in tone, & movement disorders.
## Agents/Circumstances to Avoid
Given the high prevalence of challenging behaviors in individuals with
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
There are therapies for
Search
## Genetic Counseling
The majority of individuals reported to date with
Rarely, individuals diagnosed 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.
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with
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%.
Affected sibs often display similar phenotypes although clinical variability may be observed between heterozygous family members.
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.
• The majority of individuals reported to date with
• Rarely, individuals diagnosed 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.
• * 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.* 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 an
• 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.
• * A parent with somatic and germline mosaicism for an
• 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%.
• Affected sibs often display similar phenotypes although clinical variability may be observed between heterozygous family members.
• 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
The majority of individuals reported to date with
Rarely, individuals diagnosed 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.
* A parent with somatic and germline mosaicism for an
The family history of some individuals diagnosed with
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%.
Affected sibs often display similar phenotypes although clinical variability may be observed between heterozygous family members.
If the
• The majority of individuals reported to date with
• Rarely, individuals diagnosed 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.
• * 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.* 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 an
• 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.
• * A parent with somatic and germline mosaicism for an
• 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%.
• Affected sibs often display similar phenotypes although clinical variability may be observed between heterozygous family members.
• 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
Canada
Canada
Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
•
•
•
•
• Canada
•
•
• Canada
•
•
•
•
• Speaking out for People with Intellectual and Developmental Disabilities
•
•
•
## Molecular Genetics
SLC6A1-Related Neurodevelopmental Disorder: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SLC6A1-Related Neurodevelopmental Disorder (
## Molecular Pathogenesis
## Chapter Notes
Dr Goodspeed and Dr Johannesen are actively involved in clinical research regarding individuals with
Contact Dr Lal, Dr Goodspeed, Dr Johannesen, or Dr Kang to inquire about review of
The authors would like to acknowledge the support of the SLC6A1 Connect patient advocacy group, a champion for this disorder. They would also like to acknowledge all the patients and families who have generously given their time and stories to help us learn more about this rare neurodevelopmental disorder.
9 February 2023 (sw) Review posted live
15 October 2018 (kg) Original submission
• 9 February 2023 (sw) Review posted live
• 15 October 2018 (kg) Original submission
## Author Notes
Dr Goodspeed and Dr Johannesen are actively involved in clinical research regarding individuals with
Contact Dr Lal, Dr Goodspeed, Dr Johannesen, or Dr Kang to inquire about review of
## Acknowledgments
The authors would like to acknowledge the support of the SLC6A1 Connect patient advocacy group, a champion for this disorder. They would also like to acknowledge all the patients and families who have generously given their time and stories to help us learn more about this rare neurodevelopmental disorder.
## Revision History
9 February 2023 (sw) Review posted live
15 October 2018 (kg) Original submission
• 9 February 2023 (sw) Review posted live
• 15 October 2018 (kg) Original submission
## References
## Literature Cited
|
[
"JM Bain, LG Snyder, KL Helbig, DD Cooper, WK Chung, K Goodspeed. Consistency of parent-report SLC6A1 data in Simons Searchlight with provider-based publications.. J Neurodev Disord. 2022;14:40",
"GL Carvill, JM McMahon, A Schneider, M Zemel, CT Myers, J Saykally, J Nguyen, A Robbiano, F Zara, N Specchio, O Mecarelli, RL Smith, RJ Leventer, RS Møller, M Nikanorova, P Dimova, A Jordanova, S Petrou. EuroEPINOMICS Rare Epilepsy Syndrome Myoclonic-Astatic Epilepsy & Dravet working group, Helbig I, Striano P, Weckhuysen S, Berkovic SF, Scheffer IE, Mefford HC. Mutations in the GABA transporter SLC6A1 cause epilepsy with myoclonic-atonic seizures.. Am J Hum Genet. 2015;96:808-15",
"KM Johannesen, E Gardella, T Linnankivi, C Courage, A de Saint Martin, AE Lehesjoki, C Mignot, A Afenjar, G Lesca, MT Abi-Warde, J Chelly, A Piton, JL Merritt, LH Rodan, WH Tan, LM Bird, M Nespeca, JG Gleeson, Y Yoo, M Choi, JH Chae, D Czapansky-Beilman, SC Reichert, M Pendziwiat, JS Verhoeven, HJ Schelhaas, O Devinsky, J Christensen, N Specchio, M Trivisano, YG Weber, C Nava, B Keren, D Doummar, E Schaefer, S Hopkins, H Dubbs, JE Shaw, L Pisani, CT Myers, S Tang, S Tang, DK Pal, JJ Millichap, GL Carvill, KL Helbig, O Mecarelli, P Striano, I Helbig, G Rubboli, HC Mefford, RS Møller. Defining the phenotypic spectrum of SLC6A1 mutations.. Epilepsia. 2018;59:389-402",
"JA López-Rivera, E Pérez-Palma, J Symonds, AS Lindy, DA McKnight, C Leu, S Zuberi, A Brunklaus, RS Møller, D Lal. A catalogue of new incidence estimates of monogenic neurodevelopmental disorders caused by de novo variants.. Brain. 2020;143:1099-105",
"F Mermer, S Poliquin, S Zhou, X Wang, Y Ding, F Yin, W Shen, J Wang, K Rigsby, D Xu, T Mack, G Nwosu, C Flamm, M Stein, JQ Kang. Astrocytic GABA transporter 1 deficit in novel SLC6A1 variants mediated epilepsy: connected from protein destabilization to seizures in mice and humans.. Neurobiol Dis. 2022;172",
"S Poliquin, I Hughes, W Shen, F Mermer, J Wang, T Mack, D Xu, JQ Kang. Genetic mosaicism, intrafamilial phenotypic heterogeneity, and molecular defects of a novel missense SLC6A1 mutation associated with epilepsy and ADHD.. Exp Neurol. 2021;342",
"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",
"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"
] |
9/2/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
|||
slc6a3-dtds
|
slc6a3-dtds
|
[
"DAT Deficiency",
"DAT Deficiency",
"Classic Early-Onset Dopamine Transporter Deficiency Syndrome (DTDS)",
"Atypical Later-Onset Dopamine Transporter Deficiency Syndrome (DTDS)",
"Sodium-dependent dopamine transporter",
"SLC6A3",
"SLC6A3-Related Dopamine Transporter Deficiency Syndrome"
] |
Robert VV Spaull, Manju A Kurian
|
Summary The diagnosis of In most individuals reported to date, Once the
|
Classic early-onset dopamine transporter deficiency syndrome (DTDS)
Atypical later-onset DTDS
• Classic early-onset dopamine transporter deficiency syndrome (DTDS)
• Atypical later-onset DTDS
## Diagnosis
Classic early-onset and atypical later-onset
Onset usually within the first six months of life
Early nonspecific clinical findings of irritability and difficulty feeding
Axial hypotonia
Delay in motor milestones
Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
Severe delay in motor milestones
Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
Onset from childhood to adulthood (4th decade)
Attention-deficit/hyperactivity disorder (ADHD)
Resting and action tremor
Dysarthria
Parkinsonism-dystonia
Raised homovanillic acid level (HVA, metabolite derived from dopamine) with normal 5-hydroxyindoleacetic acid level (5-HIAA, metabolite derived from serotonin). The HVA:5-HIAA ratio in
Normal pterin profile
The diagnosis of
Biallelic loss-of-function pathogenic (or likely pathogenic) variants in
A heterozygous dominant-negative
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
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by ADHD, tremor, dysarthria, and/or parkinsonism-dystonia,
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. 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 have been described: a homozygous multiexon deletion [
•
• Onset usually within the first six months of life
• Early nonspecific clinical findings of irritability and difficulty feeding
• Axial hypotonia
• Delay in motor milestones
• Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Onset usually within the first six months of life
• Early nonspecific clinical findings of irritability and difficulty feeding
• Axial hypotonia
• Delay in motor milestones
• Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
•
• Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
• Severe delay in motor milestones
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
• Severe delay in motor milestones
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Onset usually within the first six months of life
• Early nonspecific clinical findings of irritability and difficulty feeding
• Axial hypotonia
• Delay in motor milestones
• Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
• Severe delay in motor milestones
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
•
• Onset from childhood to adulthood (4th decade)
• Attention-deficit/hyperactivity disorder (ADHD)
• Resting and action tremor
• Dysarthria
• Parkinsonism-dystonia
• Onset from childhood to adulthood (4th decade)
• Attention-deficit/hyperactivity disorder (ADHD)
• Resting and action tremor
• Dysarthria
• Parkinsonism-dystonia
• Onset from childhood to adulthood (4th decade)
• Attention-deficit/hyperactivity disorder (ADHD)
• Resting and action tremor
• Dysarthria
• Parkinsonism-dystonia
• Raised homovanillic acid level (HVA, metabolite derived from dopamine) with normal 5-hydroxyindoleacetic acid level (5-HIAA, metabolite derived from serotonin). The HVA:5-HIAA ratio in
• Normal pterin profile
• Biallelic loss-of-function pathogenic (or likely pathogenic) variants in
• A heterozygous dominant-negative
• For an introduction to multigene panels click
## Suggestive Findings
Classic early-onset and atypical later-onset
Onset usually within the first six months of life
Early nonspecific clinical findings of irritability and difficulty feeding
Axial hypotonia
Delay in motor milestones
Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
Severe delay in motor milestones
Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
Onset from childhood to adulthood (4th decade)
Attention-deficit/hyperactivity disorder (ADHD)
Resting and action tremor
Dysarthria
Parkinsonism-dystonia
Raised homovanillic acid level (HVA, metabolite derived from dopamine) with normal 5-hydroxyindoleacetic acid level (5-HIAA, metabolite derived from serotonin). The HVA:5-HIAA ratio in
Normal pterin profile
•
• Onset usually within the first six months of life
• Early nonspecific clinical findings of irritability and difficulty feeding
• Axial hypotonia
• Delay in motor milestones
• Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Onset usually within the first six months of life
• Early nonspecific clinical findings of irritability and difficulty feeding
• Axial hypotonia
• Delay in motor milestones
• Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
•
• Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
• Severe delay in motor milestones
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
• Severe delay in motor milestones
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Onset usually within the first six months of life
• Early nonspecific clinical findings of irritability and difficulty feeding
• Axial hypotonia
• Delay in motor milestones
• Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
• Severe delay in motor milestones
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
•
• Onset from childhood to adulthood (4th decade)
• Attention-deficit/hyperactivity disorder (ADHD)
• Resting and action tremor
• Dysarthria
• Parkinsonism-dystonia
• Onset from childhood to adulthood (4th decade)
• Attention-deficit/hyperactivity disorder (ADHD)
• Resting and action tremor
• Dysarthria
• Parkinsonism-dystonia
• Onset from childhood to adulthood (4th decade)
• Attention-deficit/hyperactivity disorder (ADHD)
• Resting and action tremor
• Dysarthria
• Parkinsonism-dystonia
• Raised homovanillic acid level (HVA, metabolite derived from dopamine) with normal 5-hydroxyindoleacetic acid level (5-HIAA, metabolite derived from serotonin). The HVA:5-HIAA ratio in
• Normal pterin profile
## Clinical Findings
Onset usually within the first six months of life
Early nonspecific clinical findings of irritability and difficulty feeding
Axial hypotonia
Delay in motor milestones
Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
Severe delay in motor milestones
Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
Onset from childhood to adulthood (4th decade)
Attention-deficit/hyperactivity disorder (ADHD)
Resting and action tremor
Dysarthria
Parkinsonism-dystonia
•
• Onset usually within the first six months of life
• Early nonspecific clinical findings of irritability and difficulty feeding
• Axial hypotonia
• Delay in motor milestones
• Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Onset usually within the first six months of life
• Early nonspecific clinical findings of irritability and difficulty feeding
• Axial hypotonia
• Delay in motor milestones
• Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
•
• Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
• Severe delay in motor milestones
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
• Severe delay in motor milestones
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Onset usually within the first six months of life
• Early nonspecific clinical findings of irritability and difficulty feeding
• Axial hypotonia
• Delay in motor milestones
• Hyperkinetic movement disorder (chorea, ballismus, dystonia, orolingual dyskinesia) typically evident in infancy and early childhood; may persist into late childhood and adolescence
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
• Parkinsonism-dystonia including dystonic postures, resting and action tremor, difficulty initiating movements, bradykinesia, paucity of facial expression, and rigidity
• Severe delay in motor milestones
• Eye movement disorders including recurrent oculogyric crises, saccade initiation failure, ocular flutter, and eyelid myoclonus
•
• Onset from childhood to adulthood (4th decade)
• Attention-deficit/hyperactivity disorder (ADHD)
• Resting and action tremor
• Dysarthria
• Parkinsonism-dystonia
• Onset from childhood to adulthood (4th decade)
• Attention-deficit/hyperactivity disorder (ADHD)
• Resting and action tremor
• Dysarthria
• Parkinsonism-dystonia
• Onset from childhood to adulthood (4th decade)
• Attention-deficit/hyperactivity disorder (ADHD)
• Resting and action tremor
• Dysarthria
• Parkinsonism-dystonia
## Laboratory Findings
Raised homovanillic acid level (HVA, metabolite derived from dopamine) with normal 5-hydroxyindoleacetic acid level (5-HIAA, metabolite derived from serotonin). The HVA:5-HIAA ratio in
Normal pterin profile
• Raised homovanillic acid level (HVA, metabolite derived from dopamine) with normal 5-hydroxyindoleacetic acid level (5-HIAA, metabolite derived from serotonin). The HVA:5-HIAA ratio in
• Normal pterin profile
## Establishing the Diagnosis
The diagnosis of
Biallelic loss-of-function pathogenic (or likely pathogenic) variants in
A heterozygous dominant-negative
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
For an introduction to multigene panels click
When the phenotype is indistinguishable from many other inherited disorders characterized by ADHD, tremor, dysarthria, and/or parkinsonism-dystonia,
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. 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 have been described: a homozygous multiexon deletion [
• Biallelic loss-of-function pathogenic (or likely pathogenic) variants in
• A heterozygous dominant-negative
• 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 phenotype is indistinguishable from many other inherited disorders characterized by ADHD, tremor, dysarthria, and/or parkinsonism-dystonia,
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. 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 have been described: a homozygous multiexon deletion [
## Clinical Characteristics
During the first years of life some children have episodic status dystonicus. Prolonged periods of crying and irritability – without discernable triggers – are also described. Disrupted sleep patterns are common. Exacerbations of dystonia are also common, often related to intercurrent illness, infection, and/or dehydration.
To date, five individuals with atypical later-onset DTDS have been described. Four had biallelic loss-of-function
It is not yet clear whether genotype-phenotype correlations exist for
While there are no current estimates on prevalence,
## Clinical Description
During the first years of life some children have episodic status dystonicus. Prolonged periods of crying and irritability – without discernable triggers – are also described. Disrupted sleep patterns are common. Exacerbations of dystonia are also common, often related to intercurrent illness, infection, and/or dehydration.
To date, five individuals with atypical later-onset DTDS have been described. Four had biallelic loss-of-function
## Classic Early-Onset
During the first years of life some children have episodic status dystonicus. Prolonged periods of crying and irritability – without discernable triggers – are also described. Disrupted sleep patterns are common. Exacerbations of dystonia are also common, often related to intercurrent illness, infection, and/or dehydration.
## Atypical Later-Onset
To date, five individuals with atypical later-onset DTDS have been described. Four had biallelic loss-of-function
## Genotype-Phenotype Correlations
It is not yet clear whether genotype-phenotype correlations exist for
## Prevalence
While there are no current estimates on prevalence,
## Genetically Related (Allelic) Disorders
Heterozygous
## Differential Diagnosis
Hereditary (see
Genes of Interest in the Differential Diagnosis of
AR
AD = autosomal dominant; AR = autosomal recessive; DRD = dopa-responsive dystonia; DTDS = dopamine transporter deficiency syndrome; DYT = dystonia; HSP = hereditary spastic paraplegia; HVA = homovanillic acid; MOI = mode of inheritance; PARK = Parkinson disease; SCA = spinocerebellar ataxia; XL = X-linked
Glucose transporter type 1 deficiency syndrome (Glut1 DS) is most commonly inherited in an autosomal dominant manner. Rarely, Glut1 DS is inherited in an autosomal recessive manner.
Most
## Management
No clinical practice guidelines for
To establish the extent of disease and needs in an individual diagnosed with a
Eval of caloric intake & feeding by nutritionist
Speech-language therapy assessment of swallowing, drooling, & communication
Orthopedic assessment for fixed contractures / joint dislocations
Hip & spine x-rays to evaluate for hip dislocation & spinal deformity
Assess frequency of respiratory infections.
Assess for evidence of sleep disturbance due to movement disorder.
Consider sleep study to assess nocturnal respiratory pattern.
Community or
Social work involvement;
Home nursing referral.
DTDS = dopamine transporter deficiency syndrome; GERD = gastroesophageal reflux disease; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
There is no cure for
Tetrabenazine & benzodiazepines may be useful in early stages of the disease.
Chloral hydrate may also help during exacerbations.
Dopamine agonists pramipexole & ropinirole are first-line agents.
Adjuncts, such as the anticholinergic trihexyphenidyl, are often needed.
Baclofen, gabapentin, & clonidine may be used for severe dystonia.
Benzodiazepines & chloral hydrate can be useful for exacerbations.
Although the role of atypical tranquilizers (e.g., zopiclone) is not yet established, they have been used successfully in some persons.
Surgical interventions (e.g., intrathecal baclofen, deep brain stimulation) have been used rarely late in the disease course when dystonia is severe; therapeutic benefit is limited.
Avoid & treat risk factors that exacerbate the movement disorder such as discomfort, poor body positioning, & pain (e.g., dental caries, hip dislocation, scoliosis, pressure sores).
PT/OT to provide suitable aids for mobility & home adaptations
Melatonin & other sedatives as needed for sleep issues
Standard protocols are used in an intensive care setting.
Anesthetic agents
GABA-ergic medication incl GABA-A receptor agonists (benzodiazepines), GABA-enhancing medications (gabapentin, phenobarbitone), & GABA-B receptor agonists (baclofen)
Anticholinergics
Alpha-adrenergic agents (e.g., clonidine both enterally & intravenously)
For severe life-threatening or medically intractable status dystonicus, consider intrathecal baclofen & pallidal deep brain stimulation.
Nutrition mgmt to ensure adequate caloric intake
Early referral for nasogastric feeding or percutaneous gastrostomy for oral feeding issues
Alternative & augmentative communication devices for effective communication
Medical mgmt of tone issues & regular PT to ↓ risk of contractures
Focal botulinum toxin for emerging limb contractures & to prevent hip dislocation
Mgmt of bone density to ↓ risk of fractures
Standard treatments for pulmonary infections
Influenza vaccine, prophylactic antibiotics, & chest PT for persons prone to chest infections esp during winter months
For treatment of vomiting, antiemetics such as anti-serotoninergic agents (e.g., ondansetron) potentially have fewer side effects than other agents.
Standard treatments for GERD & constipation
ADHD = attention-deficit/hyperactivity disorder; 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
Dietitian/nutritionist assessment to ensure adequate caloric intake
Swallowing assessment to evaluate risk for aspiration
Speech-language assessment of communication needs
PT eval of postural issues & tone
Eval for early evidence of hip dislocation &/or spinal deformity
PT/OT eval to assess mobility, ADL, & need for adaptive devices
Assess frequency of respiratory infections.
Assess for evidence of sleep disturbance due to movement disorder.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; DTDS = dopamine transporter deficiency syndrome; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
Although dopamine agonists are used as first-line treatment of dystonia in
Drugs with anti-dopaminergic side effects (e.g., some antihistamines, sedatives, and dimenhydrinate) may exacerbate movement disorders.
The antiemetics metoclopramide, prochlorperazine, and other medicines with anti-dopaminergic effects may exacerbate movement disorders and alternatives should be used (e.g., anti-serotonergic agents).
See
Search
• Eval of caloric intake & feeding by nutritionist
• Speech-language therapy assessment of swallowing, drooling, & communication
• Orthopedic assessment for fixed contractures / joint dislocations
• Hip & spine x-rays to evaluate for hip dislocation & spinal deformity
• Assess frequency of respiratory infections.
• Assess for evidence of sleep disturbance due to movement disorder.
• Consider sleep study to assess nocturnal respiratory pattern.
• Community or
• Social work involvement;
• Home nursing referral.
• Tetrabenazine & benzodiazepines may be useful in early stages of the disease.
• Chloral hydrate may also help during exacerbations.
• Dopamine agonists pramipexole & ropinirole are first-line agents.
• Adjuncts, such as the anticholinergic trihexyphenidyl, are often needed.
• Baclofen, gabapentin, & clonidine may be used for severe dystonia.
• Benzodiazepines & chloral hydrate can be useful for exacerbations.
• Although the role of atypical tranquilizers (e.g., zopiclone) is not yet established, they have been used successfully in some persons.
• Surgical interventions (e.g., intrathecal baclofen, deep brain stimulation) have been used rarely late in the disease course when dystonia is severe; therapeutic benefit is limited.
• Avoid & treat risk factors that exacerbate the movement disorder such as discomfort, poor body positioning, & pain (e.g., dental caries, hip dislocation, scoliosis, pressure sores).
• PT/OT to provide suitable aids for mobility & home adaptations
• Melatonin & other sedatives as needed for sleep issues
• Standard protocols are used in an intensive care setting.
• Anesthetic agents
• GABA-ergic medication incl GABA-A receptor agonists (benzodiazepines), GABA-enhancing medications (gabapentin, phenobarbitone), & GABA-B receptor agonists (baclofen)
• Anticholinergics
• Alpha-adrenergic agents (e.g., clonidine both enterally & intravenously)
• For severe life-threatening or medically intractable status dystonicus, consider intrathecal baclofen & pallidal deep brain stimulation.
• Nutrition mgmt to ensure adequate caloric intake
• Early referral for nasogastric feeding or percutaneous gastrostomy for oral feeding issues
• Alternative & augmentative communication devices for effective communication
• Medical mgmt of tone issues & regular PT to ↓ risk of contractures
• Focal botulinum toxin for emerging limb contractures & to prevent hip dislocation
• Mgmt of bone density to ↓ risk of fractures
• Standard treatments for pulmonary infections
• Influenza vaccine, prophylactic antibiotics, & chest PT for persons prone to chest infections esp during winter months
• For treatment of vomiting, antiemetics such as anti-serotoninergic agents (e.g., ondansetron) potentially have fewer side effects than other agents.
• Standard treatments for GERD & constipation
• Dietitian/nutritionist assessment to ensure adequate caloric intake
• Swallowing assessment to evaluate risk for aspiration
• Speech-language assessment of communication needs
• PT eval of postural issues & tone
• Eval for early evidence of hip dislocation &/or spinal deformity
• PT/OT eval to assess mobility, ADL, & need for adaptive devices
• Assess frequency of respiratory infections.
• Assess for evidence of sleep disturbance due to movement disorder.
## Evaluations Following Initial Diagnosis
To establish the extent of disease and needs in an individual diagnosed with a
Eval of caloric intake & feeding by nutritionist
Speech-language therapy assessment of swallowing, drooling, & communication
Orthopedic assessment for fixed contractures / joint dislocations
Hip & spine x-rays to evaluate for hip dislocation & spinal deformity
Assess frequency of respiratory infections.
Assess for evidence of sleep disturbance due to movement disorder.
Consider sleep study to assess nocturnal respiratory pattern.
Community or
Social work involvement;
Home nursing referral.
DTDS = dopamine transporter deficiency syndrome; GERD = gastroesophageal reflux disease; MOI = mode of inheritance
Medical geneticist, certified genetic counselor, certified advanced genetic nurse
• Eval of caloric intake & feeding by nutritionist
• Speech-language therapy assessment of swallowing, drooling, & communication
• Orthopedic assessment for fixed contractures / joint dislocations
• Hip & spine x-rays to evaluate for hip dislocation & spinal deformity
• Assess frequency of respiratory infections.
• Assess for evidence of sleep disturbance due to movement disorder.
• Consider sleep study to assess nocturnal respiratory pattern.
• Community or
• Social work involvement;
• Home nursing referral.
## Treatment of Manifestations
There is no cure for
Tetrabenazine & benzodiazepines may be useful in early stages of the disease.
Chloral hydrate may also help during exacerbations.
Dopamine agonists pramipexole & ropinirole are first-line agents.
Adjuncts, such as the anticholinergic trihexyphenidyl, are often needed.
Baclofen, gabapentin, & clonidine may be used for severe dystonia.
Benzodiazepines & chloral hydrate can be useful for exacerbations.
Although the role of atypical tranquilizers (e.g., zopiclone) is not yet established, they have been used successfully in some persons.
Surgical interventions (e.g., intrathecal baclofen, deep brain stimulation) have been used rarely late in the disease course when dystonia is severe; therapeutic benefit is limited.
Avoid & treat risk factors that exacerbate the movement disorder such as discomfort, poor body positioning, & pain (e.g., dental caries, hip dislocation, scoliosis, pressure sores).
PT/OT to provide suitable aids for mobility & home adaptations
Melatonin & other sedatives as needed for sleep issues
Standard protocols are used in an intensive care setting.
Anesthetic agents
GABA-ergic medication incl GABA-A receptor agonists (benzodiazepines), GABA-enhancing medications (gabapentin, phenobarbitone), & GABA-B receptor agonists (baclofen)
Anticholinergics
Alpha-adrenergic agents (e.g., clonidine both enterally & intravenously)
For severe life-threatening or medically intractable status dystonicus, consider intrathecal baclofen & pallidal deep brain stimulation.
Nutrition mgmt to ensure adequate caloric intake
Early referral for nasogastric feeding or percutaneous gastrostomy for oral feeding issues
Alternative & augmentative communication devices for effective communication
Medical mgmt of tone issues & regular PT to ↓ risk of contractures
Focal botulinum toxin for emerging limb contractures & to prevent hip dislocation
Mgmt of bone density to ↓ risk of fractures
Standard treatments for pulmonary infections
Influenza vaccine, prophylactic antibiotics, & chest PT for persons prone to chest infections esp during winter months
For treatment of vomiting, antiemetics such as anti-serotoninergic agents (e.g., ondansetron) potentially have fewer side effects than other agents.
Standard treatments for GERD & constipation
ADHD = attention-deficit/hyperactivity disorder; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
• Tetrabenazine & benzodiazepines may be useful in early stages of the disease.
• Chloral hydrate may also help during exacerbations.
• Dopamine agonists pramipexole & ropinirole are first-line agents.
• Adjuncts, such as the anticholinergic trihexyphenidyl, are often needed.
• Baclofen, gabapentin, & clonidine may be used for severe dystonia.
• Benzodiazepines & chloral hydrate can be useful for exacerbations.
• Although the role of atypical tranquilizers (e.g., zopiclone) is not yet established, they have been used successfully in some persons.
• Surgical interventions (e.g., intrathecal baclofen, deep brain stimulation) have been used rarely late in the disease course when dystonia is severe; therapeutic benefit is limited.
• Avoid & treat risk factors that exacerbate the movement disorder such as discomfort, poor body positioning, & pain (e.g., dental caries, hip dislocation, scoliosis, pressure sores).
• PT/OT to provide suitable aids for mobility & home adaptations
• Melatonin & other sedatives as needed for sleep issues
• Standard protocols are used in an intensive care setting.
• Anesthetic agents
• GABA-ergic medication incl GABA-A receptor agonists (benzodiazepines), GABA-enhancing medications (gabapentin, phenobarbitone), & GABA-B receptor agonists (baclofen)
• Anticholinergics
• Alpha-adrenergic agents (e.g., clonidine both enterally & intravenously)
• For severe life-threatening or medically intractable status dystonicus, consider intrathecal baclofen & pallidal deep brain stimulation.
• Nutrition mgmt to ensure adequate caloric intake
• Early referral for nasogastric feeding or percutaneous gastrostomy for oral feeding issues
• Alternative & augmentative communication devices for effective communication
• Medical mgmt of tone issues & regular PT to ↓ risk of contractures
• Focal botulinum toxin for emerging limb contractures & to prevent hip dislocation
• Mgmt of bone density to ↓ risk of fractures
• Standard treatments for pulmonary infections
• Influenza vaccine, prophylactic antibiotics, & chest PT for persons prone to chest infections esp during winter months
• For treatment of vomiting, antiemetics such as anti-serotoninergic agents (e.g., ondansetron) potentially have fewer side effects than other agents.
• Standard treatments for GERD & constipation
## Surveillance
To monitor existing manifestations, the individual's response to supportive care, and the emergence of new manifestations, the evaluations summarized in
Dietitian/nutritionist assessment to ensure adequate caloric intake
Swallowing assessment to evaluate risk for aspiration
Speech-language assessment of communication needs
PT eval of postural issues & tone
Eval for early evidence of hip dislocation &/or spinal deformity
PT/OT eval to assess mobility, ADL, & need for adaptive devices
Assess frequency of respiratory infections.
Assess for evidence of sleep disturbance due to movement disorder.
ADHD = attention-deficit/hyperactivity disorder; ADL = activities of daily living; DTDS = dopamine transporter deficiency syndrome; GERD = gastroesophageal reflux disease; OT = occupational therapy; PT = physical therapy
• Dietitian/nutritionist assessment to ensure adequate caloric intake
• Swallowing assessment to evaluate risk for aspiration
• Speech-language assessment of communication needs
• PT eval of postural issues & tone
• Eval for early evidence of hip dislocation &/or spinal deformity
• PT/OT eval to assess mobility, ADL, & need for adaptive devices
• Assess frequency of respiratory infections.
• Assess for evidence of sleep disturbance due to movement disorder.
## Agents/Circumstances to Avoid
Although dopamine agonists are used as first-line treatment of dystonia in
Drugs with anti-dopaminergic side effects (e.g., some antihistamines, sedatives, and dimenhydrinate) may exacerbate movement disorders.
The antiemetics metoclopramide, prochlorperazine, and other medicines with anti-dopaminergic effects may exacerbate movement disorders and alternatives should be used (e.g., anti-serotonergic agents).
## Evaluation of Relatives at Risk
See
## Therapies Under Investigation
Search
## Genetic Counseling
In most individuals reported to date,
The parents of a child with autosomal recessive
Molecular genetic testing is recommended 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.
Individuals who are heterozygous for an
If both parents are known to be heterozygous for an
Individuals who are heterozygous for an
To date, there are no reports of individuals with
Unless an affected individual's reproductive partner also has
In the one individual reported to date autosomal dominant
If a proband with autosomal dominant
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
The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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 parents of a child with autosomal recessive
• Molecular genetic testing is recommended 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.
• Individuals who are heterozygous for an
• 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
• Individuals who are heterozygous for an
• To date, there are no reports of individuals with
• Unless an affected individual's reproductive partner also has
• In the one individual reported to date autosomal dominant
• If a proband with autosomal dominant
• 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
• The optimal time for determination of genetic risk and discussion of the availability of prenatal/preimplantation genetic testing is before 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
In most individuals reported to date,
## Autosomal Recessive Inheritance – Risk to Family Members
The parents of a child with autosomal recessive
Molecular genetic testing is recommended 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.
Individuals who are heterozygous for an
If both parents are known to be heterozygous for an
Individuals who are heterozygous for an
To date, there are no reports of individuals with
Unless an affected individual's reproductive partner also has
• The parents of a child with autosomal recessive
• Molecular genetic testing is recommended 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.
• Individuals who are heterozygous for an
• 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
• Individuals who are heterozygous for an
• To date, there are no reports of individuals with
• Unless an affected individual's reproductive partner also has
## Autosomal Dominant Inheritance – Risk to Family Members
In the one individual reported to date autosomal dominant
If a proband with autosomal dominant
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
• In the one individual reported to date autosomal dominant
• If a proband with autosomal dominant
• 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
## 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 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
SLC6A3-Related Dopamine Transported Deficiency Syndrome: Genes and Databases
Data are compiled from the following standard references: gene from
OMIM Entries for SLC6A3-Related Dopamine Transported Deficiency Syndrome (
To date, functional investigations indicate that
A number of nonsense variants, splice site changes, and deletions have been reported in
A DAT knockout mouse model shows several features described in humans, including reduced growth, early hyperkinesia, and difficulties with feeding. Over time, the mice develop abnormal clasping and kyphosis with progressive bradykinesia, reminiscent of the parkinsonism-dystonia phenotype in humans [
SLC6A3 Pathogenic Variants Referenced in This
AD = autosomal dominant; DTDS = dopamine transporter deficiency syndrome
Variants listed in the table have been provided by the authors.
## Molecular Pathogenesis
To date, functional investigations indicate that
A number of nonsense variants, splice site changes, and deletions have been reported in
A DAT knockout mouse model shows several features described in humans, including reduced growth, early hyperkinesia, and difficulties with feeding. Over time, the mice develop abnormal clasping and kyphosis with progressive bradykinesia, reminiscent of the parkinsonism-dystonia phenotype in humans [
SLC6A3 Pathogenic Variants Referenced in This
AD = autosomal dominant; DTDS = dopamine transporter deficiency syndrome
Variants listed in the table have been provided by the authors.
## Chapter Notes
Prof Kurian (
Contact Prof Kurian to inquire about review of
The authors would like to thank and acknowledge the families and patients with
28 September 2023 (sw) Comprehensive update posted live
27 July 2017 (bp) Review posted live
30 June 2015 (mak) Original submission
• 28 September 2023 (sw) Comprehensive update posted live
• 27 July 2017 (bp) Review posted live
• 30 June 2015 (mak) Original submission
## Author Notes
Prof Kurian (
Contact Prof Kurian to inquire about review of
## Acknowledgments
The authors would like to thank and acknowledge the families and patients with
## Revision History
28 September 2023 (sw) Comprehensive update posted live
27 July 2017 (bp) Review posted live
30 June 2015 (mak) Original submission
• 28 September 2023 (sw) Comprehensive update posted live
• 27 July 2017 (bp) Review posted live
• 30 June 2015 (mak) Original submission
## References
## Literature Cited
|
[] |
27/7/2017
|
28/9/2023
|
GeneReviews®
|
https://www.ncbi.nlm.nih.gov/books/NBK1116/
|
[
"Review",
"Clinical Review"
] |
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